Παρασκευή, 1 Ιουλίου 2016

Plasmonic Heating in Au Nanowires at Low Temperatures: The Role of Thermal Boundary Resistance

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ACS Nano
DOI: 10.1021/acsnano.6b02911
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Biventricular metastatic invasion from cervical squamous cell carcinoma

Metastasis to the heart has been previously described with primary lung and breast carcinoma, lymphoma, leukaemia, mesothelioma and melanoma. However, left-ventricular cardiac metastasis from primary cervical squamous cell carcinoma is poorly described. This report describes the clinical presentation of a patient with cardiac metastatic invasion from cervical cancer.



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NASA’s Juno spacecraft gears up for a whirlwind tour of Jupiter

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On 4 July, the Juno probe must fire its thrusters to try to go into orbit around Jupiter, where it will spend around a year and a half exploring its mysteries

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Gut bacteria spotted eating brain chemicals for the first time

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The discovery of gut bacteria that need the calming chemical GABA to survive could explain why bacteria seem to influence our mood

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NASA’s Juno spacecraft gears up for a whirlwind tour of Jupiter

On 4 July, the Juno probe must fire its thrusters to try to go into orbit around Jupiter, where it will spend around a year and a half exploring its mysteries

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Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction

Abstract

Neurotoxicity is a common side effect of chemotherapy treatment, with unclear molecular mechanisms. Clinical studies suggest that the most frequent neurotoxic adverse events affect memory and learning, attention, concentration, processing speeds and executive function. Emerging preclinical research points toward direct cellular toxicity and induction of neuroinflammation as key drivers of neurotoxicity and subsequent cognitive impairment. Emerging data now show detectable levels of some chemotherapeutic agents within the CNS, indicating potential disruption of blood brain barrier integrity or transport mechanisms. Blood brain barrier disruption is a key aspect of many neurocognitive disorders, particularly those characterised by a proinflammatory state. Importantly, many proinflammatory mediators able to modulate the blood brain barrier are generated by tissues and organs that are targets for chemotherapy-associated toxicities. This review therefore aims to explore the hypothesis that peripherally-derived inflammatory cytokines disrupt blood brain barrier permeability, thereby increasing direct access of chemotherapeutic agents into the CNS to facilitate neuroinflammation and central neurotoxicity. This article is protected by copyright. All rights reserved.



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Smc5/6 Mediated Sumoylation of the Sgs1-Top3-Rmi1 Complex Promotes Removal of Recombination Intermediates

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Jaclyn N. Bonner, Koyi Choi, Xiaoyu Xue, Nikko P. Torres, Barnabas Szakal, Lei Wei, Bingbing Wan, Meret Arter, Joao Matos, Patrick Sung, Grant W. Brown, Dana Branzei, Xiaolan Zhao
Timely removal of DNA recombination intermediates is critical for genome stability. The DNA helicase-topoisomerase complex, Sgs1-Top3-Rmi1 (STR), is the major pathway for processing these intermediates to generate conservative products. However, the mechanisms that promote STR-mediated functions remain to be defined. Here we show that Sgs1 binds to poly-SUMO chains and associates with the Smc5/6 SUMO E3 complex in yeast. Moreover, these interactions contribute to the sumoylation of Sgs1, Top3, and Rmi1 upon the generation of recombination structures. We show that reduced STR sumoylation leads to accumulation of recombination structures, and impaired growth in conditions when these structures arise frequently, highlighting the importance of STR sumoylation. Mechanistically, sumoylation promotes STR inter-subunit interactions and accumulation at DNA repair centers. These findings expand the roles of sumoylation and Smc5/6 in genome maintenance by demonstrating that they foster STR functions in the removal of recombination intermediates.

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Teaser

Bonner et al. show that the Smc5/6 SUMO ligase complex interacts with and promotes the sumoylation of the DNA helicase Sgs1 and its partner proteins Top3 and Rmi1. Sgs1-Top3-Rmi1 (STR) sumoylation fosters the removal of recombination intermediates, in part by stimulating STR inter-subunit interaction and STR accumulation at DNA repair centers.


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NKp80 Defines a Critical Step during Human Natural Killer Cell Development

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Aharon G. Freud, Karen A. Keller, Steven D. Scoville, Bethany L. Mundy-Bosse, Stephanie Cheng, Youssef Youssef, Tiffany Hughes, Xiaoli Zhang, Xiaokui Mo, Pierluigi Porcu, Robert A. Baiocchi, Jianhua Yu, William E. Carson, Michael A. Caligiuri
Human natural killer (NK) cells develop in secondary lymphoid tissues (SLTs) through distinct stages. We identified two SLT lineage (Lin)CD34CD117+/−CD94+CD16 “stage 4” subsets according to expression of the C-type lectin-like surface-activating receptor, NKp80: NKp80 (stage “4a”) and NKp80+ (stage “4b”). Whereas stage 4b cells expressed more of the transcription factors T-BET and EOMES, produced interferon-gamma, and were cytotoxic, stage 4a cells expressed more of the transcription factors RORγt and AHR and produced interleukin-22, similar to SLT LinCD34CD117+CD94CD16 “stage 3” cells, whose phenotype overlaps with that of group 3 innate lymphoid cells (ILC3s). Co-culture with dendritic cells or transplantation into immunodeficient mice produced mature NK cells from stage 3 and stage 4a populations. These data identify NKp80 as a marker of NK cell maturity in SLTs and support a model of human NK cell development through a stage 4a intermediate with ILC3-associated features.

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Human natural killer (NK) cells have potent effector functions against cancer; how NK cells develop in humans is unclear. Freud et al. demonstrate that NKp80 expression marks functionally mature NK cells as they develop in secondary lymphoid tissues. These findings help define the pathway of human NK cell development.


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Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Xavier S. Revelo, Magar Ghazarian, Melissa Hui Yen Chng, Helen Luck, Justin H. Kim, Kejing Zeng, Sally Y. Shi, Sue Tsai, Helena Lei, Justin Kenkel, Chih Long Liu, Stephanie Tangsombatvisit, Hubert Tsui, Corneliu Sima, Changting Xiao, Lei Shen, Xiaoying Li, Tianru Jin, Gary F. Lewis, Minna Woo, Paul J. Utz, Michael Glogauer, Edgar Engleman, Shawn Winer, Daniel A. Winer
Obesity-related inflammation of metabolic tissues, including visceral adipose tissue (VAT) and liver, are key factors in the development of insulin resistance (IR), though many of the contributing mechanisms remain unclear. We show that nucleic-acid-targeting pathways downstream of extracellular trap (ET) formation, unmethylated CpG DNA, or ribonucleic acids drive inflammation in IR. High-fat diet (HFD)-fed mice show increased release of ETs in VAT, decreased systemic clearance of ETs, and increased autoantibodies against conserved nuclear antigens. In HFD-fed mice, this excess of nucleic acids and related protein antigens worsens metabolic parameters through a number of mechanisms, including activation of VAT macrophages and expansion of plasmacytoid dendritic cells (pDCs) in the liver. Consistently, HFD-fed mice lacking critical responders of nucleic acid pathways, Toll-like receptors (TLR)7 and TLR9, show reduced metabolic inflammation and improved glucose homeostasis. Treatment of HFD-fed mice with inhibitors of ET formation or a TLR7/9 antagonist improves metabolic disease. These findings reveal a pathogenic role for nucleic acid targeting as a driver of metabolic inflammation in IR.

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Revelo et al. show that diet-induced obesity promotes excess release and diminished clearance of nucleic acid and related antigens, with appearance of autoantibodies. Aberrant handling of nucleic acids activates VAT macrophages and liver pDCs via TLR7/9 to promote inflammation. Nucleic acid-sensing pathways may represent therapeutic targets for obesity-related metabolic disease.


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Kataegis Expression Signature in Breast Cancer Is Associated with Late Onset, Better Prognosis, and Higher HER2 Levels

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Matteo D’Antonio, Pablo Tamayo, Jill P. Mesirov, Kelly A. Frazer
Kataegis is a mutational process observed in ∼55% of breast tumors that results in hypermutation in localized genomic regions. Using whole-genome sequence data of 97 tumors, we examined the distribution of kataegis loci, showing that these somatic mutations are over-represented on chromosomes 8, 17, and 22 and enriched in genic regions and active chromatin elements. We show that tumors harboring kataegis are associated with transcriptome-wide expression changes consistent with low invasive potential. We exploit the kataegis expression signature to predict kataegis status in 412 breast cancers with transcriptome but not whole-genome sequence data and show that kataegis loci are enriched in high-grade, HER2+ tumors in patients diagnosed with breast cancer at an older age and who have a later age at death. Our study demonstrates that kataegis loci are associated with important clinical features in breast cancer and may serve as a marker of good prognosis.

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D’Antonio et al. show kataegis is associated with breast cancer patients diagnosed at an older age and with a higher age at death and in HER2+ tumors. Tumors harboring kataegis are associated with transcriptome-wide expression changes consistent with low invasive potential. Kataegis is a marker for good prognosis in breast cancer.


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Differences in Strength and Timing of the mtDNA Bottleneck between Zebrafish Germline and Non-germline Cells

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Auke B.C. Otten, Tom E.J. Theunissen, Josien G. Derhaag, Ellen H. Lambrichs, Iris B.W. Boesten, Marie Winandy, Aafke P.A. van Montfoort, Katsiaryna Tarbashevich, Erez Raz, Mike Gerards, Jo M. Vanoevelen, Bianca J.C. van den Bosch, Marc Muller, Hubert J.M. Smeets
We studied the mtDNA bottleneck in zebrafish to elucidate size, timing, and variation in germline and non-germline cells. Mature zebrafish oocytes contain, on average, 19.0 × 106 mtDNA molecules with high variation between oocytes. During embryogenesis, the mtDNA copy number decreases to ∼170 mtDNA molecules per primordial germ cell (PGC), a number similar to that in mammals, and to ∼50 per non-PGC. These occur at the same developmental stage, implying considerable variation in mtDNA copy number in (non-)PGCs of the same female, dictated by variation in the mature oocyte. The presence of oocytes with low mtDNA numbers, if similar in humans, could explain how (de novo) mutations can reach high mutation loads within a single generation. High mtDNA copy numbers in mature oocytes are established by mtDNA replication during oocyte development. Bottleneck differences between germline and non-germline cells, due to early differentiation of PGCs, may account for different distribution patterns of familial mutations.

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Otten et al. describe the mtDNA bottleneck in zebrafish. Oocytes have a high and variable mtDNA copy number, dictating the variation in the mtDNA bottleneck size. Differences in size and timing of the bottleneck between germline and non-germline cells suggest differences in segregation and sensitivity to de novo mtDNA mutations.


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Transcription Factor NFIB Is a Driver of Small Cell Lung Cancer Progression in Mice and Marks Metastatic Disease in Patients

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Ekaterina A. Semenova, Min-chul Kwon, Kim Monkhorst, Ji-Ying Song, Rajith Bhaskaran, Oscar Krijgsman, Thomas Kuilman, Dennis Peters, Wieneke A. Buikhuisen, Egbert F. Smit, Colin Pritchard, Miranda Cozijnsen, Jan van der Vliet, John Zevenhoven, Jan-Paul Lambooij, Natalie Proost, Erwin van Montfort, Arno Velds, Ivo J. Huijbers, Anton Berns
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor, and no effective treatment is available to date. Mouse models of SCLC based on the inactivation of Rb1 and Trp53 show frequent amplifications of the Nfib and Mycl genes. Here, we report that, although overexpression of either transcription factor accelerates tumor growth, NFIB specifically promotes metastatic spread. High NFIB levels are associated with expansive growth of a poorly differentiated and almost exclusively E-cadherin (CDH1)-negative invasive tumor cell population. Consistent with the mouse data, we find that NFIB is overexpressed in almost all tested human metastatic high-grade neuroendocrine lung tumors, warranting further assessment of NFIB as a tumor progression marker in a clinical setting.

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SCLC is a highly malignant cancer with an unmet need for better intervention strategies. Semenova et al. report that the transcription factor NFIB drives SCLC growth and metastasis, defines an aggressive tumor compartment in mice, and marks a subgroup of high-grade pulmonary neuroendocrine tumors (pNETs) in patients.


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Dopamine D1 and D2 Receptors Make Dissociable Contributions to Dorsolateral Prefrontal Cortical Regulation of Rule-Guided Oculomotor Behavior

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Susheel Vijayraghavan, Alex James Major, Stefan Everling
Studies of neuromodulation of spatial short-term memory have shown that dopamine D1 receptor (D1R) stimulation in dorsolateral prefrontal cortex (DLPFC) dose-dependently modulates memory activity, whereas D2 receptors (D2Rs) selectively modulate activity related to eye movements hypothesized to encode movement feedback. We examined localized stimulation of D1Rs and D2Rs on DLPFC neurons engaged in a task involving rule representation in memory to guide appropriate eye movements toward or away from a visual stimulus. We found dissociable effects of D1R and D2R on DLPFC physiology. D1R stimulation degrades memory activity for the task rule and increases stimulus-related selectivity. In contrast, D2R stimulation affects motor activity tuning only when eye movements are made to the stimulus. Only D1R stimulation degrades task performance and increases impulsive responding. Our results suggest that D1Rs regulate rule representation and impulse control, whereas D2Rs selectively modulate eye-movement-related dynamics and not rule representation in the DLPFC.

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Prefrontal cortical activity controls rule-guided flexible behavior. Vijayraghavan et al. examined the effects of dopamine receptor stimulation on working memory activity for rules guiding eye movements. D1 receptor stimulation deteriorates rule maintenance and increases impulsive responding, whereas D2 receptor stimulation selectively enhances movement-related activity depending on the rule context.


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Spinal Microgliosis Due to Resident Microglial Proliferation Is Required for Pain Hypersensitivity after Peripheral Nerve Injury

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Nan Gu, Jiyun Peng, Madhuvika Murugan, Xi Wang, Ukpong B. Eyo, Dongming Sun, Yi Ren, Emanuel DiCicco-Bloom, Wise Young, Hailong Dong, Long-Jun Wu
Peripheral nerve injury causes neuropathic pain accompanied by remarkable microgliosis in the spinal cord dorsal horn. However, it is still debated whether infiltrated monocytes contribute to injury-induced expansion of the microglial population. Here, we found that spinal microgliosis predominantly results from local proliferation of resident microglia but not from infiltrating monocytes after spinal nerve transection (SNT) by using two genetic mouse models (CCR2RFP/+:CX3CR1GFP/+ and CX3CR1creER/+:R26tdTomato/+ mice) as well as specific staining of microglia and macrophages. Pharmacological inhibition of SNT-induced microglial proliferation correlated with attenuated neuropathic pain hypersensitivities. Microglial proliferation is partially controlled by purinergic and fractalkine signaling, as CX3CR1−/− and P2Y12−/− mice show reduced spinal microglial proliferation and neuropathic pain. These results suggest that local microglial proliferation is the sole source of spinal microgliosis, which represents a potential therapeutic target for neuropathic pain management.

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Gu et al. show that resident microglial proliferation is the major contributor to microgliosis in the spinal dorsal horn after peripheral nerve injury. However, there is no monocyte infiltration associated with injury-induced microgliosis in the dorsal horn. Pharmacological or genetic inhibition of microglial proliferation attenuates neuropathic pain hypersensitivity.


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Identification and Targeting of Long-Term Tumor-Propagating Cells in Small Cell Lung Cancer

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Nadine S. Jahchan, Jing Shan Lim, Becky Bola, Karen Morris, Garrett Seitz, Kim Q. Tran, Lei Xu, Francesca Trapani, Christopher J. Morrow, Sandra Cristea, Garry L. Coles, Dian Yang, Dedeepya Vaka, Michael S. Kareta, Julie George, Pawel K. Mazur, Thuyen Nguyen, Wade C. Anderson, Scott J. Dylla, Fiona Blackhall, Martin Peifer, Caroline Dive, Julien Sage
Small cell lung cancer (SCLC) is a neuroendocrine lung cancer characterized by fast growth, early dissemination, and rapid resistance to chemotherapy. We identified a population of long-term tumor-propagating cells (TPCs) in a mouse model of SCLC. This population, marked by high levels of EpCAM and CD24, is also prevalent in human primary SCLC tumors. Murine SCLC TPCs are numerous and highly proliferative but not intrinsically chemoresistant, indicating that not all clinical features of SCLC are linked to TPCs. SCLC TPCs possess a distinct transcriptional profile compared to non-TPCs, including elevated MYC activity. Genetic and pharmacological inhibition of MYC in SCLC cells to non-TPC levels inhibits long-term propagation but not short-term growth. These studies identify a highly tumorigenic population of SCLC cells in mouse models, cell lines, and patient tumors and a means to target them in this most fatal form of lung cancer.

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Jahchan et al. use a genetically engineered mouse model of small cell lung cancer (SCLC) to functionally characterize cancer stem cells (tumor-propagating cells, TPCs). SCLC TPCs are numerous in tumors, cycle quickly, are chemosensitive, and depend on elevated MYC activity for their ability to propagate tumors.


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A Role for Timp3 in Microbiota-Driven Hepatic Steatosis and Metabolic Dysfunction

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Maria Mavilio, Valentina Marchetti, Marta Fabrizi, Robert Stöhr, Arianna Marino, Viviana Casagrande, Loredana Fiorentino, Marina Cardellini, Ben Kappel, Ivan Monteleone, Celine Garret, Alessandro Mauriello, Giovanni Monteleone, Alessio Farcomeni, Remy Burcelin, Rossella Menghini, Massimo Federici
The effect of gut microbiota on obesity and insulin resistance is now recognized, but the underlying host-dependent mechanisms remain poorly undefined. We find that tissue inhibitor of metalloproteinase 3 knockout (Timp3−/−) mice fed a high-fat diet exhibit gut microbiota dysbiosis, an increase in branched chain and aromatic (BCAA) metabolites, liver steatosis, and an increase in circulating soluble IL-6 receptors (sIL6Rs). sIL6Rs can then activate inflammatory cells, such as CD11c+ cells, which drive metabolic inflammation. Depleting the microbiota through antibiotic treatment significantly improves glucose tolerance, hepatic steatosis, and systemic inflammation, and neutralizing sIL6R signaling reduces inflammation, but only mildly impacts glucose tolerance. Collectively, our results suggest that gut microbiota is the primary driver of the observed metabolic dysfunction, which is mediated, in part, through IL-6 signaling. Our findings also identify an important role for Timp3 in mediating the effect of the microbiota in metabolic diseases.

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Mavilio et al. show that Timp3 impacts gut-microbiome-related liver steatosis and glucose intolerance. Loss of Timp3 potentiates gut microbiota dysbiosis, leading to an increase in the development of inflammatory and metabolic abnormalities, which are mediated, in part, through IL-6 signaling. Antibiotic-mediated depletion of the microbiota improved these metabolic and inflammatory phenotypes.


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The Zfhx3-Mediated Axis Regulates Sleep and Interval Timing in Mice

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Edoardo Balzani, Glenda Lassi, Silvia Maggi, Siddharth Sethi, Michael J. Parsons, Michelle Simon, Patrick M. Nolan, Valter Tucci
An AT motif-dependent axis, modulated by the transcription factor Zfhx3, influences the circadian clock in mice. In particular, gain of function of Zfhx3 significantly shortens circadian rhythms and alters the transcriptional activity of an important class of neuropeptides that controls intercellular signaling in the suprachiasmatic nucleus (SCN) of the hypothalamus. The ZFHX3/AT axis revealed an important, largely cell-nonautonomous control of the circadian clock. Here, by studying the recently identified circadian mouse mutant Zfhx3Sci/+, we identify significant effects on sleep homeostasis, a phenomenon that is outside the canonical circadian clock system and that is modulated by the activity of those neuropeptides at a circuit level. We show that the Zfhx3Sci/+ mutation accelerates the circadian clock at both the hourly scale (i.e., advancing circadian rhythms) and the seconds-to-minutes scale (i.e., anticipating behavioral responses) in mice. The in vivo results are accompanied by a significant presence of sleep targets among protein-protein interactions of the Zfhx3Sci/+-dependent network.

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Balzani et al. report that the transcription factor Zfhx3, which is primarily expressed in the suprachiasmatic nucleus of the hypothalamus and which regulates circadian rhythms, modulates sleep homeostatic functions and short-interval behavioral responses in mice.


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NeuCode Proteomics Reveals Bap1 Regulation of Metabolism

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Joshua M. Baughman, Christopher M. Rose, Ganesh Kolumam, Joshua D. Webster, Emily M. Wilkerson, Anna E. Merrill, Timothy W. Rhoads, Rajkumar Noubade, Paula Katavolos, Justin Lesch, Donald S. Stapleton, Mary E. Rabaglia, Kathy L. Schueler, Raymond Asuncion, Melanie Domeyer, Jose Zavala-Solorio, Michael Reich, Jason DeVoss, Mark P. Keller, Alan D. Attie, Alexander S. Hebert, Michael S. Westphall, Joshua J. Coon, Donald S. Kirkpatrick, Anwesha Dey
We introduce neutron-encoded (NeuCode) amino acid labeling of mice as a strategy for multiplexed proteomic analysis in vivo. Using NeuCode, we characterize an inducible knockout mouse model of Bap1, a tumor suppressor and deubiquitinase whose in vivo roles outside of cancer are not well established. NeuCode proteomics revealed altered metabolic pathways following Bap1 deletion, including profound elevation of cholesterol biosynthetic machinery coincident with reduced expression of gluconeogenic and lipid homeostasis proteins in liver. Bap1 loss increased pancreatitis biomarkers and reduced expression of mitochondrial proteins. These alterations accompany a metabolic remodeling with hypoglycemia, hypercholesterolemia, hepatic lipid loss, and acinar cell degeneration. Liver-specific Bap1 null mice present with fully penetrant perinatal lethality, severe hypoglycemia, and hepatic lipid deficiency. This work reveals Bap1 as a metabolic regulator in liver and pancreas, and it establishes NeuCode as a reliable proteomic method for deciphering in vivo biology.

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Baughman et al. use NeuCode in vivo labeling for multiplexed quantitation in mouse tissues. Using this approach, coupled with multiple genetically engineered mouse models, they demonstrate a role for Bap1 in maintaining metabolic homeostasis in liver and pancreas.


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Activation of CDK4 Triggers Development of Non-alcoholic Fatty Liver Disease

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Jingling Jin, Leila Valanejad, Thuy Phuong Nguyen, Kyle Lewis, Mary Wright, Ashley Cast, Lauren Stock, Lubov Timchenko, Nikolai A. Timchenko
The development of non-alcoholic fatty liver disease (NAFLD) is a multiple step process. Here, we show that activation of cdk4 triggers the development of NAFLD. We found that cdk4 protein levels are elevated in mouse models of NAFLD and in patients with fatty livers. This increase leads to C/EBPα phosphorylation on Ser193 and formation of C/EBPα-p300 complexes, resulting in hepatic steatosis, fibrosis, and hepatocellular carcinoma (HCC). The disruption of this pathway in cdk4-resistant C/EBPα-S193A mice dramatically reduces development of high-fat diet (HFD)-mediated NAFLD. In addition, inhibition of cdk4 by flavopiridol or PD-0332991 significantly reduces development of hepatic steatosis, the first step of NAFLD. Thus, this study reveals that activation of cdk4 triggers NAFLD and that inhibitors of cdk4 may be used for the prevention/treatment of NAFLD.

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Jin et al. show that cdk4 activation triggers non-alcoholic fatty liver disease (NAFLD) development. They find that an increased level of cdk4 protein in mice and humans leads to C/EBPα-p300 complex formation and hepatic steatosis. Disruption of this pathway or inhibition of cdk4 prevents NAFLD development and reverses steatosis.


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Structural Insights into Arl1-Mediated Targeting of the Arf-GEF BIG1 to the trans-Golgi

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Antonio Galindo, Nicolas Soler, Stephen H. McLaughlin, Minmin Yu, Roger L. Williams, Sean Munro
The GTPase Arf1 is the major regulator of vesicle traffic at both the cis- and trans-Golgi. Arf1 is activated at the cis-Golgi by the guanine nucleotide exchange factor (GEF) GBF1 and at the trans-Golgi by the related GEF BIG1 or its paralog, BIG2. The trans-Golgi-specific targeting of BIG1 and BIG2 depends on the Arf-like GTPase Arl1. We find that Arl1 binds to the dimerization and cyclophilin binding (DCB) domain in BIG1 and report a crystal structure of human Arl1 bound to this domain. Residues in the DCB domain that bind Arl1 are required for BIG1 to locate to the Golgi in vivo. DCB domain-binding residues in Arl1 have a distinct conformation from those in known Arl1-effector complexes, and this plasticity allows Arl1 to interact with different effectors of unrelated structure. The findings provide structural insight into how Arf1 GEFs, and hence active Arf1, achieve their correct subcellular distribution.

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The GTPase Arf1 is essential for Golgi function and is activated on the trans-Golgi by the BIG1 exchange factor. A second GTPase, Arl1, is required for BIG1 recruitment. Galindo et al. find that Arl1 binds to the DCB domain of BIG1 and determine the structure of human Arl1 bound to this domain.


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Oxidative Homeostasis Regulates the Response to Reductive Endoplasmic Reticulum Stress through Translation Control

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Shuvadeep Maity, Asher Rajkumar, Latika Matai, Ajay Bhat, Asmita Ghosh, Ganesh Agam, Simarjot Kaur, Niraj R. Bhatt, Arnab Mukhopadhyay, Shantanu Sengupta, Kausik Chakraborty
Reductive stress leads to the loss of disulfide bond formation and induces the unfolded protein response of the endoplasmic reticulum (UPRER), necessary to regain proteostasis in the compartment. Here we show that peroxide accumulation during reductive stress attenuates UPRER amplitude by altering translation without any discernible effect on transcription. Through a comprehensive genetic screen in Saccharomyces cerevisiae, we identify modulators of reductive stress-induced UPRER and demonstrate that oxidative quality control (OQC) genes modulate this cellular response in the presence of chronic but not acute reductive stress. Using a combination of microarray and relative quantitative proteomics, we uncover a non-canonical translation attenuation mechanism that acts in a bipartite manner to selectively downregulate highly expressed proteins, decoupling the cell’s transcriptional and translational response during reductive ER stress. Finally, we demonstrate that PERK, a canonical translation attenuator in higher eukaryotes, helps in bypassing a ROS-dependent, non-canonical mode of translation attenuation.

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Maity et al. show that oxidative stress plays an important role in controlling the cellular response to ER stress. They show that this happens through a non-canonical translation regulation by reactive oxygen species that decrease the level of abundant proteins and increase the level of non-abundant ones.


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Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Hai Li, Takaaki Kuwajima, Derek Oakley, Elena Nikulina, Jianwei Hou, Wan Seok Yang, Emily Rhodes Lowry, Nuno Jorge Lamas, Mackenzie Weygandt Amoroso, Gist F. Croft, Raghavendra Hosur, Hynek Wichterle, Said Sebti, Marie T. Filbin, Brent Stockwell, Christopher E. Henderson
Suboptimal axonal regeneration contributes to the consequences of nervous system trauma and neurodegenerative disease, but the intrinsic mechanisms that regulate axon growth remain unclear. We screened 50,400 small molecules for their ability to promote axon outgrowth on inhibitory substrata. The most potent hits were the statins, which stimulated growth of all mouse- and human-patient-derived neurons tested, both in vitro and in vivo, as did combined inhibition of the protein prenylation enzymes farnesyltransferase (PFT) and geranylgeranyl transferase I (PGGT-1). Compensatory sprouting of motor axons may delay clinical onset of amyotrophic lateral sclerosis (ALS). Accordingly, elevated levels of PGGT1B, which would be predicted to reduce sprouting, were found in motor neurons of early- versus late-onset ALS patients postmortem. The mevalonate-prenylation pathway therefore constitutes an endogenous brake on axonal growth, and its inhibition provides a potential therapeutic approach to accelerate neuronal regeneration in humans.

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Teaser

Using a high-throughput phenotypic screen, Li et al. identify statins and inhibitors of protein prenylation as potent neurite-outgrowth-promoting agents. High levels of prenylation enzyme are found in patients with earlier-onset forms of ALS. Prenylation may limit axonal growth in both normal and pathological situations.


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PCNA Retention on DNA into G2/M Phase Causes Genome Instability in Cells Lacking Elg1

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Catherine Johnson, Vamsi K. Gali, Tatsuro S. Takahashi, Takashi Kubota
Loss of the genome maintenance factor Elg1 causes serious genome instability that leads to cancer, but the underlying mechanism is unknown. Elg1 forms the major subunit of a replication factor C-like complex, Elg1-RLC, which unloads the ring-shaped polymerase clamp PCNA from DNA during replication. Here, we show that prolonged retention of PCNA on DNA into G2/M phase is the major cause of genome instability in elg1Δ yeast. Overexpression-induced accumulation of PCNA on DNA causes genome instability. Conversely, disassembly-prone PCNA mutants that relieve PCNA accumulation rescue the genome instability of elg1Δ cells. Covalent modifications to the retained PCNA make only a minor contribution to elg1Δ genome instability. By engineering cell-cycle-regulated ELG1 alleles, we show that abnormal accumulation of PCNA on DNA during S phase causes moderate genome instability and its retention through G2/M phase exacerbates genome instability. Our results reveal that PCNA unloading by Elg1-RLC is critical for genome maintenance.

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Teaser

Loss of the genome maintenance factor Elg1 causes serious genome instability. Johnson et al. find that PCNA unloading by Elg1 is critical for genome maintenance, and that PCNA retention on DNA into G2/M phase causes genome instability in cells lacking Elg1.


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Impaired Recall of Positional Memory following Chemogenetic Disruption of Place Field Stability

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Rong Zhao, Stacy D. Grunke, Madhusudhanan M. Keralapurath, Michael J. Yetman, Alexander Lam, Tang-Cheng Lee, Konstantinos Sousounis, Yongying Jiang, Deborah A. Swing, Lino Tessarollo, Daoyun Ji, Joanna L. Jankowsky
The neural network of the temporal lobe is thought to provide a cognitive map of our surroundings. Functional analysis of this network has been hampered by coarse tools that often result in collateral damage to other circuits. We developed a chemogenetic system to temporally control electrical input into the hippocampus. When entorhinal input to the perforant path was acutely silenced, hippocampal firing patterns became destabilized and underwent extensive remapping. We also found that spatial memory acquired prior to neural silencing was impaired by loss of input through the perforant path. Together, our experiments show that manipulation of entorhinal activity destabilizes spatial coding and disrupts spatial memory. Moreover, we introduce a chemogenetic model for non-invasive neuronal silencing that offers multiple advantages over existing strategies in this setting.

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Teaser

Zhao et al. present a chemogenetic model for acute neuronal silencing. Suppression of the entorhinal cortex causes remapping of hippocampal CA1 place fields and impairs recall of spatial memory. The concurrent disruption of place fields and spatial recall suggest that stable cognitive maps remain critical for navigation in a familiar setting.


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2.8-Å Cryo-EM Structure of the Large Ribosomal Subunit from the Eukaryotic Parasite Leishmania

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Moran Shalev-Benami, Yan Zhang, Donna Matzov, Yehuda Halfon, Arie Zackay, Haim Rozenberg, Ella Zimmerman, Anat Bashan, Charles L. Jaffe, Ada Yonath, Georgios Skiniotis
Leishmania is a single-cell eukaryotic parasite of the Trypanosomatidae family, whose members cause an array of tropical diseases. The often fatal outcome of infections, lack of effective vaccines, limited selection of therapeutic drugs, and emerging resistant strains, underline the need to develop strategies to combat these pathogens. The Trypanosomatid ribosome has recently been highlighted as a promising therapeutic target due to structural features that are distinct from other eukaryotes. Here, we present the 2.8-Å resolution structure of the Leishmania donovani large ribosomal subunit (LSU) derived from a cryo-EM map, further enabling the structural observation of eukaryotic rRNA modifications that play a significant role in ribosome assembly and function. The structure illustrates the unique fragmented nature of leishmanial LSU rRNA and highlights the irregular distribution of rRNA modifications in Leishmania, a characteristic with implications for anti-parasitic drug development.

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Teaser

Shalev-Benami et al. describe the structure of the Leishmania donovani large ribosomal subunit (LSU), obtained by cryo-EM at 2.8-Å resolution. The structure shows the fragmented nature of leishmanial rRNA and highlights the irregular distribution of rRNA modifications with implications for drug development against this protozoan parasite, which afflicts millions of people worldwide.


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Paleo Profile: Pangu's Wing

This new pterosaur had a snaggletoothed jaw.

-- Read more on ScientificAmerican.com
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Battle of the Somme, 1916

1916-07-15-big-map.jpg

The Events of July 1, 1916, as reported in Scientific American on July 7 and July 14, 1916

-- Read more on ScientificAmerican.com
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New U.S. Regulations on Ivory Sales are Great--But They Don't Go Far Enough

The U.S. should also ban the importation of all trophies from elephant hunting

-- Read more on ScientificAmerican.com
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Video interviews from IARC 50th anniversary conference

iarc50-logo.jpgAs part of its series of highlights from international oncology meetings, ecancer.tv features video interviews with participants at the International Agency for Research on Cancer (IARC) 50th anniversary conference, held in Lyon on 7-10 June 2016.

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