bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting eIF4F translation initiation complex with SBI-756 sensitises B lymphoma cells to venetoclax
Authors: Herzog Lee-or , Walters Beth , Buono Roberta , Lee J. Scott , Mallya Sharmila , Fung Amos , Chiu Honyin , Nguyen Nancy , Li Boyang , Pinkerton Anthony B. , Jackson Michael R. , Schneider Robert J. , Ronai Ze’ev A. , Fruman David A. 
Published: December 2020

Abstract
Background
The BCL2 inhibitor venetoclax has shown efficacy in several hematologic malignancies, with the greatest response rates in indolent blood cancers such as chronic lymphocytic leukaemia. There is a lower response rate to venetoclax monotherapy in diffuse large B-cell lymphoma (DLBCL).

Methods
We tested inhibitors of cap-dependent mRNA translation for the ability to sensitise DLBCL and mantle cell lymphoma (MCL) cells to apoptosis by venetoclax. We compared the mTOR kinase inhibitor (TOR-KI) MLN0128 with SBI-756, a compound targeting eukaryotic translation initiation factor 4G1 (eIF4G1), a scaffolding protein in the eIF4F complex.

Results
Treatment of DLBCL and MCL cells with SBI-756 synergised with venetoclax to induce apoptosis in vitro, and enhanced venetoclax efficacy in vivo. SBI-756 prevented eIF4E-eIF4G1 association and cap-dependent translation without affecting mTOR substrate phosphorylation. In TOR-KI-resistant DLBCL cells lacking eIF4E binding protein-1, SBI-756 still sensitised to venetoclax. SBI-756 selectively reduced translation of mRNAs encoding ribosomal proteins and translation factors, leading to a reduction in protein synthesis rates in sensitive cells. When normal lymphocytes were treated with SBI-756, only B cells had reduced viability, and this correlated with reduced protein synthesis.

Conclusions
Our data highlight a novel combination for treatment of aggressive lymphomas, and establishes its efficacy and selectivity using preclinical models.
An autoregulatory feedback loop of miR-21/VMP1 is responsible for the abnormal expression of miR-21 in colorectal cancer cells
Authors: Wang Caixia , Peng Rui , Zeng Min , Zhang Zhenhua , Liu Shengpeng , Jiang Dan , Lu Yuanyuan , Zou Fangdong 
Published: December 2020

AbstractMircoRNA-21 (miR-21) was found to be highly expressed in various solid tumors, and its oncogenic properties have been extensively studied in recent years. However, the reason why miR-21 is highly expressed in various tumors remains elusive. Here, we found that the expression of miR-21 was negatively correlated with the expression of vacuole membrane protein-1 (VMP1) in colorectal cancer. Transcription of VMP1 activated either by small activating RNA (saRNA) or transcriptional activator GLI3 inhibited miR-21 expression through reducing its transcripts of VMP1-miR-21 and pri-miR-21, while no significant change in miR-21 expression after exogenous overexpression VMP1 in colorectal cancer cell HCT116. Considering the overlapping location of VMP1 and miR-21 gene in genome, the result suggested that the transcription of miR-21 was inhibited by the endogenous transcriptional activation of VMP1. Furthermore, we identified that miR-21 inhibited the activation and nuclear translocation of transcription factor EB (TFEB) through reducing the inhibitory of PTEN on AKT phosphorylation, which can directly activate the transcription of VMP1. Loss of miR-21 significantly increased VMP1 expression, which could be blocked by PTEN inhibitor (VO-Ohpic) or TFEB siRNA. These results showed that miR-21 negatively regulated VMP1 transcription through the PTEN/AKT/TFEB pathway, and TFEB-induced transcriptional activation of VMP1 could inhibit miR-21 expression, thus forming a feedback regulatory loop of miR-21/VMP1. We further found that disrupting the miR-21/VMP1 feedback loop will decrease the expression of miR-21, reduce the malignancy, and increase their sensitivity to 5-fluorouracil in colorectal cancer cells. Taken together, our results revealed a novel regulatory mechanism of miR-21 expression, and targeting the miR-21/VMP1 feedback loop may provide a new approach to inhibit miR-21 expression in colorectal cancer cells.
Biochemical phenotyping of multiple myeloma patients at diagnosis reveals a disorder of mitochondrial complexes I and II and a Hartnup-like disturbance as underlying conditions, also influencing different stages of the disease
Authors: da Silva Ismael Dale Cotrim Guerreiro , de Castro Levatti Erica Valadares , Pedroso Amanda Paula , Marchioni Dirce Maria Lobo , Carioca Antonio Augusto Ferreira , Colleoni Gisele Wally Braga 
Published: December 2020

AbstractThe aim of this study was to identify novel plasma metabolic signatures with possible relevance during multiple myeloma (MM) development and progression. A biochemical quantitative phenotyping platform based on targeted electrospray ionization tandem mass spectrometry technology was used to aid in the identification of any eventual perturbed biochemical pathway in peripheral blood plasma from 36 MM patients and 73 healthy controls. Our results showed that MM cases present an increase in short and medium/long-chain species of acylcarnitines resembling Multiple AcylCoA Dehydrogenase Deficiency (MADD), particularly, associated with MM advanced International Staging System (ISS). Lipids profile showed lower concentrations of phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and sphingomyelins (SM) in the MM patients and its respective ISS groups. MM cases were accompanied by a drop in the concentration of essential amino acids, especially tryptophan, with a significant inverse correlation between the progressive drop in tryptophan with the elevation of β2-microglobulin, with the increase in systemic methylation levels (Symmetric Arginine Dimethylation, SDMA) and with the accumulation of esterified carnitines in relation to free carnitine (AcylC/C0). Serotonin was significantly elevated in cases of MM, without a clear association with ISS. Kynurenine/tryptophan ratio demonstrates that the activity of dioxigenases is even higher in the cases classified as ISS 3. In conclusion, our study showed that MM patients at diagnosis showed metabolic disorders resembling both mitochondrial complexes I and II and Hartnup-like disturbances as underlying conditions, also influencing different stages of the disease.
MZB1 enables efficient interferon α secretion in stimulated plasmacytoid dendritic cells
Authors: Kapoor Tanya , Corrado Mauro , Pearce Erika L. , Pearce Edward J. , Grosschedl Rudolf 
Published: December 2020

AbstractMZB1 is an endoplasmic reticulum (ER)-resident protein that plays an important role in the humoral immune response by enhancing the interaction of the μ immunoglobulin (Ig) heavy chain with the chaperone GRP94 and by augmenting the secretion of IgM. Here, we show that MZB1 is also expressed in plasmacytoid dendritic cells (pDCs). Mzb1−/− pDCs have a defect in the secretion of interferon (IFN) α upon Toll-like receptor (TLR) 9 stimulation and a reduced ability to enhance B cell differentiation towards plasma cells. Mzb1−/− pDCs do not properly expand the ER upon TLR9 stimulation, which may be accounted for by an impaired activation of ATF6, a regulator of the unfolded protein response (UPR). Pharmacological inhibition of ATF6 cleavage in stimulated wild type pDCs mimics the diminished IFNα secretion by Mzb1−/− pDCs. Thus, MZB1 enables pDCs to secrete high amounts of IFNα by mitigating ER stress via the ATF6-mediated UPR.
Minimal system for assembly of SARS-CoV-2 virus like particles
Authors: Swann Heather , Sharma Abhimanyu , Preece Benjamin , Peterson Abby , Eldredge Crystal , Belnap David M. , Vershinin Michael , Saffarian Saveez 
Published: December 2020

AbstractSARS-CoV-2 virus is the causative agent of COVID-19. Here we demonstrate that non-infectious SARS-CoV-2 virus like particles (VLPs) can be assembled by co-expressing the viral proteins S, M and E in mammalian cells. The assembled SARS-CoV-2 VLPs possess S protein spikes on particle exterior, making them ideal for vaccine development. The particles range in shape from spherical to elongated with a characteristic size of 129 ± 32 nm. We further show that SARS-CoV-2 VLPs dried in ambient conditions can retain their structural integrity upon repeated scans with Atomic Force Microscopy up to a peak force of 1 nN.
Using functional connectivity changes associated with cognitive fatigue to delineate a fatigue network
Authors: Wylie G. R. , Yao B. , Genova H. M. , Chen M. H. , DeLuca J. 
Published: December 2020

AbstractCognitive fatigue, or fatigue related to mental work, is a common experience. A growing body of work using functional neuroimaging has identified several regions that appear to be related to cognitive fatigue and that potentially comprise a “fatigue network”. These include the striatum of the basal ganglia, the dorsolateral prefrontal cortex (DLPFC), the dorsal anterior cingulate cortex (dACC), the ventro-medial prefrontal cortex (vmPFC) and the anterior insula. However, no work has been conducted to assess whether the connectivity between these regions changes as a function of cognitive fatigue. We used a task-based functional neuroimaging paradigm to induce fatigue in 39 healthy individuals, regressed the signal associated with the task out of the data, and investigated how the functional connectivity between these regions changed as cognitive fatigue increased. We observed functional connectivity between these regions and other frontal regions largely decreased as cognitive fatigue increased while connectivity between these seeds and more posterior regions increased. Furthermore the striatum, the DLPFC, the insula and the vmPFC appeared to be central ‘nodes’ or hubs of the fatigue network. These findings represent the first demonstration that the functional connectivity between these areas changes as a function of cognitive fatigue.
Yeast cell wall mannan rich fraction modulates bacterial cellular respiration potentiating antibiotic efficacy
Authors: Smith Helen , Grant Sharon , Parker Joanne , Murphy Richard 
Published: December 2020

AbstractNow more than ever there is a demand to understand the mechanisms surrounding antibiotic resistance and look for alternative ways to impact phenotypic antibiotic outcome. Cellular energetics can be impacted by many bacteriostatic and bactericidal antibiotics, which affect metabolism and energy output, resulting in a reduction of cell growth or induction of cell death respectively. In this study, we provide evidence that a mannan rich fraction (MRF) from the cell wall of Saccharomyces cerevisiae modulates growth of antibiotic susceptible and resistant Escherichia coli and potentiates bactericidal antibiotic efficiency through modulation of bacterial cellular respiration. The role of MRF in modulating bactericidal impact and cellular metabolic state were assessed in E. coli by monitoring microbial growth and by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using the Seahorse XFe96 Analyser, respectively. This work further illustrates the link between bacterial susceptibility to antibiotics (phenotypic resistance) and resistance through modulation of bacterial metabolism. This is the first example of yeast MRF enabling collateral sensitivity to antibiotics in vitro and supports the search for alternative strategies to promote animal health without contributing to the growing issue of antimicrobial resistance.
Intracellular role of IL-6 in mesenchymal stromal cell immunosuppression and proliferation
Authors: Dorronsoro Akaitz , Lang Valérie , Ferrin Izaskun , Fernández-Rueda Jon , Zabaleta Lorea , Pérez-Ruiz Estibaliz , Sepúlveda Pilar , Trigueros César 
Published: December 2020

AbstractInterleukin (IL)-6 is a pleiotropic cytokine involved in the regulation of hematological and immune responses. IL-6 is secreted chiefly by stromal cells, but little is known about its precise role in the homeostasis of human mesenchymal stromal cells (hMSCs) and the role it may play in hMSC-mediated immunoregulation. We studied the role of IL-6 in the biology of bone marrow derived hMSC in vitro by silencing its expression using short hairpin RNA targeting. Our results show that IL-6 is involved in immunosuppression triggered by hMSCs. Cells silenced for IL-6 showed a reduced capacity to suppress activated T-cell proliferation. Moreover, silencing of IL-6 significantly blocked the capacity of hMSCs to proliferate. Notably, increasing the intracellular level of IL-6 but not recovering the extracellular level could restore the proliferative impairment observed in IL-6-silenced hMSC. Our data indicate that IL-6 signals in hMSCs by a previously undescribed intracellular mechanism.
Betaine inhibits Toll-like receptor 4 responses and restores intestinal microbiota in acute liver failure mice
Authors: Chen Qian , Wang Yao , Jiao Fangzhou , Shi Chunxia , Pei Maohua , Wang Luwen , Gong Zuojiong 
Published: December 2020

AbstractPrevious research has revealed that the gut microbiome has a marked impact on acute liver failure (ALF). Here, we evaluated the impact of betaine on the gut microbiota composition in an ALF animal model. The potential protective effect of betaine by regulating Toll-like receptor 4 (TLR4) responses was explored as well. Both mouse and cell experiments included normal, model, and betaine groups. The rat small intestinal cell line IEC-18 was used for in vitro experiments. Betaine ameliorated the small intestine tissue and IEC-18 cell damage in the model group by reducing the high expression of TLR4 and MyD88. Furthermore, the intestinal permeability in the model group was improved by enhancing the expression of the (ZO)-1 and occludin tight junction proteins. There were 509 operational taxonomic units (OTUs) that were identified in mouse fecal samples, including 156 core microbiome taxa. Betaine significantly improved the microbial communities, depleted the gut microbiota constituents Coriobacteriaceae, Lachnospiraceae, Enterorhabdus and Coriobacteriales and markedly enriched the taxa Bacteroidaceae, Bacteroides, Parabacteroides and Prevotella in the model group. Betaine effectively improved intestinal injury in ALF by inhibiting the TLR4/MyD88 signaling pathway, improving the intestinal mucosal barrier and maintaining the gut microbiota composition.
Gas hydrate versus seabed morphology offshore Lebu (Chilean margin)
Authors: Vargas-Cordero Iván , Tinivella Umberta , Villar-Muñoz Lucía , Bento Joaquim P. , Cárcamo Carolina , López-Acevedo Diego , Fernandoy Francisco , Rivero Alessandra , Juan Marion San 
Published: December 2020

AbstractGas-hydrate occurrences along the Chilean margin have been widely documented, but the processes associated with fluid escapes caused by the dissociation of gas hydrates are still unknown. We report a seabed morphology growth related to fluid migration offshore Lebu associated with mud cones by analysing oxygen and deuterium stable water isotopes in pore water, bathymetric, biological and sedimentological data. A relief was observed at − 127 m water depth with five peaks. Enrichment values of δ18O (0.0–1.8‰) and δD (0.0–5.6‰) evidenced past hydrate melting. The orientation of the relief could be associated with faults and fractures, which constitute pathways for fluid migration. The benthic foraminifera observed can be associated with cold seep areas. We model that the mud cones correspond to mud growing processes related to past gas-hydrate dissociation. The integration of (i) the seismic data analysis performed in the surrounding area, (ii) the orientation of our studied relief, (iii) the infaunal foraminifera observed, (iv) the grain size and (v) the total organic matter and isotope values revealed that this area was formerly characterised by the presence of gas hydrates. Hence, this part of the Chilean margin represents a suitable area for investigating fluid-migration processes.
Samul-tang ameliorates oocyte damage due to cyclophosphamide-induced chronic ovarian dysfunction in mice
Authors: Kim Jihyun , You Sooseong 
Published: December 2020

AbstractSamul-tang (SM), a traditional herbal medicine, has been used to treat menstrual irregularities and infertility in women. However, the cellular and molecular mechanisms underlying the effects of SM remain elusive. We investigated the potential protective effect of SM against chronic ovarian dysfunction and used bioinformatics analysis to identify its underlying mechanism in a mouse model of cyclophosphamide (CP)-induced diminished ovarian reserve. Female C57BL/6 mice were intraperitoneally injected with CP three times a week, followed by oral administration of distilled water (CP group) or SM (CP + SM group) for 4 weeks. Four weeks later, the effect of SM was assessed by ovarian tissue histological analysis, steroid hormone measurement, oocyte quality, and mRNA and microRNA microarray analysis in the ovaries. Although SM administration did not prevent CP-induced follicle loss in mice, the quality of oocytes was better in CP + SM mice than in CP mice. Gene expression analysis revealed that the expression of fertilisation- and ovarian follicle development-related genes was altered by CP treatment but normalized after SM administration. Further bioinformatics analysis showed possible interactions between differentially expressed mRNAs and microRNAs. Therefore, we demonstrated the protective effects of SM on ovarian function and oocyte maturation against CP-induced damage via multiple epigenetic mechanisms.
A negative binomial regression model for risk estimation of 0–2 axillary lymph node metastases in breast cancer patients
Authors: Zeng De , Lin Hao-Yu , Zhang Yu-Ling , Wu Jun-Dong , Lin Kun , Xu Ya , Chen Chun-Fa 
Published: December 2020

AbstractExtensive clinical trials indicate that patients with negative sentinel lymph node biopsy do not need axillary lymph node dissection (ALND). However, the ACOSOG Z0011 trial indicates that patients with clinically negative axillary lymph nodes (ALNs) and 1–2 positive sentinel lymph nodes having breast conserving surgery with whole breast radiotherapy do not benefit from ALND. The aim of this study is therefore to identify those patients with 0–2 positive nodes who might avoid ALND. A total of 486 patients were eligible for the study with 212 patients in the modeling group and 274 patients in the validation group, respectively. Clinical lymph node status, histologic grade, estrogen receptor status, and human epidermal growth factor receptor 2 status were found to be significantly associated with ALN metastasis. A negative binomial regression (NBR) model was developed to predict the probability of having 0–2 ALN metastases with the area under the curve of 0.881 (95% confidence interval 0.829–0.921, P < 0.001) in the modeling group and 0.758 (95% confidence interval 0.702–0.807, P < 0.001) in the validation group. Decision curve analysis demonstrated that the model was clinically useful. The NBR model demonstrated adequate discriminative ability and clinical utility for predicting 0–2 ALN metastases.
Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity
Authors: Jin Ling , Kim Eun-Yeong , Chung Tae-Wook , Han Chang Woo , Park So Young , Han Jung Ho , Bae Sung-Jin , Lee Jong Rok , Kim Young Woo , Jang Se Bok , Ha Ki-Tae 
Published: December 2020

AbstractMost cancer cells primarily produce their energy through a high rate of glycolysis followed by lactic acid fermentation even in the presence of abundant oxygen. Pyruvate dehydrogenase kinase (PDK) 1, an enzyme responsible for aerobic glycolysis via phosphorylating and inactivating pyruvate dehydrogenase (PDH) complex, is commonly overexpressed in tumors and recognized as a therapeutic target in colorectal cancer. Hemistepsin A (HsA) is a sesquiterpene lactone isolated from Hemistepta lyrata Bunge (Compositae). Here, we report that HsA is a PDK1 inhibitor can reduce the growth of colorectal cancer and consequent activation of mitochondrial ROS-dependent apoptotic pathway both in vivo and in vitro. Computational simulation and biochemical assays showed that HsA directly binds to the lipoamide-binding site of PDK1, and subsequently inhibits the interaction of PDK1 with the E2 subunit of PDH complex. As a result of PDK1 inhibition, lactate production was decreased, but oxygen consumption was increased. Mitochondrial ROS levels and mitochondrial damage were also increased. Consistent with these observations, the apoptosis of colorectal cancer cells was promoted by HsA with enhanced activation of caspase-3 and -9. These results suggested that HsA might be a potential candidate for developing a novel anti-cancer drug through suppressing cancer metabolism.
Logistic regression analysis of environmental and other variables and incidences of tuberculosis in respiratory patients
Authors: Pathak Ashutosh K. , Sharma Mukesh , Katiyar Subodh K. , Katiyar Sandeep , Nagar Pavan K. 
Published: December 2020

AbstractThe objective of this study was to examine the association of 14 variables with TB in respiratory patients. The variables included: urban/rural, persons in 1200 sqft area, TB in family, crowding, smoking (family member), gender, age, education, smoking, workplace, kitchen location, cooking fuel, ventilation, and kerosene uses. Eight hundred respiratory patients were tested for sputum positive pulmonary TB; 500 had TB and 300 did not. An analysis of the unadjusted odds ratio (UOR) and adjusted OR (AOR) was undertaken using logistic regression to link the probability of TB incidences with the variables. There was an inconsistency in the significance of variables using UOR and AOR. A subset model of 4 variables (kerosene uses, ventilation, workplace, and gender) based on significant AOR was adjudged acceptable for estimating the probability of TB incidences. Uses of kerosene (AOR 2.62 (1.95, 3.54)) consistently related to incidences of TB. It was estimated that 50% reduction in kerosene uses could reduce the probability of TB by 13.29% in respiratory patients. The major recommendation was to replace kerosene uses from households with a supply of clean fuel like liquid petroleum or natural gas and rural electrification.
Functional and computational identification of a rescue mutation near the active site of an mRNA methyltransferase
Authors: Colin Pierre-Yves , Dalby Paul A. 
Published: December 2020

AbstractRNA-based drugs are an emerging class of therapeutics combining the immense potential of DNA gene-therapy with the absence of genome integration-associated risks. While the synthesis of such molecules is feasible, large scale in vitro production of humanised mRNA remains a biochemical and economical challenge. Human mRNAs possess two post-transcriptional modifications at their 5′ end: an inverted methylated guanosine and a unique 2′O-methylation on the ribose of the penultimate nucleotide. One strategy to precisely methylate the 2′ oxygen is to use viral mRNA methyltransferases that have evolved to escape the host’s cell immunity response following virus infection. However, these enzymes are ill-adapted to industrial processes and suffer from low turnovers. We have investigated the effects of homologous and orthologous active-site mutations on both stability and transferase activity, and identified new functional motifs in the interaction network surrounding the catalytic lysine. Our findings suggest that despite their low catalytic efficiency, the active-sites of viral mRNA methyltransferases have low mutational plasticity, while mutations in a defined third shell around the active site have strong effects on folding, stability and activity in the variant enzymes, mostly via network-mediated effects.