bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunoglobulin light chain amyloidosis diagnosis and treatment algorithm 2018
Authors: Gertz Morie A. 
Published: May 2018

AbstractImmunoglobulin light chain amyloidosis (AL) should be considered in any patient that presents to a cancer care provider with nephrotic range proteinuria, heart failure with preserved ejection fraction, non-diabetic peripheral neuropathy, unexplained hepatomegaly or diarrhea. More importantly, patients being monitored for smoldering multiple myeloma and a monoclonal gammopathy of undetermined significance (MGUS) are at risk for developing AL amyloidosis. MGUS and myeloma patients that have atypical features, including unexplained weight loss; lower extremity edema, early satiety, and dyspnea on exertion should be considered at risk for light chain amyloidosis. Overlooking the diagnosis of light chain amyloidosis leading to therapy delay is common, and it represents an error of diagnostic consideration. Algorithms will be provided on how to evaluate patients with suspected AL amyloid as well as how to manage patients referred from other medical specialties with biopsy-proven amyloid. An organized stepwise approach to the treatment of patients with light chain amyloidosis, including established and investigational therapies, will be reviewed.
Long non-coding RNA Gm2199 rescues liver injury and promotes hepatocyte proliferation through the upregulation of ERK1/2
Authors: Gao Qiang , Gu Yunyan , Jiang Yanan , Fan Li , Wei Zixiang , Jin Haobin , Yang Xirui , Wang Lijuan , Li Xuguang , Tai Sheng , Yang Baofeng , Liu Yan 
Published: May 2018

AbstractLong non-coding RNAs (lncRNAs) are a new class of regulators of various human diseases. This study was designed to explore the potential role of lncRNAs in experimental hepatic damage. In vivo hepatic damage in mice and in vitro hepatocyte damage in AML12 and NCTC1469 cells were induced by carbon tetrachloride (CCl4) treatments. Expression profiles of lncRNAs and mRNAs were analyzed by microarray. Bioinformatics analyses were conducted to predict the potential functions of differentially expressed lncRNAs with respect to hepatic damage. Overexpression of lncRNA Gm2199 was achieved by transfection of the pEGFP-N1-Gm2199 plasmid in vitro and adeno-associated virus-Gm2199 in vivo. Cell proliferation and viability was detected by cell counting kit-8 and 5-ethynyl-2′-deoxyuridine assay. Protein and mRNA expressions of extracellular signal-regulated kinase-1/2 (ERK1/2) were detected by western blot and quantitative real-time reverse-transcription PCR (qRT-PCR). Microarray analysis identified 190 and 148 significantly differentially expressed lncRNAs and mRNAs, respectively. The analyses of lncRNA-mRNA co-expression and lncRNA-biological process networks unraveled potential roles of the differentially expressed lncRNAs including Gm2199 in the pathophysiological processes leading to hepatic damage. Gm2199 was downregulated in both damaged livers and hepatocyte lines. Overexpression of Gm2199 restored the reduced proliferation of damaged hepatocyte lines and increased the expression of ERK1/2. Overexpression of Gm2199 also promoted the proliferation and viability of normal hepatocyte lines and increased the level of p-ERK1/2. Overexpression of Gm2199 in vivo also protected mouse liver injury induced by CCl4, evidenced by more proliferating hepatocytes, less serum alanine aminotransferase, less serum aspartate aminotransferase, and decreased hepatic hydroxyproline. The ability of Gm2199 to maintain hepatic proliferation capacity indicates it as a novel anti-liver damage lncRNA.
Tamoxifen-induced knockdown of the mitochondrial calcium uniporter in Thy1-expressing neurons protects mice from hypoxic/ischemic brain injury
Authors: Nichols Matthew , Pavlov Evgeny V. , Robertson George S. 
Published: May 2018

AbstractThe mitochondrial calcium uniporter (MCU) mediates high-capacity mitochondrial calcium uptake that stimulates energy production. However, excessive MCU activity can cause ischemic heart injury. To examine if the MCU is also involved in hypoxic/ischemic (HI) brain injury, we have generated conditional MCU knockout mice by tamoxifen (TMX) administration to adult MCU-floxed (MCUfl/fl) mice expressing a construct encoding Thy1-cre/ERT2-eYFP. Relative to TMX/Thy1-cre/ERT2-eYFP controls, HI-induced sensorimotor deficits, forebrain neuron loss and mitochondrial damage were decreased for conditional MCU knockout mice. MCU knockdown by siRNA-induced silencing in cortical neuron cultures also reduced cell death and mitochondrial respiratory deficits following oxygen-glucose deprivation. Furthermore, MCU silencing did not produce metabolic abnormalities in cortical neurons observed previously for global MCU nulls that increased reliance on glycolysis for energy production. Based on these findings, we propose that brain-penetrant MCU inhibitors have strong potential to be well-tolerated and highly-efficacious neuroprotectants for the acute management of ischemic stroke.
The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses
Authors: Cao Yu , Chen Min , Tang Dehua , Yan Hongli , Ding Xiwei , Zhou Fan , Zhang Mingming , Xu Guifang , Zhang Weijie , Zhang Shu , Zhuge Yuzheng , Wang Lei , Zou Xiaoping 
Published: May 2018

AbstractProton pump inhibitors (PPIs) play a role in antitumor activity, with studies showing specialized impacts of PPIs on cancer cell apoptosis, metastasis, and autophagy. In this study, we demonstrated that pantoprazole (PPI) increased autophagosomes formation and affected autophagic flux depending on the pH conditions. PPI specifically elevated SQSTM1 protein levels by increasing SQSTM1 transcription via NFE2L2 activation independent of the specific effect of PPI on autophagic flux. Via decreasing proteasome subunits expression, PPI significantly impaired the function of the proteasome, accompanied by the accumulation of undegraded poly-ubiquitinated proteins. Notably, PPI-induced autophagy functioned as a downstream response of proteasome inhibition by PPI, while suppressing protein synthesis abrogated autophagy. Blocking autophagic flux in neutral pH condition or further impairing proteasome function with proteasome inhibitors, significantly aggravated PPI cytotoxicity by worsening protein degradation ability. Interestingly, under conditions of mitochondrial stress, PPI showed significant synergism when combined with Bcl-2 inhibitors. Taken together, these findings provide a new understanding of the impact of PPIs on cancer cells’ biological processes and highlight the potential to develop more efficient and effective combination therapies.
Long noncoding RNA gastric cancer-related lncRNA1 mediates gastric malignancy through miRNA-885-3p and cyclin-dependent kinase 4
Authors: Lin Zhijuan , Zhou Zhixia , Guo Hang , He Yuqi , Pang Xin , Zhang Xumei , Liu Ying , Ao Xiang , Li Peifeng , Wang Jianxun 
Published: May 2018

AbstractGastric cancer (GC) is one of the most common malignancy and the third leading cancer-related death in China. Long noncoding RNAs (lncRNAs) have been implicated in numerous tumors, including GC, however, the mechanism of many functional lncRNAs is still unclear. In this study, we identified the abundantly expressed lncRNA, RP11-290F20.3, in GC cells and patient tumor tissues. We named this lncRNA as GC-related lncRNA1 (GCRL1), which could regulate gastric cell proliferation and metastasis, both in vitro and in vivo. Mechanistically, miRNA-885-3p (miR-885-3p) could inhibit the cell proliferation and metastasis in GC by negatively regulating the expression of cyclin-dependent kinase 4 (CDK4) at the post-transcriptional level. Further, GCRL1 promoted the cell proliferation and metastasis by sponging miR-885-3p and hence, positively regulating CDK4 in GC cells. Taken together, our results demonstrate a novel regulatory axis of malignant cell proliferation and invasion in GC, comprising GCRL1, miR-885-3p, and CDK4, which may serve as a potential therapeutic target in GC.
Transcriptional and epigenetic modulation of autophagy promotes EBV oncoprotein EBNA3C induced B-cell survival
Authors: Bhattacharjee Shaoni , Bose Priyanka , Patel Krishna , Roy Shatadru Ghosh , Gain Chandrima , Gowda Harsha , Robertson Erle S. , Saha Abhik 
Published: May 2018

AbstractEpstein-Barr virus (EBV) oncoprotein EBNA3C is indispensable for primary B-cell transformation and maintenance of lymphoblastoid cells outgrowth. EBNA3C usurps two putative cellular pathways—cell-cycle and apoptosis, essentially through modulating ubiquitin-mediated protein-degradation or gene transcription. In cancer cells, these two pathways are interconnected with autophagy,—a survival-promoting catabolic network in which cytoplasmic material including mis/un-folded protein aggregates and damaged organelles along with intracellular pathogens are degraded and recycled in lysosomal compartments. Studies have shown that tumor viruses including EBV can manipulate autophagy as a survival strategy. Here, we demonstrate that EBNA3C elevates autophagy, which serves as a prerequisite for apoptotic inhibition and maintenance of cell growth. Using PCR based micro-array we show that EBNA3C globally accelerates autophagy gene transcription under growth limiting conditions. Reanalyzing the ENCODE ChIP-sequencing data (GSE52632 and GSE26386) followed by ChIP-PCR demonstrate that EBNA3C recruits several histone activation epigenetic marks (H3K4me1, H3K4me3, H3K9ac, and H3K27ac) for transcriptional activation of autophagy genes, notably ATG3, ATG5, and ATG7 responsible for autophagosome formation. Moreover, under growth limiting conditions EBNA3C further stimulates the autophagic response through upregulation of a number of tumor suppressor genes, notably cyclin-dependent kinase inhibitors—CDKN1B (p27Kip1) and CDKN2A (p16INK4a) and autophagy mediated cell-death modulators—DRAM1 and DAPK1. Together our data highlight a new role of an essential EBV oncoprotein in regulating autophagy cascade as a survival mechanism and offer novel-targets for potential therapeutic expansion against EBV induced B-cell lymphomas.
Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells
Authors: Winge Sofia Boeg , Dalgaard Marlene Danner , Belling Kirstine G , Jensen Jacob Malte , Nielsen John Erik , Aksglaede Lise , Schierup Mikkel Heide , Brunak Søren , Skakkebæk Niels Erik , Juul Anders , Rajpert-De Meyts Ewa , Almstrup Kristian 
Published: May 2018

AbstractThe most common human sex chromosomal disorder is Klinefelter syndrome (KS; 47,XXY). Adult patients with KS display a diverse phenotype but are nearly always infertile, due to testicular degeneration at puberty. To identify mechanisms causing the selective destruction of the seminiferous epithelium, we performed RNA-sequencing of 24 fixed paraffin-embedded testicular tissue samples. Analysis of informative transcriptomes revealed 235 differentially expressed transcripts (DETs) in the adult KS testis showing enrichment of long non-coding RNAs, but surprisingly not of X-chromosomal transcripts. Comparison to 46,XY samples with complete spermatogenesis and Sertoli cell-only-syndrome allowed prediction of the cellular origin of 71 of the DETs. DACH2 and FAM9A were validated by immunohistochemistry and found to mark apparently undifferentiated somatic cell populations in the KS testes. Moreover, transcriptomes from fetal, pre-pubertal, and adult KS testes showed a limited overlap, indicating that different mechanisms are likely to operate at each developmental stage. Based on our data, we propose that testicular degeneration in men with KS is a consequence of germ cells loss initiated during early development in combination with disturbed maturation of Sertoli- and Leydig cells.
Carnitine palmitoyltransferase gene upregulation by linoleic acid induces CD4+ T cell apoptosis promoting HCC development
Authors: Brown Zachary J. , Fu Qiong , Ma Chi , Kruhlak Michael , Zhang Haibo , Luo Ji , Heinrich Bernd , Yu Su Jong , Zhang Qianfei , Wilson Andrew , Shi Zhen-Dan , Swenson Rolf , Greten Tim F. 
Published: May 2018

AbstractHepatocellular carcinoma (HCC) is a common cause of cancer-related death worldwide. As obesity and diabetes become more prevalent, the contribution of non-alcoholic fatty liver disease (NAFLD) to HCC is rising. Recently, we reported intrahepatic CD4+ T cells are critical for anti-tumor surveillance in NAFLD. Lipid accumulation in the liver is the hallmark of NAFLD, which may perturb T cell function. We sought to investigate how the lipid-rich liver environment influences CD4+ T cells by focusing on carnitine palmitoyltransferase (CPT) family members, which control the mitochondrial β-oxidation of fatty acids and act as key molecules in lipid catabolism. Linoleic acid (C18:2) co-localized within the mitochondria along with a corresponding increase in CPT gene upregulation. This CPT upregulation can be recapitulated by feeding mice with a high-C18:2 diet or the NAFLD promoting methionine-choline-deficient (MCD) diet. Using an agonist and antagonist, the induction of CPT genes was found to be mediated by peroxisome proliferator-activated receptor alpha (PPAR-α). CPT gene upregulation increased mitochondrial reactive oxygen species (ROS) and led to cell apoptosis. In vivo, using liver-specific inducible MYC transgenic mice fed MCD diet, blocking CPT with the pharmacological inhibitor perhexiline decreased apoptosis of intrahepatic CD4+ T cells and inhibited HCC tumor formation. These results provide useful information for potentially targeting the CPT family to rescue intrahepatic CD4+ T cells and to aid immunotherapy for NAFLD-promoted HCC.
Cordycepin induces apoptosis of human ovarian cancer cells by inhibiting CCL5-mediated Akt/NF-κB signaling pathway
Authors: Cui Zhen Yang , Park Soo Jung , Jo Eunbi , Hwang In-Hu , Lee Kyung-Bok , Kim Sung-Woo , Kim Dae Joon , Joo Jong Chun , Hong Seok Hoon , Lee Min-Goo , Jang Ik-Soon 
Published: May 2018

AbstractThe chemokine, CCL5, is a key mediator for the recruitment of immune cells into tumors and tissues. Akt/NF-κB signaling is significantly activated by CCL5. However, the role of NF-κB inactivation in apoptosis induced by negative regulation of CCL5 remains unclear. Here, we analyzed the effect of cordycepin on NF-κB activity in SKOV-3 cells and found that cordycepin-mediated inhibition of NF-κB signaling induced apoptosis in SKOV-3 cells via the serial activation of caspases. In addition, immune-blotting analysis showed that CCL5 is highly expressed in SKOV-3 cells. In addition to activating caspases, we show that, cordycepin prevents TNF-α-induced increase in CCL5, Akt, NF-κB, and c-FLIPL activation and that CCL5 siRNA could inhibit Akt/NF-κB signaling. Moreover, cordycepin negatively regulated the TNF-α-mediated IκB/NF-κB pathway and c-FLIPL activation to promote JNK phosphorylation, resulting in caspase-3 activation and apoptosis. Also, we show that c-FLIPL is rapidly lost in NF-κB activation-deficient. siRNA mediated c-FLIP inhibition increased JNK. SP600125, a selective JNK inhibitor, downregulated p-JNK expression in cordycepin-treated SKOV-3 cells, leading to suppression of cordycepin-induced apoptosis. Thus, these results indicate that cordycepin inhibits CCL5-mediated Akt/NF-κB signaling, which upregulates caspase-3 activation in SKOV-3 cells, supporting the potential of cordycepin as a therapeutic agent for ovarian cancer.
Lipid analysis of Eimeria sporozoites reveals exclusive phospholipids, a phylogenetic mosaic of endogenous synthesis, and a host-independent lifestyle
Authors: Kong Pengfei , Lehmann Maik J. , Helms J. Bernd , Brouwers Jos F. , Gupta Nishith 
Published: May 2018

AbstractSuccessful inter-host transmission of most apicomplexan parasites requires the formation of infective sporozoites within the oocysts. Unlike all other infective stages that are strictly intracellular and depend on host resources, the sporozoite stage develops outside the host cells, but little is known about its self-governing metabolism. This study deployed Eimeria falciformis, a parasite infecting the mouse as its natural host, to investigate the process of phospholipid biogenesis in sporozoites. Lipidomic analyses demonstrated the occurrence of prototypical phospholipids along with abundant expression of at least two exclusive lipids, phosphatidylthreonine (PtdThr) and inositol phosphorylceramide with a phytosphingosine backbone, in sporozoites. To produce them de novo, the parasite harbors nearly the entire biogenesis network, which is an evolutionary mosaic of eukaryotic-type and prokaryotic-type enzymes. Notably, many have no phylogenetic counterpart or functional equivalent in the mammalian host. Using Toxoplasma gondii as a gene-tractable surrogate to examine Eimeria enzymes, we show a highly compartmentalized network of lipid synthesis spread primarily in the apicoplast, endoplasmic reticulum, mitochondrion, and Golgi complex. Likewise, trans-genera complementation of a Toxoplasma mutant with the PtdThr synthase from Eimeria reveals a convergent role of PtdThr in fostering the lytic cycle of coccidian parasites. Taken together, our work establishes a model of autonomous membrane biogenesis involving significant inter-organelle cooperation and lipid trafficking in sporozoites. Phylogenetic divergence of certain pathways offers attractive drug targets to block the sporulation and subsequent transmission. Not least, our results vindicate the possession of an entire de novo lipid synthesis network in a representative protist adapted to an obligate intracellular parasitic lifestyle.
The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity
Authors: Bricambert Julien , Alves-Guerra Marie-Clotilde , Esteves Pauline , Prip-Buus Carina , Bertrand-Michel Justine , Guillou Hervé , Chang Christopher J. , Vander Wal Mark N. , Canonne-Hergaux François , Mathurin Philippe , Raverdy Violeta , Pattou François , Girard Jean , Postic Catherine , Dentin Renaud 
Published: May 2018

AbstractAberrant histone methylation profile is reported to correlate with the development and progression of NAFLD during obesity. However, the identification of specific epigenetic modifiers involved in this process remains poorly understood. Here, we identify the histone demethylase Plant Homeodomain Finger 2 (Phf2) as a new transcriptional co-activator of the transcription factor Carbohydrate Responsive Element Binding Protein (ChREBP). By specifically erasing H3K9me2 methyl-marks on the promoter of ChREBP-regulated genes, Phf2 facilitates incorporation of metabolic precursors into mono-unsaturated fatty acids, leading to hepatosteatosis development in the absence of inflammation and insulin resistance. Moreover, the Phf2-mediated activation of the transcription factor NF-E2-related factor 2 (Nrf2) further reroutes glucose fluxes toward the pentose phosphate pathway and glutathione biosynthesis, protecting the liver from oxidative stress and fibrogenesis in response to diet-induced obesity. Overall, our findings establish a downstream epigenetic checkpoint, whereby Phf2, through facilitating H3K9me2 demethylation at specific gene promoters, protects liver from the pathogenesis progression of NAFLD.
Inharmonic speech reveals the role of harmonicity in the cocktail party problem
Authors: Popham Sara , Boebinger Dana , Ellis Dan P. W. , Kawahara Hideki , McDermott Josh H. 
Published: May 2018

AbstractThe “cocktail party problem” requires us to discern individual sound sources from mixtures of sources. The brain must use knowledge of natural sound regularities for this purpose. One much-discussed regularity is the tendency for frequencies to be harmonically related (integer multiples of a fundamental frequency). To test the role of harmonicity in real-world sound segregation, we developed speech analysis/synthesis tools to perturb the carrier frequencies of speech, disrupting harmonic frequency relations while maintaining the spectrotemporal envelope that determines phonemic content. We find that violations of harmonicity cause individual frequencies of speech to segregate from each other, impair the intelligibility of concurrent utterances despite leaving intelligibility of single utterances intact, and cause listeners to lose track of target talkers. However, additional segregation deficits result from replacing harmonic frequencies with noise (simulating whispering), suggesting additional grouping cues enabled by voiced speech excitation. Our results demonstrate acoustic grouping cues in real-world sound segregation.
Asymmetric transfer of CO2 across a broken sea surface
Authors: Leighton Timothy G. , Coles David G. H. , Srokosz Meric , White Paul R. , Woolf David K. 
Published: May 2018

AbstractMost estimates of the climatically-important transfer of atmospheric gases into, and out of, the ocean assume that the ocean surface is unbroken by breaking waves. However the trapping of bubbles of atmospheric gases in the ocean by breaking waves introduces an asymmetry in this flux. This asymmetry occurs as a bias towards injecting gas into the ocean where it dissolves, and against the evasion/exsolution of previously-dissolved gas coming out of solution from the oceans and eventually reaching the atmosphere. Here we use at-sea measurements and modelling of the bubble clouds beneath the ocean surface to show that the numbers of large bubbles found metres below the sea surface in high winds are sufficient to drive a large and asymmetric flux of carbon dioxide. Our results imply a much larger asymmetry for carbon dioxide than previously proposed. This asymmetry contradicts an assumption inherent in most existing estimates of ocean-atmosphere gas transfer. The geochemical and climate implications include an enhanced invasion of carbon dioxide into the stormy temperate and polar seas.
Exciton Relaxation Cascade in two-dimensional Transition Metal Dichalcogenides
Authors: Brem Samuel , Selig Malte , Berghaeuser Gunnar , Malic Ermin 
Published: May 2018

AbstractMonolayers of transition metal dichalcogenides (TMDs) are characterized by an extraordinarily strong Coulomb interaction giving rise to tightly bound excitons with binding energies of hundreds of meV. Excitons dominate the optical response as well as the ultrafast dynamics in TMDs. As a result, a microscopic understanding of exciton dynamics is the key for a technological application of these materials. In spite of this immense importance, elementary processes guiding the formation and relaxation of excitons after optical excitation of an electron-hole plasma has remained unexplored to a large extent. Here, we provide a fully quantum mechanical description of momentum- and energy-resolved exciton dynamics in monolayer molybdenum diselenide (MoSe2) including optical excitation, formation of excitons, radiative recombination as well as phonon-induced cascade-like relaxation down to the excitonic ground state. Based on the gained insights, we reveal experimentally measurable features in pump-probe spectra providing evidence for the exciton relaxation cascade.