bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neddylation pathway alleviates chronic pancreatitis by reducing HIF1α-CCL5-dependent macrophage infiltration
Authors: Lin Yuli , Chen Yusheng , Feng Wenxue , Hua Rong , Zhang Junfeng , Huo Yanmiao , Jiang Hong , Yin Bo , Yang Xuguang 
Published: March 2021

AbstractChronic pancreatitis (CP) is characterized by a wide range of irreversible fibro-inflammatory diseases with largely ambiguous pathogenesis. Although neddylation pathway has been implicated in regulating immune responses, whether the dysregulation of neddylation is involved in the progression of CP and how neddylation regulates the inflammatory microenvironment of CP have not yet been reported. Here, we demonstrate that global inactivation of neddylation pathway by MLN4924 significantly exacerbates chronic pancreatitis. The increased M2 macrophage infiltration, mediated by the upregulated chemokine (C-C motif) ligand 5 (CCL5), is responsible for the enhanced pancreatitis-promoting activity of MLN4924. Both CCL5 blockade and macrophage depletion contribute to alleviating pancreatic fibrosis and inflammation in MLN4924-treated CP mice. Mechanistic investigation identifies that inactivation of Cullin-RING ligases (CRLs) stabilizes cellular levels of hypoxia-inducible factor 1α (HIF-1α), which increases CCL5 expression by promoting CCL5 transactivation. Clinically, UBE2M expression remarkably decreases in human CP tissues compared with normal specimens and the levels of CCL5 and M2 marker CD163 are negatively correlated with UBE2M intensity, suggesting that neddylation is involved in the pathogenesis of pancreatitis. Hence, our studies reveal a neddylation-associated immunopathogenesis of chronic pancreatitis and provide new ideas for the disease treatment.
Protectin DX restores Treg/Th17 cell balance in rheumatoid arthritis by inhibiting NLRP3 inflammasome via miR-20a
Authors: Jin Shengwei , Sun Siyuan , Ling Hanzhi , Ma Jinglan , Zhang Xu , Xie Zhen , Zhan Ning , Zheng Wenjie , Li Man , Qin Yang , Zhao Heping , Chen Yan , Yang Xinyu , Wang Jianguang 
Published: March 2021

AbstractRegulatory T-cell (Treg)/T-helper 17 (Th17) cell balance plays an important role in the progression of rheumatoid arthritis (RA). Our study explored the protective effect of protectin DX (PDX), which restored Treg/Th17 cell balance in RA, and the role of the nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome pathway in this process. Using mass spectrometry, we discovered that level of PDX decreased in active-RA patients and increased in inactive-RA patients compared with HCs, and serum PDX was a potential biomarker in RA activity detection (area under the curve [AUC] = 0.86). In addition, a collagen-induced arthritis (CIA) mice model was constructed and PDX obviously delayed RA progression in the CIA model, upregulating Tregs and anti-inflammatory cytokines while downregulating Th17 cells and pro-inflammatory cytokines. Moreover, NLRP3 knockout and rescue experiments demonstrated that NLRP3 participated in PDX-mediated Treg/Th17 cell balance restoration, joint injury amelioration and inflammatory-response attenuation using Nlrp3−/− mice. Furthermore, microarray and verified experiments confirmed that PDX reduced NLRP3 expression via miRNA-20a (miR-20a). In summary, we confirmed for the first time that PDX could effectively ameliorate CIA progression by restoring Treg/Th17 cell balance, which was mediated by inhibition of the NLRP3 inflammasome pathway via miR-20a.
Plasma IL-6 levels following corticosteroid therapy as an indicator of ICU length of stay in critically ill COVID-19 patients
Authors: Awasthi Samir , Wagner Tyler , Venkatakrishnan A. J. , Puranik Arjun , Hurchik Matthew , Agarwal Vineet , Conrad Ian , Kirkup Christian , Arunachalam Raman , O’Horo John , Kremers Walter , Kashyap Rahul , Morice William , Halamka John , Williams Amy W. , Faubion William A. , Badley Andrew D. , Gores Gregory J. , Soundararajan Venky 
Published: March 2021

AbstractIntensive care unit (ICU) admissions and mortality in severe COVID-19 patients are driven by “cytokine storms” and acute respiratory distress syndrome (ARDS). Interim clinical trial results suggest that the corticosteroid dexamethasone displays better 28-day survival in severe COVID-19 patients requiring ventilation or oxygen. In this study, 10 out of 16 patients (62.5%) that had an average plasma IL-6 value over 10 pg/mL post administration of corticosteroids also had worse outcomes (i.e., ICU stay >15 days or death), compared to 8 out of 41 patients (19.5%) who did not receive corticosteroids (p-value = 0.0024). Given this potential association between post-corticosteroid IL-6 levels and COVID-19 severity, we hypothesized that the glucocorticoid receptor (GR or NR3C1) may be coupled to IL-6 expression in specific cell types that govern cytokine release syndrome (CRS). Examining single-cell RNA-seq data from BALF of severe COVID-19 patients and nearly 2 million cells from a pan-tissue scan shows that alveolar macrophages, smooth muscle cells, and endothelial cells co-express NR3C1 and IL-6, motivating future studies on the links between the regulation of NR3C1 function and IL-6 levels.
The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro
Authors: Zhang Shiqi , Shao Zhengbo , Liu Xinna , Hou Mingying , Cheng Fang , Lei Dawei , Yuan Huiping 
Published: March 2021

AbstractThe glaucoma-associated E50K mutation in optineurin (OPTN) is known to affect autophagy and cause the apoptosis of retinal ganglion cells (RGCs), but the pathogenic mechanism remains unclear. In this study, we investigated whether the OPTN (E50K) mutation caused TDP-43 aggregation by disrupting autophagy in vivo and in vitro. OPTN (E50K) mutant mice were generated and analysed for genotype and phenotype. Adeno-associated virus type 2 vectors containing either GFP only, GFP-tagged wild-type OPTN or GFP-tagged E50K-mutated OPTN were used to transfect R28 cells. Loss of RGCs decreased retinal thickness and visual impairment were observed in OPTN (E50K) mice compared with WT mice. Moreover, overexpression of E50K OPTN induced R28 cell apoptosis. Increased p62/SQSTM1 and LC3-II levels indicated that autophagic flux was inhibited and contributed to TDP-43 aggregation in vivo and in vitro. We found that rapamycin effectively reduced the aggregation of TDP-43 in OPTN (E50K) mice and decreased the protein levels of p62/SQSTM1 and the autophagic marker LC3-II. Moreover, rapamycin increased the RGC number and visual function of E50K mice. In addition, we also observed increased cytoplasmic TDP-43 in the spinal cord and motor dysfunction in 24-month-old OPTN (E50K) mice, indicating that TDP-43 accumulation may be the common pathological mechanism of glaucoma and amyotrophic lateral sclerosis (ALS). In conclusion, the disruption of autophagy by OPTN (E50K) affected the degradation of TDP-43 and may play an important role in OPTN (E50K)-mediated glaucomatous retinal neurodegeneration.
Threats of global warming to the world’s freshwater fishes
Authors: Barbarossa Valerio , Bosmans Joyce , Wanders Niko , King Henry , Bierkens Marc F. P. , Huijbregts Mark A. J. , Schipper Aafke M. 
Published: March 2021

AbstractClimate change poses a significant threat to global biodiversity, but freshwater fishes have been largely ignored in climate change assessments. Here, we assess threats of future flow and water temperature extremes to ~11,500 riverine fish species. In a 3.2 °C warmer world (no further emission cuts after current governments’ pledges for 2030), 36% of the species have over half of their present-day geographic range exposed to climatic extremes beyond current levels. Threats are largest in tropical and sub-arid regions and increases in maximum water temperature are more threatening than changes in flow extremes. In comparison, 9% of the species are projected to have more than half of their present-day geographic range threatened in a 2 °C warmer world, which further reduces to 4% of the species if warming is limited to 1.5 °C. Our results highlight the need to intensify (inter)national commitments to limit global warming if freshwater biodiversity is to be safeguarded.
The genetic architecture of structural left–right asymmetry of the human brain
Authors: Sha Zhiqiang , Schijven Dick , Carrion-Castillo Amaia , Joliot Marc , Mazoyer Bernard , Fisher Simon E. , Crivello Fabrice , Francks Clyde 
Published: March 2021

AbstractLeft–right hemispheric asymmetry is an important aspect of healthy brain organization for many functions including language, and it can be altered in cognitive and psychiatric disorders. No mechanism has yet been identified for establishing the human brain’s left–right axis. We performed multivariate genome-wide association scanning of cortical regional surface area and thickness asymmetries, and subcortical volume asymmetries, using data from 32,256 participants from the UK Biobank. There were 21 significant loci associated with different aspects of brain asymmetry, with functional enrichment involving microtubule-related genes and embryonic brain expression. These findings are consistent with a known role of the cytoskeleton in left–right axis determination in other organs of invertebrates and frogs. Genetic variants associated with brain asymmetry overlapped with those associated with autism, educational attainment and schizophrenia. Comparably large datasets will likely be required in future studies, to replicate and further clarify the associations of microtubule-related genes with variation in brain asymmetry, behavioural and psychiatric traits.
Countrywide population movement monitoring using mobile devices generated (big) data during the COVID-19 crisis
Authors: Szocska Miklos , Pollner Peter , Schiszler Istvan , Joo Tamas , Palicz Tamas , McKee Martin , Asztalos Aron , Bencze Laszlo , Kapronczay Mor , Petrecz Peter , Toth Benedek , Szabo Adam , Weninger Attila , Ader Krisztian , Bacskai Peter , Karaszi Peter , Terplan Gyozo , Tuboly Gabor , Sohonyai Adam , Szoke Jozsef , Toth Adam , Gaal Peter 
Published: March 2021

AbstractMobile phones have been used to monitor mobility changes during the COVID-19 pandemic but surprisingly few studies addressed in detail the implementation of practical applications involving whole populations. We report a method of generating a “mobility-index” and a “stay-at-home/resting-index” based on aggregated anonymous Call Detail Records of almost all subscribers in Hungary, which tracks all phones, examining their strengths and weaknesses, comparing it with Community Mobility Reports from Google, limited to smartphone data. The impact of policy changes, such as school closures, could be identified with sufficient granularity to capture a rush to shops prior to imposition of restrictions. Anecdotal reports of large scale movement of Hungarians to holiday homes were confirmed. At the national level, our results correlated well with Google mobility data, but there were some differences at weekends and national holidays, which can be explained by methodological differences. Mobile phones offer a means to analyse population movement but there are several technical and privacy issues. Overcoming these, our method is a practical and inexpensive way forward, achieving high levels of accuracy and resolution, especially where uptake of smartphones is modest, although it is not an alternative to smartphone-based solutions used for contact tracing and quarantine monitoring.
An integrative approach sheds new light onto the systematics and ecology of the widespread ciliate genus Coleps (Ciliophora, Prostomatea)
Authors: Pröschold Thomas , Rieser Daniel , Darienko Tatyana , Nachbaur Laura , Kammerlander Barbara , Qian Kuimei , Pitsch Gianna , Bruni Estelle Patricia , Qu Zhishuai , Forster Dominik , Rad-Menendez Cecilia , Posch Thomas , Stoeck Thorsten , Sonntag Bettina 
Published: March 2021

AbstractSpecies of the genus Coleps are one of the most common planktonic ciliates in lake ecosystems. The study aimed to identify the phenotypic plasticity and genetic variability of different Coleps isolates from various water bodies and from culture collections. We used an integrative approach to study the strains by (i) cultivation in a suitable culture medium, (ii) screening of the morphological variability including the presence/absence of algal endosymbionts of living cells by light microscopy, (iii) sequencing of the SSU and ITS rDNA including secondary structures, (iv) assessment of their seasonal and spatial occurrence in two lakes over a one-year cycle both from morphospecies counts and high-throughput sequencing (HTS), and, (v) proof of the co-occurrence of Coleps and their endosymbiotic algae from HTS-based network analyses in the two lakes. The Coleps strains showed a high phenotypic plasticity and low genetic variability. The algal endosymbiont in all studied strains was Micractinium conductrix and the mutualistic relationship turned out as facultative. Coleps is common in both lakes over the whole year in different depths and HTS has revealed that only one genotype respectively one species, C. viridis, was present in both lakes despite the different lifestyles (mixotrophic with green algal endosymbionts or heterotrophic without algae). Our results suggest a future revision of the species concept of the genus Coleps.
Specific microbiome profile in Takayasu’s arteritis and giant cell arteritis
Authors: Desbois Anne Claire , Ciocan Dragos , Saadoun David , Perlemuter Gabriel , Cacoub Patrice 
Published: March 2021

AbstractRecent studies have provided evidence of a close link between specific microbiota and inflammatory disorders. While the vessel wall microbiota has been recently described in large vessel vasculitis (LVV) and controls, the blood microbiome in these diseases has not been previously reported (LVV). We aimed to analyse the blood microbiome profile of LVV patients (Takayasu’s arteritis [TAK], giant cell arteritis [GCA]) and healthy blood donors (HD). We studied the blood samples of 13 patients with TAK (20 samples), 9 patients with GCA (11 samples) and 15 HD patients. We assessed the blood microbiome profile by sequencing the 16S rDNA blood bacterial DNA. We used linear discriminant analysis (LDA) coupled with linear discriminant effect size measurement (LEfSe) to investigate the differences in the blood microbiome profile between TAK and GCA patients. An increase in the levels of Clostridia, Cytophagia and Deltaproteobacteria and a decrease in Bacilli at the class level were found in TAK patients compared with HD patients (LDA > 2, p < 0.05). Active TAK patients had significantly lower levels of Staphylococcus compared with inactive TAK patients. Samples of GCA patients had an increased abundance of Rhodococcus and an unidentified member of the Cytophagaceae family. Microbiota of TAK compared with GCA patients was found to show higher levels of Candidatus Aquiluna and Cloacibacterium (LDA > 2; p < 0.05). Differences highlighted in the blood microbiome were also associated with a shift of bacterial predicted metabolic functions in TAK in comparison with HD. Similar results were also found in patients with active versus inactive TAK. In conclusion, patients with TAK were found to present a specific blood microbiome profile in comparison with healthy donors and GCA subjects. Significant changes in the blood microbiome profiles of TAK patients were associated with specific metabolic functions.
Blast-induced temporal alterations in blood–brain barrier properties in a rodent model
Authors: Kawoos Usmah , Abutarboush Rania , Gu Ming , Chen Ye , Statz Jonathan K. , Goodrich Samantha Y. , Ahlers Stephen T. 
Published: March 2021

AbstractThe consequences of blast-induced traumatic brain injury (bTBI) on the blood–brain barrier (BBB) and components of the neurovascular unit are an area of active research. In this study we assessed the time course of BBB integrity in anesthetized rats exposed to a single blast overpressure of 130 kPa (18.9 PSI). BBB permeability was measured in vivo via intravital microscopy by imaging extravasation of fluorescently labeled tracers (40 kDa and 70 kDa molecular weight) through the pial microvasculature into brain parenchyma at 2–3 h, 1, 3, 14, or 28 days after the blast exposure. BBB structural changes were assessed by immunostaining and molecular assays. At 2–3 h and 1 day after blast exposure, significant increases in the extravasation of the 40 kDa but not the 70 kDa tracers were observed, along with differential reductions in the expression of tight junction proteins (occludin, claudin-5, zona occluden-1) and increase in the levels of the astrocytic water channel protein, AQP-4, and matrix metalloprotease, MMP-9. Nearly all of these measures were normalized by day 3 and maintained up to 28 days post exposure. These data demonstrate that blast-induced changes in BBB permeability are closely coupled to structural and functional components of the BBB.
Computational modeling reveals a key role for polarized myeloid cells in controlling osteoclast activity during bone injury repair
Authors: Lo Chen Hao , Baratchart Etienne , Basanta David , Lynch Conor C. 
Published: March 2021

AbstractBone-forming osteoblasts and -resorbing osteoclasts control bone injury repair, and myeloid-derived cells such as monocytes and macrophages are known to influence their behavior. However, precisely how these multiple cell types coordinate and regulate each other over time within the bone marrow to restore bone is difficult to dissect using biological approaches. Conversely, mathematical modeling lends itself well to this challenge. Therefore, we generated an ordinary differential equation (ODE) model powered by experimental data (osteoblast, osteoclast, bone volume, pro- and anti-inflammatory myeloid cells) obtained from intra-tibially injured mice. Initial ODE results using only osteoblast/osteoclast populations demonstrated that bone homeostasis could not be recovered after injury, but this issue was resolved upon integration of pro- and anti-inflammatory myeloid population dynamics. Surprisingly, the ODE revealed temporal disconnects between the peak of total bone mineralization/resorption, and osteoblast/osteoclast numbers. Specifically, the model indicated that osteoclast activity must vary greatly (> 17-fold) to return the bone volume to baseline after injury and suggest that osteoblast/osteoclast number alone is insufficient to predict bone the trajectory of bone repair. Importantly, the values of osteoclast activity fall within those published previously. These data underscore the value of mathematical modeling approaches to understand and reveal new insights into complex biological processes.
Structural insights of human N-acetyltransferase 10 and identification of its potential novel inhibitors
Authors: Dalhat Mahmood Hassan , Altayb Hisham N. , Khan Mohammad Imran , Choudhry Hani 
Published: March 2021

AbstractN-acetyltransferase 10 (NAT10), is an acetyltransferase that regulates RNA stability and translation processes. Association of NAT10 with several diseases including cancer, makes it a promising therapeutic target. Remodelin is the only known NAT10 inhibitor, but the structural information related to its binding with NAT10 is still obscure. Here, we predicted the human NAT10 structure using homology modeling that was not available previously and used human NAT10 to identify the novel binding site(s) of Remodelin. The alignment of the modeled human NAT10 showed 24% identity and 37% positivity with crystal structure of tRNA (Met) cytidine acetyltransferase. Molecular docking showed binding of Remodelin with NAT10 in acetyl-CoA binding pocket. Additionally, we screened a library of FDA-approved drugs for the identification of novel inhibitors of NAT10 activity. Binding score showed that four drugs namely, Fosaprepitant (− 11.709), Leucal (− 10.46), Fludarabine (− 10.347) and Dantrolene (− 9.875) bind to NAT10 and have better binding capability when compared with Acetyl-CoA (− 5.691) and Remodelin (− 5.3). Acetyl-CoA, Remodelin, and others exhibit hits for hydrophobic, hydrophilic and hydrogen interactions. Interestingly, Remodelin and others interact with the amino acid residues ILE629, GLY639, GLY641, LEU719, and PHE722 in the Acetyl-CoA binding pocket of NAT10 similar to Acetyl-CoA. Our findings revealed that Fosaprepitant, Leucal, Fludarabine, and Dantrolene are promising molecules that can be tested and developed as potential inhibitors of NAT10 acetyltransferase activity.
Gossypol decreased cell viability and down-regulated the expression of a number of genes in human colon cancer cells
Authors: Cao Heping , Sethumadhavan Kandan , Cao Fangping , Wang Thomas T. Y. 
Published: March 2021

AbstractPlant polyphenol gossypol has anticancer activities. This may increase cottonseed value by using gossypol as a health intervention agent. It is necessary to understand its molecular mechanisms before human consumption. The aim was to uncover the effects of gossypol on cell viability and gene expression in cancer cells. In this study, human colon cancer cells (COLO 225) were treated with gossypol. MTT assay showed significant inhibitory effect under high concentration and longtime treatment. We analyzed the expression of 55 genes at the mRNA level in the cells; many of them are regulated by gossypol or ZFP36/TTP in cancer cells. BCL2 mRNA was the most stable among the 55 mRNAs analyzed in human colon cancer cells. GAPDH and RPL32 mRNAs were not good qPCR references for the colon cancer cells. Gossypol decreased the mRNA levels of DGAT, GLUT, TTP, IL families and a number of previously reported genes. In particular, gossypol suppressed the expression of genes coding for CLAUDIN1, ELK1, FAS, GAPDH, IL2, IL8 and ZFAND5 mRNAs, but enhanced the expression of the gene coding for GLUT3 mRNA. The results showed that gossypol inhibited cell survival with decreased expression of a number of genes in the colon cancer cells.
The serotonin reuptake inhibitor Fluoxetine inhibits SARS-CoV-2 in human lung tissue
Authors: Zimniak Melissa , Kirschner Luisa , Hilpert Helen , Geiger Nina , Danov Olga , Oberwinkler Heike , Steinke Maria , Sewald Katherina , Seibel Jürgen , Bodem Jochen 
Published: March 2021

AbstractTo circumvent time-consuming clinical trials, testing whether existing drugs are effective inhibitors of SARS-CoV-2, has led to the discovery of Remdesivir. We decided to follow this path and screened approved medications "off-label" against SARS-CoV-2. Fluoxetine inhibited SARS-CoV-2 at a concentration of 0.8 µg/ml significantly in these screenings, and the EC50 was determined with 387 ng/ml. Furthermore, Fluoxetine reduced viral infectivity in precision-cut human lung slices showing its activity in relevant human tissue targeted in severe infections. Fluoxetine treatment resulted in a decrease in viral protein expression. Fluoxetine is a racemate consisting of both stereoisomers, while the S-form is the dominant serotonin reuptake inhibitor. We found that both isomers show similar activity on the virus, indicating that the R-form might specifically be used for SARS-CoV-2 treatment. Fluoxetine inhibited neither Rabies virus, human respiratory syncytial virus replication nor the Human Herpesvirus 8 or Herpes simplex virus type 1 gene expression, indicating that it acts virus-specific. Moreover, since it is known that Fluoxetine inhibits cytokine release, we see the role of Fluoxetine in the treatment of SARS-CoV-2 infected patients of risk groups.