bluuebunny/crossref_metadata_2025_split huggingface dataset:
LncRNA FIRRE functions as a tumor promoter by interaction with PTBP1 to stabilize BECN1 mRNA and facilitate autophagy
Authors: Wang Yajie , Li Zhengyang , Xu Shizan , Li Wenjun , Chen Mengyun , Jiang Miao , Fan Xiaoming 
Published: February 2022

AbstractLong non-coding RNAs (lncRNAs) play critical functions in various cancers. Firre intergenic repeating RNA element (FIRRE), a lncRNA located in the nucleus, was overexpressed in colorectal cancer (CRC). However, the detailed mechanism of FIRRE in CRC remains elusive. Results of RNA sequence and qPCR illustrated overexpression of FIRRE in CRC cell lines and tissues. The aberrant expression of FIRRE was correlated with the migration, invasion, and proliferation in cell lines. In accordance, it was also associated with lymphatic metastasis and distant metastasis in patients with CRC. FIRRE was identified to physically interact with Polypyrimidine tract-binding protein (PTBP1) by RNA pull-down and RNA immunoprecipitation (RIP). Overexpression of FIRRE induced the translocation of PTBP1 from nucleus to cytoplasm, which was displayed by immunofluorescence and western blot. In turn, delocalization of FIRRE from nucleus to cytoplasm is observed after the loss of PTBP1. The RNA-protein complex in the cytoplasm directly bound to BECN1 mRNA, and the binding site was at the 3' end of the mRNA. Cells with FIRRE and PTBP1 depletion alone or in combination were treated by Actinomycin D (ACD). Results of qPCR showed FIRRE stabilized BECN1 mRNA in a PTBP1-medieated manner. In addition, FIRRE contributed to autophagy activity. These findings indicate FIRRE acts as an oncogenic factor in CRC, which induces tumor development through stabilizing BECN1 mRNA and facilitating autophagy in a PTBP1-mediated manner.
Adenine overload induces ferroptosis in human primary proximal tubular epithelial cells
Authors: Khan Muhammad Ali , Nag Purba , Grivei Anca , Giuliani Kurt T. K. , Wang Xiangju , Diwan Vishal , Hoy Wendy , Healy Helen , Gobe Glenda , Kassianos Andrew J. 
Published: February 2022

AbstractThe pathogenesis of crystal nephropathy involves deposition of intratubular crystals, tubular obstruction and cell death. The deposition of 8-dihydroxyadenine (DHA) crystals within kidney tubules, for instance, is caused by a hereditary deficiency of adenine phosphoribosyl transferase in humans or adenine overload in preclinical models. However, the downstream pathobiological patterns of tubular cell attrition in adenine/DHA-induced nephropathy remain poorly understood. In this study, we investigated: (i) the modes of adenine-induced tubular cell death in an experimental rat model and in human primary proximal tubular epithelial cells (PTEC); and (ii) the therapeutic effect of the flavonoid baicalein as a novel cell death inhibitor. In a rat model of adenine diet-induced crystal nephropathy, significantly elevated levels of tubular iron deposition and lipid peroxidation (4-hydroxynonenal; 4-HNE) were detected. This phenotype is indicative of ferroptosis, a novel form of regulated necrosis. In cultures of human primary PTEC, adenine overload-induced significantly increased mitochondrial superoxide levels, mitochondrial depolarisation, DNA damage and necrotic cell death compared with untreated PTEC. Molecular interrogation of adenine-stimulated PTEC revealed a significant reduction in the lipid repair enzyme glutathione peroxidase 4 (GPX4) and the significant increase in 4-HNE compared with untreated PTEC, supporting the concept of ferroptotic cell death. Moreover, baicalein treatment inhibited ferroptosis in adenine-stimulated PTEC by selectively modulating the mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) and thus, suppressing mitochondrial superoxide production and DNA damage. These data identify ferroptosis as the primary pattern of PTEC necrosis in adenine-induced nephropathy and establish baicalein as a potential therapeutic tool for the clinical management of ferroptosis-associated crystal nephropathies (e.g., DHA nephropathy, oxalate nephropathy).
Transketolase promotes colorectal cancer metastasis through regulating AKT phosphorylation
Authors: Li Minle , Zhao Xue , Yong Hongmei , Xu Jian , Qu Pengfei , Qiao Shuxi , Hou Pingfu , Li Zhongwei , Chu Sufang , Zheng Junnian , Bai Jin 
Published: February 2022

AbstractTransketolase (TKT) which is an important metabolic enzyme in the pentose phosphate pathway (PPP) participates in maintaining ribose 5-phosphate levels. TKT is necessary for maintaining cell growth. However, we found that in addition to this, TKT can also affect tumor progression through other ways. Our previous study indicate that TKT could promote the development of liver cancer by affecting bile acid metabolism. And in this study, we discovered that TKT expression was remarkably upregulated in colorectal cancer, abnormal high expression of TKT is associated with poor prognosis of colorectal cancer. Additionally, TKT promoted colorectal cancer cell growth and metastasis. Further study demonstrated that TKT interacted with GRP78 and promoted colorectal cancer cell glycolysis through increasing AKT phosphorylation, thereby enhancing colorectal cancer cell metastasis. Thus, TKT is expected to become an indicator for judging the prognosis of colorectal cancer, and provide a theoretical basis for drug development of new treatment targets for colorectal cancer.
A pan-CRISPR analysis of mammalian cell specificity identifies ultra-compact sgRNA subsets for genome-scale experiments
Authors: Zhao Boyang , Rao Yiyun , Leighow Scott , O’Brien Edward P. , Gilbert Luke , Pritchard Justin R. 
Published: February 2022

AbstractA genetic knockout can be lethal to one human cell type while increasing growth rate in another. This context specificity confounds genetic analysis and prevents reproducible genome engineering. Genome-wide CRISPR compendia across most common human cell lines offer the largest opportunity to understand the biology of cell specificity. The prevailing viewpoint, synthetic lethality, occurs when a genetic alteration creates a unique CRISPR dependency. Here, we use machine learning for an unbiased investigation of cell type specificity. Quantifying model accuracy, we find that most cell type specific phenotypes are predicted by the function of related genes of wild-type sequence, not synthetic lethal relationships. These models then identify unexpected sets of 100-300 genes where reduced CRISPR measurements can produce genome-scale loss-of-function predictions across >18,000 genes. Thus, it is possible to reduce in vitro CRISPR libraries by orders of magnitude—with some information loss—when we remove redundant genes and not redundant sgRNAs.
Primary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells
Authors: Borriello Lucia , Coste Anouchka , Traub Brian , Sharma Ved P. , Karagiannis George S. , Lin Yu , Wang Yarong , Ye Xianjun , Duran Camille L. , Chen Xiaoming , Friedman Madeline , Sosa Maria Soledad , Sun Dan , Dalla Erica , Singh Deepak K. , Oktay Maja H. , Aguirre-Ghiso Julio A. , Condeelis John S. , Entenberg David 
Published: February 2022

AbstractMetastases are initiated by disseminated tumor cells (DTCs) that colonize distant organs. Growing evidence suggests that the microenvironment of the primary tumor primes DTCs for dormant or proliferative fates. However, the manner in which this occurs remains poorly understood. Here, using the Window for High-Resolution Intravital Imaging of the Lung (WHRIL), we study the live lung longitudinally and follow the fate of individual DTCs that spontaneously disseminate from orthotopic breast tumors. We find that spontaneously DTCs have increased levels of retention, increased speed of extravasation, and greater survival after extravasation, compared to experimentally metastasized tumor cells. Detailed analysis reveals that a subset of macrophages within the primary tumor induces a pro-dissemination and pro-dormancy DTC phenotype. Our work provides insight into how specific primary tumor microenvironments prime a subpopulation of cells for expression of proteins associated with dissemination and dormancy.
A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase
Authors: Shannon Ashleigh , Fattorini Véronique , Sama Bhawna , Selisko Barbara , Feracci Mikael , Falcou Camille , Gauffre Pierre , El Kazzi Priscila , Delpal Adrien , Decroly Etienne , Alvarez Karine , Eydoux Cécilia , Guillemot Jean-Claude , Moussa Adel , Good Steven S. , La Colla Paolo , Lin Kai , Sommadossi Jean-Pierre , Zhu Yingxiao , Yan Xiaodong , Shi Hui , Ferron François , Canard Bruno 
Published: February 2022

AbstractThe guanosine analog AT-527 represents a promising candidate against Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2). AT-527 recently entered phase III clinical trials for the treatment of COVID-19. Once in cells, AT-527 is converted into its triphosphate form, AT-9010, that presumably targets the viral RNA-dependent RNA polymerase (RdRp, nsp12), for incorporation into viral RNA. Here we report a 2.98 Å cryo-EM structure of the SARS-CoV-2 nsp12-nsp7-nsp82-RNA complex, showing AT-9010 bound at three sites of nsp12. In the RdRp active-site, one AT-9010 is incorporated at the 3′ end of the RNA product strand. Its modified ribose group (2′-fluoro, 2′-methyl) prevents correct alignment of the incoming NTP, in this case a second AT-9010, causing immediate termination of RNA synthesis. The third AT-9010 is bound to the N-terminal domain of nsp12 - known as the NiRAN. In contrast to native NTPs, AT-9010 is in a flipped orientation in the active-site, with its guanine base unexpectedly occupying a previously unnoticed cavity. AT-9010 outcompetes all native nucleotides for NiRAN binding, inhibiting its nucleotidyltransferase activity. The dual mechanism of action of AT-527 at both RdRp and NiRAN active sites represents a promising research avenue against COVID-19.
Delayed Antarctic sea-ice decline in high-resolution climate change simulations
Authors: Rackow Thomas , Danilov Sergey , Goessling Helge F. , Hellmer Hartmut H. , Sein Dmitry V. , Semmler Tido , Sidorenko Dmitry , Jung Thomas 
Published: February 2022

AbstractDespite global warming and Arctic sea-ice loss, on average the Antarctic sea-ice extent has not declined since 1979 when satellite data became available. In contrast, climate model simulations tend to exhibit strong negative sea-ice trends for the same period. This Antarctic sea-ice paradox leads to low confidence in 21st-century sea-ice projections. Here we present multi-resolution climate change projections that account for Southern Ocean mesoscale eddies. The high-resolution configuration simulates stable September Antarctic sea-ice extent that is not projected to decline until the mid-21st century. We argue that one reason for this finding is a more realistic ocean circulation that increases the equatorward heat transport response to global warming. As a result, the ocean becomes more efficient at moderating the anthropogenic warming around Antarctica and hence at delaying sea-ice decline. Our study suggests that explicitly simulating Southern Ocean eddies is necessary for providing Antarctic sea-ice projections with higher confidence.
Gut microbiome of the largest living rodent harbors unprecedented enzymatic systems to degrade plant polysaccharides
Authors: Cabral Lucelia , Persinoti Gabriela F. , Paixão Douglas A. A. , Martins Marcele P. , Morais Mariana A. B. , Chinaglia Mariana , Domingues Mariane N. , Sforca Mauricio L. , Pirolla Renan A. S. , Generoso Wesley C. , Santos Clelton A. , Maciel Lucas F. , Terrapon Nicolas , Lombard Vincent , Henrissat Bernard , Murakami Mario T. 
Published: February 2022

AbstractThe largest living rodent, capybara, can efficiently depolymerize and utilize lignocellulosic biomass through microbial symbiotic mechanisms yet elusive. Herein, we elucidate the microbial community composition, enzymatic systems and metabolic pathways involved in the conversion of dietary fibers into short-chain fatty acids, a main energy source for the host. In this microbiota, the unconventional enzymatic machinery from Fibrobacteres seems to drive cellulose degradation, whereas a diverse set of carbohydrate-active enzymes from Bacteroidetes, organized in polysaccharide utilization loci, are accounted to tackle complex hemicelluloses typically found in gramineous and aquatic plants. Exploring the genetic potential of this community, we discover a glycoside hydrolase family of β-galactosidases (named as GH173), and a carbohydrate-binding module family (named as CBM89) involved in xylan binding that establishes an unprecedented three-dimensional fold among associated modules to carbohydrate-active enzymes. Together, these results demonstrate how the capybara gut microbiota orchestrates the depolymerization and utilization of plant fibers, representing an untapped reservoir of enzymatic mechanisms to overcome the lignocellulose recalcitrance, a central challenge toward a sustainable and bio-based economy.
Microwave background temperature at a redshift of 6.34 from H2O absorption
Authors: Riechers Dominik A. , Weiss Axel , Walter Fabian , Carilli Christopher L. , Cox Pierre , Decarli Roberto , Neri Roberto 
Published: February 2022

AbstractDistortions of the observed cosmic microwave background provide a direct measurement of the microwave background temperature at redshifts from 0 to 1 (refs. 1,2). Some additional background temperature estimates exist at redshifts from 1.8 to 3.3 based on molecular and atomic line-excitation temperatures in quasar absorption-line systems, but are model dependent3. No deviations from the expected (1 + z) scaling behaviour of the microwave background temperature have been seen4, but the measurements have not extended deeply into the matter-dominated era of the Universe at redshifts z > 3.3. Here we report observations of submillimetre line absorption from the water molecule against the cosmic microwave background at z = 6.34 in a massive starburst galaxy, corresponding to a lookback time of 12.8 billion years (ref. 5). Radiative pumping of the upper level of the ground-state ortho-H2O(110–101) line due to starburst activity in the dusty galaxy HFLS3 results in a cooling to below the redshifted microwave background temperature, after the transition is initially excited by the microwave background. This implies a microwave background temperature of 16.4–30.2 K (1σ range) at z = 6.34, which is consistent with a background temperature increase with redshift as expected from the standard ΛCDM cosmology4.
Crystallographic snapshots of a B12-dependent radical SAM methyltransferase
Authors: Fyfe Cameron D. , Bernardo-García Noelia , Fradale Laura , Grimaldi Stéphane , Guillot Alain , Brewee Clémence , Chavas Leonard M. G. , Legrand Pierre , Benjdia Alhosna , Berteau Olivier 
Published: February 2022

AbstractBy catalysing the microbial formation of methane, methyl-coenzyme M reductase has a central role in the global levels of this greenhouse gas1,2. The activity of methyl-coenzyme M reductase is profoundly affected by several unique post-translational modifications3–6, such as a unique C-methylation reaction catalysed by methanogenesis marker protein 10 (Mmp10), a radical S-adenosyl-l-methionine (SAM) enzyme7,8. Here we report the spectroscopic investigation and atomic resolution structure of Mmp10 from Methanosarcina acetivorans, a unique B12 (cobalamin)-dependent radical SAM enzyme9. The structure of Mmp10 reveals a unique enzyme architecture with four metallic centres and critical structural features involved in the control of catalysis. In addition, the structure of the enzyme–substrate complex offers a glimpse into a B12-dependent radical SAM enzyme in a precatalytic state. By combining electron paramagnetic resonance spectroscopy, structural biology and biochemistry, our study illuminates the mechanism by which the emerging superfamily of B12-dependent radical SAM enzymes catalyse chemically challenging alkylation reactions and identifies distinctive active site rearrangements to provide a structural rationale for the dual use of the SAM cofactor for radical and nucleophilic chemistry.
Differentiation of intestinal tuberculosis and Crohn’s disease through an explainable machine learning method
Authors: Weng Futian , Meng Yu , Lu Fanggen , Wang Yuying , Wang Weiwei , Xu Long , Cheng Dongsheng , Zhu Jianping 
Published: February 2022

AbstractDifferentiation between Crohn’s disease and intestinal tuberculosis is difficult but crucial for medical decisions. This study aims to develop an effective framework to distinguish these two diseases through an explainable machine learning (ML) model. After feature selection, a total of nine variables are extracted, including intestinal surgery, abdominal, bloody stool, PPD, knot, ESAT-6, CFP-10, intestinal dilatation and comb sign. Besides, we compared the predictive performance of the ML methods with traditional statistical methods. This work also provides insights into the ML model’s outcome through the SHAP method for the first time. A cohort consisting of 200 patients’ data (CD = 160, ITB = 40) is used in training and validating models. Results illustrate that the XGBoost algorithm outperforms other classifiers in terms of area under the receiver operating characteristic curve (AUC), sensitivity, specificity, precision and Matthews correlation coefficient (MCC), yielding values of 0.891, 0.813, 0.969, 0.867 and 0.801 respectively. More importantly, the prediction outcomes of XGBoost can be effectively explained through the SHAP method. The proposed framework proves that the effectiveness of distinguishing CD from ITB through interpretable machine learning, which can obtain a global explanation but also an explanation for individual patients.
Bacterial distribution on the ocular surface of patients with primary Sjögren’s syndrome
Authors: Kim Yong Chan , Ham Baknoon , Kang Kui Dong , Yun Jun Myeong , Kwon Man Jae , Kim Hyun Seung , Hwang Hyung Bin 
Published: February 2022

AbstractMany studies have shown that gut microbial dysbiosis is a major factor in the etiology of autoimmune diseases but none have suggested that the ocular surface (OS) microbiome is associated with Sjögren’s syndrome (SS). In this prospective study, we analyzed bacterial distribution on the OS in patients with primary SS. Among the 120 subjects included in this study, 48 patients (group A) had primary SS, whereas 72 subjects (group B) had dry eye symptoms that were unrelated to SS. We evaluated clinical dry eye parameters such as the OS disease index, ocular staining score (OSS), Schirmer’s I test, and tear break-up time (TBUT). Conjunctival swabs were used to analyze the microbial communities from the two groups. Bacterial 16S rRNA genes were sequenced using the Illumina MiSeq platform, and the data were analyzed using the QIIME 1.9.1 program. The Shannon index was significantly lower in group A than in group B microbiota (p < 0.05). An analysis of similarity using the Bray–Curtis distance method found no difference in beta-diversity between the two groups (p > 0.05). In group A, Actinobacteria at the phylum level and Corynebacteria at the genus level exhibited low abundance than group B, but the differences were not statistically significant (p > 0.05). SS apparently decreases the diversity of the OS microbial community. These observations may be related to the pathophysiology of SS and should be investigated in future studies.
Features of the cytoprotective effect of selenium nanoparticles on primary cortical neurons and astrocytes during oxygen–glucose deprivation and reoxygenation
Authors: Turovsky E. A. , Mal’tseva V. N. , Sarimov R. M. , Simakin A. V. , Gudkov S. V. , Plotnikov E. Y. 
Published: February 2022

AbstractThe study is aimed at elucidating the effect of selenium nanoparticles (SeNPs) on the death of cells in the primary culture of mouse cerebral cortex during oxygen and glucose deprivation (OGD). A primary cell culture of the cerebral cortex containing neurons and astrocytes was subjected to OGD and reoxygenation to simulate cerebral ischemia-like conditions in vitro. To evaluate the neuroprotective effect of SeNPs, cortical astrocytes and neurons were incubated for 24 h with SeNPs, and then subjected to 2-h OGD, followed by 24-h reoxygenation. Vitality tests, fluorescence microscopy, and real-time PCR have shown that incubation of primary cultured neurons and astrocytes with SeNPs at concentrations of 2.5–10 µg/ml under physiological conditions has its own characteristics depending on the type of cells (astrocytes or neurons) and leads to a dose-dependent increase in apoptosis. At low concentration SeNPs (0.5 µg/ml), on the contrary, almost completely suppressed the processes of basic necrosis and apoptosis. Both high (5 µg/ml) and low (0.5 µg/ml) concentrations of SeNPs, added for 24 h to the cells of cerebral cortex, led to an increase in the expression level of genes Bcl-2, Bcl-xL, Socs3, while the expression of Bax was suppressed. Incubation of the cells with 0.5 µg/ml SeNPs led to a decrease in the expression of SelK and SelT. On the contrary, 5 µg/ml SeNPs caused an increase in the expression of SelK, SelN, SelT, SelP. In the ischemic model, after OGD/R, there was a significant death of brain cells by the type of necrosis and apoptosis. OGD/R also led to an increase in mRNA expression of the Bax, SelK, SelN, and SelT genes and suppression of the Bcl-2, Bcl-xL, Socs3, SelP genes. Pre-incubation of cell cultures with 0.5 and 2.5 µg/ml SeNPs led to almost complete inhibition of OGD/R-induced necrosis and greatly reduced apoptosis. Simultaneously with these processes we observed suppression of caspase-3 activation. We hypothesize that the mechanisms of the protective action of SeNPs involve the activation of signaling cascades recruiting nuclear factors Nrf2 and SOCS3/STAT3, as well as the activation of adaptive pathways of ESR signaling of stress arising during OGD and involving selenoproteins SelK and SelT, proteins of the Bcl-2 family ultimately leading to inactivation of caspase-3 and inhibition of apoptosis. Thus, our results demonstrate that SeNPs can act as neuroprotective agents in the treatment of ischemic brain injuries.
Comparing Geant4 physics models for proton-induced dose deposition and radiolysis enhancement from a gold nanoparticle
Authors: Rajabpour Saeed , Saberi Hassan , Rasouli Javad , Jabbari Nasrollah 
Published: February 2022

AbstractGold nanoparticles (GNPs) are materials that make the tumor cells more radiosensitive when irradiated with ionizing radiation. The present study aimed to evaluate the impact of different physical interaction models on the dose calculations and radiochemical results around the GNP. By applying the Geant4 Monte Carlo (MC) toolkit, a single 50-nm GNP was simulated, which was immersed in a water phantom and irradiated with 5, 50, and 150 MeV proton beams. The present work assessed various parameters including the secondary electron spectra, secondary photon spectra, radial dose distribution (RDD), dose enhancement factor (DEF), and radiochemical yields around the GNP. The results with an acceptable statistical uncertainty of less than 1% indicated that low-energy electrons deriving from the ionization process formed a significant part of the total number of secondary particles generated in the presence of GNP; the Penelope model produced a larger number of these electrons by a factor of about 30%. Discrepancies of the secondary electron spectrum between Livermore and Penelope were more obvious at energies of less than 1 keV and reached the factor of about 30% at energies between 250 eV and 1 keV. The RDDs for Livermore and Penelope models were very similar with small variations within the first 6 nm from NP surface by a factor of 10%. In addition, neither the G-value nor the REF was affected by the choice of physical interaction models with the same energy cut-off. This work illustrated the similarity of the Livermore and Penelope models (within 15%) available in Geant4 for future simulation studies of GNP enhanced proton therapy with physical, physicochemical, and chemical mechanisms.