bluuebunny/crossref_metadata_2025_split huggingface dataset:
The therapeutic effects of intratumoral injection of IL12IL2GMCSF fusion protein on canine tumors
Authors: Du Xiaobo , Zhang Bin , Hu Fan , Xie Chuantao , Tian Haiyan , Gu Qiang , Gong Haohan , Bai Xiaoguang , Zhang Jinyu 
Published: June 2020

AbstractRegulating the immune system through tumor immunotherapy to defeat tumors is currently one of the most popular methods of tumor treatment. We previously found that the combinations of IL12, IL2 and GMCSF has superior antitumor activities. In this study, IL12IL2GMCSF fusion protein was produced from 293 cells transduced by expression lentiviral vector. IL12IL2GMCSF fusion protein was injected into canine tumors, and the efficacy was monitored to evaluate the potential of tumor immunotherapy. In 14 canines injected with IL12IL2GMCSF protein, 6 had a complete response (CR), 7 had a partial response (PR), and 1 had stable disease (SD). IL12IL2GMCSF fusion protein has great anti-tumor potential. Intratumoral injection of IL12IL2GMCSF can effectively treat tumors without severe adverse effects. It provides a promising immune therapeutics in canine cancers.
The Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation
Authors: Li Feng , Lo Tsz Y. , Miles Leann , Wang Qin , Li Dan , Niu Jingwen , Goldshteyn Jessica I , Wang Chuxi , Wang Shuchao , Qiu Jingyun , Trombley Shannon , Pogoda Katarzyna , Brewster Megan , Rompolas Panteleimon , He Ye , Janmey Paul A. , Thomas Gareth M. , Song Yuanquan 
Published: June 2020

ABSTRACTAtr is a serine/threonine kinase, known to sense single-stranded DNA breaks and activate the DNA damage checkpoint by phosphorylating Chek1, which inhibits Cdc25, causing cell cycle arrest. This pathway has not been implicated in neuroregeneration. We show that inDrosophilasensory neurons, removing Atr or Chek1, or overexpressing Cdc25 promotes regeneration, whereas Atr or Chek1 overexpression, or Cdc25 knockdown impedes regeneration. Inhibiting the Atr-associated checkpoint complex in neurons promotes regeneration and improves synapse/behavioral recovery after CNS injury. Independent of DNA damage, Atr responds to the mechanical stimulus elicited during regeneration, via the mechanosensitive ion channel Piezo and its downstream NO signaling. Sensory neuron-specific knockout of Atr in adult mice, or pharmacological inhibition of Atr-Chek1 in mammalian neuronsin vitroand in fliesin vivoenhance regeneration. Our findings reveal the Piezo-Atr-Chek1-Cdc25 axis as an evolutionarily conserved inhibitory mechanism for regeneration, and identify potential therapeutic targets for treating nervous system trauma.
pH dependent inhibition from ammonium ions in the Pseudomonas mevalonii HMG-CoA Reductase crystallization environment
Authors: Purohit Vatsal , Steussy C. Nicklaus , Rosales Anthony R. , Critchelow Chandra J. , Schmidt Tim , Helquist Paul , Wiest Olaf , Mesecar Andrew , Stauffacher Cynthia V. 
Published: June 2020

ABSTRACTHMG-CoA reductase (Pseudomonas mevalonii) utilizes mevalonate, coenzyme A (CoA) and the cofactor NAD in a complex mechanism involving two hydride transfers with cofactor exchange, accompanied by large conformational changes by a 50 residue subdomain, to generate HMG-CoA. Details about this mechanism such as the conformational changes that allow intermediate formation, cofactor exchange and product release remain unknown. The formation of the proposed intermediates has also not been observed in structural studies with natural substrates. Having been shown to be an essential enzyme for the survival of gram-positive antibiotic resistant pathogenic bacteria, studying its mechanism in detail will be beneficial in developing novel antibacterials. The enzyme has been shown to be catalytically active inside the crystal with dithio-HMG-CoA and NADH but curiously is found to be inactive in the reverse direction in the structure bound to mevalonate, CoA and NAD.To understand the factors limiting activity in the HMGR crystal with mevalonate, CoA and NAD, we studied the effect of crystallization components and pH on enzymatic activity. We observed a strong inhibition in the crystallization buffer and an increase in activity with increasing pH. We attribute this inhibitive effect to the presence of ammonium ions present in the crystal since inhibition is also observed with several other ammonium salt buffers. Additionally, the lack of inhibition was observed in the absence of ammonium. The effect of each ligand (mevalonate, CoA and NAD) on the rate of the enzymatic reaction in the crystallization environment was further investigated by measuring their Kmin the crystallization buffer. The Kmmeasurements indicate that the hydride transfer step between NAD and mevalonate is inhibited in the crystallization environment. To test this further, we solved a crystal structure of pmHMGR bound to the post-hydride transfer intermediate (mevaldehyde) and cofactor Coenzyme A. The resulting turnover with the formation of a thiohemiacetal indicated that the crystallization environment inhibited the oxidative acylation of mevalonate and the reaction intermediate mevaldyl-CoA.
Human iPSC-derived alveolar and airway epithelial cells can be cultured at air-liquid interface and express SARS-CoV-2 host factors
Authors: Abo Kristine M. , Ma Liang , Matte Taylor , Huang Jessie , Alysandratos Konstantinos D. , Werder Rhiannon B. , Mithal Aditya , Beermann Mary Lou , Lindstrom-Vautrin Jonathan , Mostoslavsky Gustavo , Ikonomou Laertis , Kotton Darrell N. , Hawkins Finn , Wilson Andrew , Villacorta-Martin Carlos 
Published: June 2020

AbstractDevelopment of an anti-SARS-CoV-2 therapeutic is hindered by the lack of physiologically relevant model systems that can recapitulate host-viral interactions in human cell types, specifically the epithelium of the lung. Here, we compare induced pluripotent stem cell (iPSC)-derived alveolar and airway epithelial cells to primary lung epithelial cell controls, focusing on expression levels of genes relevant for COVID-19 disease modeling. iPSC-derived alveolar epithelial type II-like cells (iAT2s) and iPSC-derived airway epithelial lineages express key transcripts associated with lung identity in the majority of cells produced in culture. They expressACE2andTMPRSS2, transcripts encoding essential host factors required for SARS-CoV-2 infection, in a minor subset of each cell sub-lineage, similar to frequencies observed in primary cells. In order to prepare human culture systems that are amenable to modeling viral infection of both the proximal and distal lung epithelium, we adapt iPSC-derived alveolar and airway epithelial cells to two-dimensional air-liquid interface cultures. These engineered human lung cell systems represent sharable, physiologically relevant platforms for SARS-CoV-2 infection modeling and may therefore expedite the development of an effective pharmacologic intervention for COVID-19.
Hypothetical Human Immune Genome Complex Gradient May Help to Explain the Congenital Zika Symdrome Catastrophe in Brazil: A New Theory
Authors: Oliveira F.R.S , Bresani-Salvi C.C. , Morais C. N.L. , Bigham A.W. , Braga-Neto U. , Maestre G.E. , Wandebergh j. l. , Marques E.T.A , Acioli-Santos B. 
Published: June 2020

ABSTRACTThere are few data considering human genetics as an important risk factor for birth abnormalities related to ZIKV infection during pregnancy, even though sub-Saharan African populations are apparently more resistant to CZS as compared to populations in the Americas. We hypothesized that single nucleotide variants (SNVs), especially in innate immune genes, could make some populations more susceptible to Zika congenital complications than others. Differences in the SNV frequencies among continental populations provide great potential for Machine Learning techniques. We explored a key immune genomic gradient between individuals from Africa, Asia and Latin America, working with complex signatures, using 297 SNVs. We employed a two-step approach. In the first step, decision trees (DTs) were used to extract the most discriminating SNVs among populations. In the second step, machine learning algorithms were used to evaluate the quality of the SNV pool identified in step one for discriminating between individuals from sub-Saharan African and Latin-American populations. Our results suggest that 10 SNVs from 10 genes (CLEC4M, CD58, OAS2, CD80, VEPH1, CTLA4, CD274, CD209, PLAAT4, CREB3L1) were able to discriminate sub-Saharan Africans from Latin American populations using only immune genome data, with an accuracy close to 100%. Moreover, we found that these SNVs form a genome gradient across the three main continental populations. These SNVs are important elements of the innate immune system and in the response against viruses. Our data support theHuman Immune Genome Complex Gradienthypothesis as a new theory that may help to explain the CZS catastrophe in Brazil.
Elovl2 but not Elovl5 is essential for the biosynthesis of docosahexaenoic acid (DHA) in zebrafish: insight from a comparative gene knockout study
Authors: Liu Chengjie , Ye Ding , Wang Houpeng , He Mudan , Sun Yonghua 
Published: June 2020

AbstractTeleost fish can synthesize one of the major omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs), docosahexaenoic acid (DHA, 22:6n-3), from dietary α-linolenic acid (ALA; 18:3n-3), via elongase of very long chain fatty acid (Elovl) and fatty acid desaturase (Fads). However, it remains unclear which elongase is responsible for the endogenous synthesis of DHA. Here in this study, the knockout models of the two major elongases, Elovl2 and Elovl5, were generated by CRISPR/Cas9 approach in zebrafish and comparatively analyzed. The homozygous mutants were validated by Sanger sequencing, mutation-mediated PCR and whole-mount in situ hybridization analysis of the endogenous target genes. Compared with wildtype (WT) counterparts, the content of DHA was significantly reduced by 67.1% (p<0.05) in the adult liver and by 91.7% (p<0.01) in the embryo at 3 day-post-fertilization (dpf) of the elovl2 mutant, but not of the elovl5 mutant. Further study revealed that elovl2 and fads2 was upregulated by 9.9-fold (p<0.01) and 9.7-fold (p<0.01) in the elovl5 mutant, and elovl5 and fads2 was upregulated by 15.1-fold (p<0.01) and 21.5-fold (p<0.01) in the elovl2 mutant. Our study indicates that although both Elovl2 and Elovl5 have the elongase activity toward C20, the upregulation of elovl2 could completely replace the genetic depletion of elovl5, but upregulation of elovl5 could not compensate the endogenous deficiency of elovl2 in mediating DHA synthesis. In conclusion, the endogenous synthesis of DHA in is mediated by Elovl2 but not Elovl5 in teleost, and a DHA-deficient genetic model of zebrafish has been generated.
Interplay of mesoscale physics and agent-like behaviors in the parallel evolution of aggregative multicellularity
Authors: Arias Del Angel Juan A. , Nanjundiah Vidyanand , Benítez Mariana , Newman Stuart A. 
Published: June 2020

ABSTRACTMyxobacteria and dictyostelids are prokaryotic and eukaryotic multicellular lineages, respectively, that after nutrient depletion aggregate and develop into structures called fruiting bodies. The developmental processes and the resulting morphological outcomes resemble one another to a remarkable extent despite their independent origins, the evolutionary distance between them and the lack of traceable levels of homology in the molecular mechanisms of the groups. We hypothesize that the morphological parallelism between the two lineages arises as the consequence of the interplay, within multicellular aggregates, betweengeneric processes, physical and physicochemical processes operating similarly in living and non-living matter at the mesoscale (~10-3-10-1m) andagent-like behaviors, unique to living systems, characteristic of the constituent cells. To this effect, we analyze the relative contribution of the generic and agent-like determinants in the main phenomena of myxobacteria and dictyostelid development, and their roles in the emergence of their shared traits. We show that as a consequence of aggregation collective cell-cell contacts mediate the emergence of liquid-like properties, making nascent multicellular masses subject to new sets of patterning and morphogenetic processes. In both lineages, this leads to behaviors such as streaming, rippling, and rounding up, similar to effects observed in non-living fluids. Later the aggregates solidify, leading them to exhibit additional generic properties and motifs. We consider evidence that the morphological phenotypes of the multicellular masses deviate from the predictions of generic physics due to the contribution of agent-like behaviors. These include directed migration, quiescence, and oscillatory signal transduction of the cells mediated by responses to external cues acting through species-specific regulatory and signaling mechanisms reflecting the evolutionary histories of the respective organisms. We suggest that the similar developmental trajectories of Myxobacteria and Dictyostelia are more plausibly due to shared generic physical processes in coordination with analogous agent-type behaviors than to convergent evolution under parallel selection regimes. Finally, we discuss the broader implications of the existence and synergy of these two categories of developmental factors for evolutionary theory.
Assessment of neuropsychological function in brain tumour treatment: A comparison of traditional neuropsychological assessment with app-based cognitive screening
Authors: Romero-Garcia Rafael , Owen Mallory , McDonald Alexa , Woodberry Emma , Assem Moataz , Coelho Pedro , Morris Rob C , Price Stephen J , Santarius Tom , Suckling John , Manly Tom , Erez Yaara , Hart Michael G 
Published: June 2020

ABSTRACTBackgroundGliomas are typically considered to cause relatively few neurological impairments. However, cognitive difficulties can arise, for example during treatment, with potential detrimental effects on quality of life. Accurate, reproducible, and accessible cognitive assessment is therefore vital in understanding the effects of both tumour and treatments. Our aim is to compare traditional neuropsychological assessment with an app-based cognitive screening tool in patients with glioma before and after surgical resection. Our hypotheses were that cognitive impairments would be apparent, even in a young and high functioning cohort, and that app-based cognitive screening would complement traditional neuropsychological assessment.MethodsSeventeen patients with diffuse gliomas completed a traditional neuropsychological assessment and an app-based touchscreen tablet assessment (OCS-BRIDGE) pre- and post-operatively. The app assessment was also conducted at 3- and 12-month follow-up. Impairment rates, mean performance, and pre- and post-operative changes were compared using standardized Z-scores.ResultsApproximately 2-3 hours of traditional assessment indicated an average of 2.88 cognitive impairments per patient, whilst the 30-minute screen indicated 1.18. As might be expected, traditional assessment using multiple items across the difficulty range proved more sensitive than brief screening measures in areas such as memory and attention. However, the capacity of the screening app to capture reaction times enhanced its sensitivity, relative to traditional assessment, in the area of non-verbal function. Where there was overlap between the two assessments, for example digit span tasks, the results were broadly equivalent.ConclusionsCognitive impairments were common in this sample and app-based screening complemented traditional neuropsychological assessment. Implications for clinical assessment and follow-up are discussed.
Suppressive myeloid cells are a hallmark of severe COVID-19
Authors: Schulte-Schrepping Jonas , Reusch Nico , Paclik Daniela , Baßler Kevin , Schlickeiser Stephan , Zhang Bowen , Krämer Benjamin , Krammer Tobias , Brumhard Sophia , Bonaguro Lorenzo , De Domenico Elena , Wendisch Daniel , Grasshoff Martin , Kapellos Theodore S. , Beckstette Michael , Pecht Tal , Saglam Adem , Dietrich Oliver , Mei Henrik E. , Schulz Axel R. , Conrad Claudia , Kunkel Désirée , Vafadarnejad Ehsan , Xu Cheng-Jian , Horne Arik , Herbert Miriam , Drews Anna , Thibeault Charlotte , Pfeiffer Moritz , Hippenstiel Stefan , Hocke Andreas , Müller-Redetzky Holger , Heim Katrin-Moira , Machleidt Felix , Uhrig Alexander , de Jarcy Laure Bousquillon , Jürgens Linda , Stegemann Miriam , Glösenkamp Christoph R. , Volk Hans-Dieter , Goffinet Christine , Raabe Jan , Kaiser Kim Melanie , Vinh Michael To , Rieke Gereon , Meisel Christian , Ulas Thomas , Becker Matthias , Geffers Robert , Witzenrath Martin , Drosten Christian , Suttorp Norbert , von Kalle Christof , Kurth Florian , Händler Kristian , Schultze Joachim L. , Aschenbrenner Anna C , Li Yang , Nattermann Jacob , Sawitzki Birgit , Saliba Antoine-Emmanuel , Sander Leif Erik ,   Deutsche COVID-19 OMICS Initiative (DeCOI)
Published: June 2020

Abstract‘Severe Acute Respiratory Syndrome - Coronavirus-2’ (SARS-CoV-2) infection causes Coronavirus Disease 2019 (COVID-19), a mild to moderate respiratory tract infection in the majority of patients. A subset of patients, however, progresses to severe disease and respiratory failure with acute respiratory distress syndrome (ARDS). Severe COVID-19 has been associated with increased neutrophil counts and dysregulated immune responses. The mechanisms of protective immunity in mild forms and the pathogenesis of dysregulated inflammation in severe courses of COVID-19 remain largely unclear. Here, we combined two single-cell RNA-sequencing technologies and single-cell proteomics in whole blood and peripheral blood mononuclear cells (PBMC) to determine changes in immune cell composition and activation in two independent dual-center patient cohorts (n=46+n=54 COVID-19 samples), each with mild and severe cases of COVID-19. We observed a specific increase of HLA-DRhiCD11chiinflammatory monocytes that displayed a strong interferon (IFN)-stimulated gene signature in patients with mild COVID-19, which was absent in severe disease. Instead, we found evidence of emergency myelopoiesis, marked by the occurrence of immunosuppressive pre-neutrophils and immature neutrophils and populations of dysfunctional and suppressive mature neutrophils, as well as suppressive HLA-DRtomonocytes in severe COVID-19. Our study provides detailed insights into systemic immune response to SARS-CoV-2 infection and it reveals profound alterations in the peripheral myeloid cell compartment associated with severe courses of COVID-19.
Discrete SIR modelling using empirical infection data shows that SARS-CoV-2 infection provides short-term immunity
Authors: McMahon Andrew , Robb Nicole C. 
Published: June 2020

AbstractBackgroundThe novel coronavirus SARS-CoV-2, which causes the COVID-19 disease, has resulted in a global pandemic. Since its emergence in December 2019, the virus has infected millions of people, caused the deaths of hundreds of thousands and resulted in incalculable social and economic damage. Understanding the infectivity and transmission dynamics of the virus is essential for understanding how best to reduce mortality whilst ensuring minimal social restrictions to the lives of the general population. Anecdotal evidence is available, but detailed studies have not yet revealed whether infection with the virus results in immunity.ObjectiveThe objective of the study was to use mathematical modelling to investigate the reinfection frequency of COVID-19.MethodsWe have used the SIR (Susceptible, Infected, Recovered) framework and random processing based on empirical SARS-CoV-2 infection and fatality data from different regions to calculate the number of reinfections that would be expected to occur if no immunity to the disease occurred.ResultsOur model predicts that cases of reinfection should have been observed by now if primary SARS-CoV-2 infection did not protect from subsequent exposure in the short term, however, no such cases have been documented.ConclusionsThis work concludes that infection with the SARS-CoV-2 virus provides short-term immunity to reinfection and therefore provides a useful insight for serological testing strategies, lockdown easing and vaccine design.
County-Level Proportions of Black and Hispanic populations, and Socioeconomic Characteristics in Association with Confirmed COVID-19 Cases and Deaths in the United States
Authors: Khanijahani Ahmad 
Published: June 2020

AbstractObjectivesThe objective of this study was to investigate potential county-level disparities among racial/ethnic and economic groups in COVID-19 burden which was measured using confirmed cases and deaths in 100,000 population.DesignSecondary data analysis using county-level data for 3,142 US counties was conducted in 2020. Hierarchical linear regression and concentration curve analyses were performed. The association of COVID-19 cases and deaths was examined separately by sociodemographic and economic characteristics of the county population. American Community Survey (ACS) 5-year estimates (2014-2018), Area Health Resources File (AHRF) 2018-2019, and 2020 COVID-19 data from Johns Hopkins University were used in this study.ResultsAfter adjusting for covariates, US counties with a higher proportion of black population, and a higher proportion of adults with less than high school diploma had disproportionately higher COVID-19 cases and deaths (β>0, p<0.05). A higher proportion of the Hispanic population was associated with higher confirmed cases (β= 1.03, 95% CI= 0.57-1.5), and higher housing cost to household income ratio was associated with higher deaths (β= 3.74, 95% CI= 2.14-5.37). This observed disparities can potentially aggravate the existing health disparities among these population groups.ConclusionsIdentification of disproportionately impacted population groups can pave the way towards narrowing the disparity gaps and guide policymakers and stakeholders in designing and implementing population group-specific interventions to mitigate the negative consequences of COVID-19 pandemic.
Three Risk Scores For Mortality Prediction In Minimally Invasive Cardiac Surgery
Authors: Margaryan R. , Bianchi G. , Concistre G. , Gasbarri T. , Kallushi E. , Farneti P. , Solinas M. 
Published: June 2020

AbstractObjectiveThe Society of Thoracic Surgeons score performance relative to other scores in minimally invasive cardiac surgery is not known.MethodsPatients who underwent surgery from 2003 to 2018 identified from database. Additional variables included for STS score calculation, EuroSCORE II and age, creatinine and ejection fraction score calculation.ResultsA total of 4751 patients were identified from main database. There were actual 47 (0.99%) hospitals deaths. The mean STS score predicted mortality were 2.0 ± 2.1. Discriminatory power was uniformly good (for STS Mortality: area under curve, 0.86; 95% confidence interval, 0.81 - 0.91). The mean EuroSCORE II predicted mortality were 2.9 ± 3.8. Discriminatory power was uniformly good similar to that of STS (for EuroSCORE II Mortality: area under curve, 0.9; 95% confidence interval, 0.86 - 0.93). The mean ACEF predicted mortality were 2.5 ± 2.3. Discriminatory power was uniformly good but inferior to that of STS and EuroSCORE II (for ACEF Mortality: area under curve, 0.72; 95% confidence interval, 0.65 - 0.8).Calibration pattern for STS score was the best for of mortality prediction (p < 0.01), EuroSCORE II and ACEF were constantly overestimating mortality (respectively, p < 0.01 and p < 0.01). scores.ConclusionsThe STS score has acceptable discrimination power for this sub-population. However, it is not calibrated for the the subset. EuroSCORE II is has good discrimination power, but not calibrate for the this subset of patients. ACEF score had similar performance to EuroSCORE. No algorithm seems suitable for accurate risk estimation.