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Uncertainty, Precaution, And Adaptive Management In Wildlife Trade, Annecoos Wiersema Oct 2015

Uncertainty, Precaution, And Adaptive Management In Wildlife Trade, Annecoos Wiersema

Michigan Journal of International Law

Wildlife trade is big business. Legal international trade in just some of the wild animals and plants traded worldwide is estimated at $350 to $530 million per year. The United States is the primary importer of virtually every major taxon of these species, including mammals, reptiles, fish, and plants. When it comes to illegal trade, estimates of its value range from $7 to $23 billion annually, covering wild animals, fish, and timber. This illegal trade fuels organized crime and militia and terrorist groups. In the face of all this pressure, some wild species appear to be traded in sustainable amounts. …


The Foot Of Homo Naledi, W. E.H Harcourt-Smith, Z. Throckmorton, K. A. Congdon, B. Zipfel, A. S. Deane, M. S.M. Drapeau, S. E. Churchill, L. R. Berger, J. M. Desilva Oct 2015

The Foot Of Homo Naledi, W. E.H Harcourt-Smith, Z. Throckmorton, K. A. Congdon, B. Zipfel, A. S. Deane, M. S.M. Drapeau, S. E. Churchill, L. R. Berger, J. M. Desilva

Dartmouth Scholarship

Modern humans are characterized by a highly specialized foot that reflects our obligate bipedalism. Our understanding of hominin foot evolution is, although, hindered by a paucity of well-associated remains. Here we describe the foot of Homo naledi from Dinaledi Chamber, South Africa, using 107 pedal elements, including one nearly-complete adult foot. The H. naledi foot is predominantly modern human-like in morphology and inferred function, with an adducted hallux, an elongated tarsus, and derived ankle and calcaneocuboid joints. In combination, these features indicate a foot well adapted for striding bipedalism. However, the H. naledi foot differs from modern humans in having …


The Nicotine Metabolite, Cotinine, Alters The Assembly And Trafficking Of A Subset Of Nicotinic Acetylcholine Receptors, Ashley M. Fox, Faruk H. Moonschi, Christopher I. Richards Oct 2015

The Nicotine Metabolite, Cotinine, Alters The Assembly And Trafficking Of A Subset Of Nicotinic Acetylcholine Receptors, Ashley M. Fox, Faruk H. Moonschi, Christopher I. Richards

Chemistry Faculty Publications

Exposure to nicotine alters the trafficking and assembly of nicotinic receptors (nAChRs), leading to their up-regulation on the plasma membrane. Although the mechanism is not fully understood, nicotine-induced up-regulation is believed to contribute to nicotine addiction. The effect of cotinine, the primary metabolite of nicotine, on nAChR trafficking and assembly has not been extensively investigated. We utilize a pH-sensitive variant of GFP, super ecliptic pHluorin, to differentiate between intracellular nAChRs and those expressed on the plasma membrane to quantify changes resulting from cotinine and nicotine exposure. Similar to nicotine, exposure to cotinine increases the number of α4β2 receptors on the …


Iv And Ip Administration Of Rhodamine In Visualization Of Wbc-Bbb Interactions In Cerebral Vessels., Zachary Wilmer Reichenbach, Hongbo Li, John P. Gaughan, Melanie B. Elliott, Ronald Tuma Oct 2015

Iv And Ip Administration Of Rhodamine In Visualization Of Wbc-Bbb Interactions In Cerebral Vessels., Zachary Wilmer Reichenbach, Hongbo Li, John P. Gaughan, Melanie B. Elliott, Ronald Tuma

Department of Neurosurgery Faculty Papers

Epi-illuminescence intravital fluorescence microscopy has been employed to study leukocyte-endothelial interactions in a number of brain pathologies. Historically, dyes such as Rhodamine 6G have been injected intravenously. However, intravenous injections can predispose experimental animals to a multitude of complications and requires a high degree of technical skill. Here, we study the efficacy of injecting Rhodamine 6G into the peritoneum (IP) for the purpose of analyzing leukocyte-endothelial interactions through a cranial window during real time intravital microscopy. After examining the number of rolling and adherent leukocytes through a cranial window, we found no advantage to the intravenous injection (IV). Additionally, we …


Lipin1 Regulates Skeletal Muscle Differentiation Through Extracellular Signal-Regulated Kinase (Erk) Activation And Cyclin D Complex-Regulated Cell Cycle Withdrawal, Weihua Jiang, Jing Zhu, Xun Zhuang, Xiping Zhang, Tao Luo, Karyn Esser, Hongmei Ren Sep 2015

Lipin1 Regulates Skeletal Muscle Differentiation Through Extracellular Signal-Regulated Kinase (Erk) Activation And Cyclin D Complex-Regulated Cell Cycle Withdrawal, Weihua Jiang, Jing Zhu, Xun Zhuang, Xiping Zhang, Tao Luo, Karyn Esser, Hongmei Ren

Saha Cardiovascular Research Center Faculty Publications

Lipin1, an intracellular protein, plays critical roles in controlling lipid synthesis and energy metabolism through its enzymatic activity and nuclear transcriptional functions. Several mouse models of skeletal muscle wasting are associated with lipin1 mutation or altered expression. Recent human studies have suggested that children with homozygous null mutations in the LPIN1 gene suffer from rhabdomyolysis. However, the underlying pathophysiologic mechanism is still poorly understood. In the present study we examined whether lipin1 contributes to regulating muscle regeneration. We characterized the time course of skeletal muscle regeneration in lipin1-deficient fld mice after injury. We found that fld mice exhibited smaller regenerated …


Differential Gene Expression Profiles Reflecting Macrophage Polarization In Aging And Periodontitis Gingival Tissues, Octavio A. Gonzalez, Michael John Novak, Sreenatha S. Kirakodu, Arnold J. Stromberg, R. Nagarajan, Chifu B. Huang, K. C. Chen, Luis Orraca, J. Martinez-Gonzalez, Jeffrey L. Ebersole Sep 2015

Differential Gene Expression Profiles Reflecting Macrophage Polarization In Aging And Periodontitis Gingival Tissues, Octavio A. Gonzalez, Michael John Novak, Sreenatha S. Kirakodu, Arnold J. Stromberg, R. Nagarajan, Chifu B. Huang, K. C. Chen, Luis Orraca, J. Martinez-Gonzalez, Jeffrey L. Ebersole

Center for Oral Health Research Faculty Publications

Recent evidence has determined a phenotypic and functional heterogeneity for macrophage populations. This plasticity of macrophage function has been related to specific properties of subsets (M1 and M2) of these cells in inflammation, adaptive immune responses and resolution of tissue destructive processes. This investigation hypothesized that targeted alterations in the distribution of macrophage phenotypes in aged individuals, and with periodontitis would be skewed towards M1 inflammatory macrophages in gingival tissues. The study used a non-human primate model to evaluate gene expression profiles as footprints of macrophage variation in healthy and periodontitis gingival tissues from animals 3-23 years of age and …


Animal Experimentation As A Form Of Rescue, Alexander Zambrano Mr. Sep 2015

Animal Experimentation As A Form Of Rescue, Alexander Zambrano Mr.

Between the Species

In this paper I explore a new approach to the ethics of animal experimentation by conceiving of it as a form of rescue. The notion of rescue, I suggest, involves some moral agent(s) performing an action or series of actions, whose end is to prevent or alleviate serious harm to another party, harm that otherwise would have occurred or would have continued to occur, had that moral agent not intervened. Animal experiments that are utilized as a means to alleviate human illnesses mirror the structure of rescue cases and this means that we can and should apply principles of rescue …


Autophagy Is Induced Upon Platelet Activation And Is Essential For Hemostasis And Thrombosis, Madhu M. Ouseph, Yunjie Huang, Meenakshi Banerjee, Smita Joshi, Laura Macdonald, Yu Zhong, Huijuan Liu, Xianting Li, Binggang Xiang, Guoying Zhang, Masaaki Komatsu, Zhenyu Yue, Zhenyu Li, Brian Storrie, Sidney W. Whiteheart, Qing Jun Wang Sep 2015

Autophagy Is Induced Upon Platelet Activation And Is Essential For Hemostasis And Thrombosis, Madhu M. Ouseph, Yunjie Huang, Meenakshi Banerjee, Smita Joshi, Laura Macdonald, Yu Zhong, Huijuan Liu, Xianting Li, Binggang Xiang, Guoying Zhang, Masaaki Komatsu, Zhenyu Yue, Zhenyu Li, Brian Storrie, Sidney W. Whiteheart, Qing Jun Wang

Molecular and Cellular Biochemistry Faculty Publications

Autophagy is important for maintaining cellular homeostasis, and thus its deficiency is implicated in a broad spectrum of human diseases. Its role in platelet function has only recently been examined. Our biochemical and imaging studies demonstrate that the core autophagy machinery exists in platelets, and that autophagy is constitutively active in resting platelets. Moreover, autophagy is induced upon platelet activation, as indicated by agonist-induced loss of the autophagy marker LC3II. Additional experiments, using inhibitors of platelet activation, proteases, and lysosomal acidification, as well as platelets from knockout mouse strains, show that agonist-induced LC3II loss is a consequence of platelet signaling …


Delivery Of Nucleic Acids And Nanomaterials By Cell-Penetrating Peptides: Opportunities And Challenges, Yue-Wern Huang, Han-Jung Lee, Larry Tolliver, Robert Aronstam Sep 2015

Delivery Of Nucleic Acids And Nanomaterials By Cell-Penetrating Peptides: Opportunities And Challenges, Yue-Wern Huang, Han-Jung Lee, Larry Tolliver, Robert Aronstam

Biological Sciences Faculty Research & Creative Works

Many viral and nonviral systems have been developed to aid delivery of biologically active molecules into cells. Among these, cell-penetrating peptides (CPPs) have received increasing attention in the past two decades for biomedical applications. In this review, we focus on opportunities and challenges associated with CPP delivery of nucleic acids and nanomaterials. We first describe the nature of versatile CPPs and their interactions with various types of cargoes. We then discuss in vivo and in vitro delivery of nucleic acids and nanomaterials by CPPs. Studies on the mechanisms of cellular entry and limitations in the methods used are detailed.


Positional Differences In Reactive Hyperemia Provide Insight Into Initial Phase Of Exercise Hyperemia., Jeffrey L Jasperse, J Kevin Shoemaker, Eric J Gray, Philip S Clifford Sep 2015

Positional Differences In Reactive Hyperemia Provide Insight Into Initial Phase Of Exercise Hyperemia., Jeffrey L Jasperse, J Kevin Shoemaker, Eric J Gray, Philip S Clifford

Kinesiology Publications

Studies have reported a greater blood flow response to muscle contractions when the limb is below the heart compared with above the heart, and these results have been interpreted as evidence for a skeletal muscle pump contribution to exercise hyperemia. If limb position affects the blood flow response to other vascular challenges such as reactive hyperemia, this interpretation may not be correct. We hypothesized that the magnitude of reactive hyperemia would be greater with the limb below the heart. Brachial artery blood flow (Doppler ultrasound) and blood pressure (finger-cuff plethysmography) were measured in 10 healthy volunteers. Subjects lay supine with …


Profibrotic Role For Interleukin-4 In Cardiac Remodeling And Dysfunction, Hongmei Peng, Zeyd Sarwar, Xiao-Ping Yang, Edward L. Peterson, Jiang Xu, Brana Janic, Nadia Rhaleb, Oscar A. Carretero, Nour-Eddine Rhaleb Sep 2015

Profibrotic Role For Interleukin-4 In Cardiac Remodeling And Dysfunction, Hongmei Peng, Zeyd Sarwar, Xiao-Ping Yang, Edward L. Peterson, Jiang Xu, Brana Janic, Nadia Rhaleb, Oscar A. Carretero, Nour-Eddine Rhaleb

Hypertension and Vascular Research Articles

Elevated interleukin-4 (IL-4) levels are associated with cardiac fibrosis in hypertension and heart failure in both patients and experimental animals. We hypothesized that chronically elevated IL-4 induces cardiac fibrosis, resulting in a predisposition of the heart to angiotensin II-induced damage. Wild-type Balb/c (WT, high circulating IL-4) and IL-4-deficient Balb/c mice (IL-4(-/-)) were used. WT mice exhibited cardiac fibrosis (evidenced by an increase in expression of procollagen genes/interstitial collagen fraction), enlarged left ventricle chamber, and declined cardiac function associated with a greater number of mast cells and macrophages in the heart compared with IL-4(-/-). In contrast, IL-4(-/-) mice had normal cardiac …


Muscle Weakness During Aging: A Deficiency State Involving Declining Angiogenesis, Charles T. Ambrose Sep 2015

Muscle Weakness During Aging: A Deficiency State Involving Declining Angiogenesis, Charles T. Ambrose

Microbiology, Immunology, and Molecular Genetics Faculty Publications

This essay begins by proposing that muscle weakness of old age from sarcopenia is due in large part to reduced capillary density in the muscles, as documented in 9 reports of aged persons and animals. Capillary density (CD) is determined by local levels of various angiogenic factors, which also decline in muscles with aging, as reported in 7 studies of old persons and animals. There are also numerous reports of reduced CD in the aged brain and other studies showing reduced CD in the kidney and heart of aged animals. Thus a waning angiogenesis throughout the body may be …


Rna-Seq Analysis Of Differential Splice Junction Usage And Intron Retentions By Dexseq, Yafang Li, Xiayu Rao, William W. Mattox, Christopher I. Amos, Bin Liu Sep 2015

Rna-Seq Analysis Of Differential Splice Junction Usage And Intron Retentions By Dexseq, Yafang Li, Xiayu Rao, William W. Mattox, Christopher I. Amos, Bin Liu

Dartmouth Scholarship

Alternative splicing is an important biological process in the generation of multiple functional transcripts from the same genomic sequences. Differential analysis of splice junctions (SJs) and intron retentions (IRs) is helpful in the detection of alternative splicing events. In this study, we conducted differential analysis of SJs and IRs by use of DEXSeq, a Bioconductor package originally designed for differential exon usage analysis in RNA-seq data analysis. We set up an analysis pipeline including mapping of RNA-seq reads, the preparation of count tables of SJs and IRs as the input files, and the differential analysis in DEXSeq. We analyzed the …


Coordination Between Autophagy And The Heat Shock Response: Evidence From Exercise In Animals And Humans, Nathan H. Cole Sep 2015

Coordination Between Autophagy And The Heat Shock Response: Evidence From Exercise In Animals And Humans, Nathan H. Cole

Health, Exercise, and Sports Sciences ETDs

Proteins play a critical role in nearly every biological activity. In consequence, organismal health and homeostasis often hinges on the ability of intracellular regulatory systems to sustain the quality and function of these diverse, structurally complex macromolecules. Correct protein function depends on correct form, and during periods of destabilizing cellular stress, protein quality is managed in part by the heat shock response, which acts to support, isolate, and reform new or damaged proteins, and in part by the autophagic recycling of abnormal proteins, cytotoxic protein aggregates, and terminally damaged organelles. We conducted a pooled analysis of available research in humans …


Insecticides Promote Viral Outbreaks By Altering Herbivore Competition, Huipeng Pan, Evan L. Preisser, Dong Chu, Shaoli Wang, Qingjun Wu, Yves Carriére, Xuguo Zhou, Youjun Zhang Sep 2015

Insecticides Promote Viral Outbreaks By Altering Herbivore Competition, Huipeng Pan, Evan L. Preisser, Dong Chu, Shaoli Wang, Qingjun Wu, Yves Carriére, Xuguo Zhou, Youjun Zhang

Entomology Faculty Publications

While the management of biological invasions is often characterized by a series of single-specieg decisions, invasive species exist within larger food webs. These biotic interactions can alter the impact of control/eradication programs and may cause suppression efforts to inadvertently facilitate invasion spread and impact. We document the rapid replacement of the invasive Bemisia Middle East-Asia Minor I (MEAM1) cryptic biotype by the cryptic Mediterranean (MED) biotype throughout China and demonstrate that MED is more tolerant of insecticides and a better vector of tomato yellow leaf curl virus (TYLCV) than MEAMJ. While MEAM1 usually excludes MED under natural conditions, insecticide application …


A Mitochondria-Anchored Isoform Of The Actin-Nucleating Spire Protein Regulates Mitochondrial Division, Uri Manor, Sadie Bartholomew, Gonen Golani, Eric Christenson, Michael Kozlov, Henry Higgs, James Spudich, Jennifer Lippincott-Schwartz Aug 2015

A Mitochondria-Anchored Isoform Of The Actin-Nucleating Spire Protein Regulates Mitochondrial Division, Uri Manor, Sadie Bartholomew, Gonen Golani, Eric Christenson, Michael Kozlov, Henry Higgs, James Spudich, Jennifer Lippincott-Schwartz

Dartmouth Scholarship

Mitochondrial division, essential for survival in mammals, is enhanced by an inter-organellar process involving ER tubules encircling and constricting mitochondria. The force for constriction is thought to involve actin polymerization by the ER-anchored isoform of the formin protein inverted formin 2 (INF2). Unknown is the mechanism triggering INF2-mediated actin polymerization at ER-mitochondria intersections. We show that a novel isoform of the formin-binding, actin-nucleating protein Spire, Spire1C, localizes to mitochondria and directly links mitochondria to the actin cytoskeleton and the ER. Spire1C binds INF2 and promotes actin assembly on mitochondrial surfaces. Disrupting either Spire1C actin- or formin-binding activities reduces mitochondrial constriction …


Calmodulin Methyltransferase Is Required For Growth, Muscle Strength, Somatosensory Development And Brain Function, Sitvanit Haziza, Roberta Magnani, Dima Lan, Omer Keinan, Ann Saada, Eli Hershkovitz, Nurit Yanay, Yoram Cohen, Yoram Nevo, Robert L. Houtz, Val C. Sheffield, Hava Golan, Ruti Parvari Aug 2015

Calmodulin Methyltransferase Is Required For Growth, Muscle Strength, Somatosensory Development And Brain Function, Sitvanit Haziza, Roberta Magnani, Dima Lan, Omer Keinan, Ann Saada, Eli Hershkovitz, Nurit Yanay, Yoram Cohen, Yoram Nevo, Robert L. Houtz, Val C. Sheffield, Hava Golan, Ruti Parvari

Horticulture Faculty Publications

Calmodulin lysine methyl transferase (CaM KMT) is ubiquitously expressed and highly conserved from plants to vertebrates. CaM is frequently trimethylated at Lys-115, however, the role of CaM methylation in vertebrates has not been studied. CaM KMT was found to be homozygously deleted in the 2P21 deletion syndrome that includes 4 genes. These patients present with cystinuria, severe intellectual disabilities, hypotonia, mitochondrial disease and facial dysmorphism. Two siblings with deletion of three of the genes included in the 2P21 deletion syndrome presented with cystinuria, hypotonia, a mild/moderate mental retardation and a respiratory chain complex IV deficiency. To be able to attribute …


Structure-Based Screen Identifies A Potent Small Molecule Inhibitor Of Stat5a/B With Therapeutic Potential For Prostate Cancer And Chronic Myeloid Leukemia., Zhiyong Liao, Lei Gu, Jenny Vergalli, Samanta A. Mariani, Marco De Dominici, Ravi K. Lokareddy, Ayush Dagvadorj, Puranik Purushottamachar, Peter A. Mccue, Edouard J. Trabulsi, Costas D. Lallas, Shilpa Gupta, Elyse Ellsworth, Shauna Blackmon, Adam Ertel, Paolo Fortina, Benjamin E. Leiby, Guanjun Xia, Hallgeir Rui, David T. Hoang, Leonard G Gomella, Gino Cingolani, Vincent Njar, Nagarajan Pattabiraman, Bruno Calabretta, Marja T. Nevalainen Aug 2015

Structure-Based Screen Identifies A Potent Small Molecule Inhibitor Of Stat5a/B With Therapeutic Potential For Prostate Cancer And Chronic Myeloid Leukemia., Zhiyong Liao, Lei Gu, Jenny Vergalli, Samanta A. Mariani, Marco De Dominici, Ravi K. Lokareddy, Ayush Dagvadorj, Puranik Purushottamachar, Peter A. Mccue, Edouard J. Trabulsi, Costas D. Lallas, Shilpa Gupta, Elyse Ellsworth, Shauna Blackmon, Adam Ertel, Paolo Fortina, Benjamin E. Leiby, Guanjun Xia, Hallgeir Rui, David T. Hoang, Leonard G Gomella, Gino Cingolani, Vincent Njar, Nagarajan Pattabiraman, Bruno Calabretta, Marja T. Nevalainen

Department of Cancer Biology Faculty Papers

Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic …


The Sea Lamprey Meiotic Map Improves Resolution Of Ancient Vertebrate Genome Duplications, Jeramiah James Smith, Melissa C. Keinath Aug 2015

The Sea Lamprey Meiotic Map Improves Resolution Of Ancient Vertebrate Genome Duplications, Jeramiah James Smith, Melissa C. Keinath

Biology Faculty Publications

It is generally accepted that many genes present in vertebrate genomes owe their origin to two whole-genome duplications that occurred deep in the ancestry of the vertebrate lineage. However, details regarding the timing and outcome of these duplications are not well resolved. We present high-density meiotic and comparative genomic maps for the sea lamprey (Petromyzon marinus), a representative of an ancient lineage that diverged from all other vertebrates ~550 million years ago. Linkage analyses yielded a total of 95 linkage groups, similar to the estimated number of germline chromosomes (1n ~ 99), spanning a total of 5570.25 cM. …


Adiporon, The First Orally Active Adiponectin Receptor Activator, Attenuates Postischemic Myocardial Apoptosis Through Both Ampk-Mediated And Ampk-Independent Signalings., Yanqing Zhang, Jianli Zhao, Rui Li, Wayne Bond Lau, Yue-Xing Yuan, Bin Liang, Rong Li, Er-He Gao, Walter J. Koch, Xin-Liang Ma, Ya-Jing Wang Aug 2015

Adiporon, The First Orally Active Adiponectin Receptor Activator, Attenuates Postischemic Myocardial Apoptosis Through Both Ampk-Mediated And Ampk-Independent Signalings., Yanqing Zhang, Jianli Zhao, Rui Li, Wayne Bond Lau, Yue-Xing Yuan, Bin Liang, Rong Li, Er-He Gao, Walter J. Koch, Xin-Liang Ma, Ya-Jing Wang

Department of Emergency Medicine Faculty Papers

Adiponectin (APN) is a cardioprotective molecule. Its reduction in diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury. Although APN administration in animals attenuates MI/R injury, multiple factors limit its clinical application. The current study investigated whether AdipoRon, the first orally active molecule that binds APN receptors, may protect the heart against MI/R injury, and if so, to delineate the involved mechanisms. Wild-type (WT), APN knockout (APN-KO), and cardiomyocyte specific-AMPK dominant negative (AMPK-DN) mice were treated with vehicle or AdipoRon (50 mg/kg, 10 min prior to MI) and subjected to MI/R (30 min/3-24 h). Compared with vehicle, oral administration of AdipoRon to WT …


Scarnas Regulate Splicing And Vertebrate Heart Development., Prakash Patil, Nataliya Kibiryeva, Tamayo Uechi, Jennifer A. Marshall, James E. O'Brien, Michael Artman, Naoya Kenmochi, Douglas C. Bittel Aug 2015

Scarnas Regulate Splicing And Vertebrate Heart Development., Prakash Patil, Nataliya Kibiryeva, Tamayo Uechi, Jennifer A. Marshall, James E. O'Brien, Michael Artman, Naoya Kenmochi, Douglas C. Bittel

Manuscripts, Articles, Book Chapters and Other Papers

Alternative splicing (AS) plays an important role in regulating mammalian heart development, but a link between misregulated splicing and congenital heart defects (CHDs) has not been shown. We reported that more than 50% of genes associated with heart development were alternatively spliced in the right ventricle (RV) of infants with tetralogy of Fallot (TOF). Moreover, there was a significant decrease in the level of 12 small cajal body-specific RNAs (scaRNAs) that direct the biochemical modification of specific nucleotides in spliceosomal RNAs. We sought to determine if scaRNA levels influence patterns of AS and heart development. We used primary cells derived …


Numerical Chromosomal Instability Mediates Susceptibility To Radiation Treatment, Samuel F. Bakhoum, Lilian Kabeche, Matthew D. Wood, Christopher D. Laucius Jul 2015

Numerical Chromosomal Instability Mediates Susceptibility To Radiation Treatment, Samuel F. Bakhoum, Lilian Kabeche, Matthew D. Wood, Christopher D. Laucius

Dartmouth Scholarship

The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated radiation therapy. However, the mechanism for this cell cycle-dependent vulnerability is unknown. Here we show that treatment with IR leads to mitotic chromosome segregation errors in vivo and long-lasting aneuploidy in tumour-derived cell lines. These mitotic errors generate an abundance of micronuclei that predispose chromosomes to subsequent catastrophic pulverization thereby independently amplifying radiation-induced genome damage. Experimentally suppressing whole-chromosome missegregation reduces downstream chromosomal defects and significantly increases the viability of irradiated mitotic cells. Further, orthotopically transplanted human glioblastoma tumours in which …


Nf-Κb Regulation Of C-Flip Promotes Tnfα-Mediated Raf Inhibitor Resistance In Melanoma., Yongping Shao, Kaitlyn Le, Hanyin Cheng, Andrew E. Aplin Jul 2015

Nf-Κb Regulation Of C-Flip Promotes Tnfα-Mediated Raf Inhibitor Resistance In Melanoma., Yongping Shao, Kaitlyn Le, Hanyin Cheng, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Targeted inhibitors elicit heterogeneous clinical responses in genetically stratified groups of patients. Although most studies focus on tumor intrinsic properties, factors in the tumor microenvironment were recently found to modulate the response to inhibitors. Here, we show that in cutaneous BRAF V600E melanoma, the cytokine tumor necrosis factor-α (TNFα) blocks RAF inhibitor-induced apoptosis via activation of NF-κB. Several NF-κB-dependent factors are upregulated following TNFα and RAF inhibitor treatment. Of these factors, we show that death receptor inhibitor cellular caspase 8 (FLICE)-like inhibitory protein (c-FLIP) is required for TNFα-induced protection against RAF inhibitor. Overexpression of c-FLIP_S or c-FLIP_L isoform decreased RAF …


Achilles Tendons From Decorin- And Biglycan-Null Mouse Models Have Inferior Mechanical And Structural Properties Predicted By An Image-Based Empirical Damage Model., Joshua A. Gordon, Benjamin R. Freedman, Andrey Zuskov, Renato V. Iozzo, David E. Birk, Louis J. Soslowsky Jul 2015

Achilles Tendons From Decorin- And Biglycan-Null Mouse Models Have Inferior Mechanical And Structural Properties Predicted By An Image-Based Empirical Damage Model., Joshua A. Gordon, Benjamin R. Freedman, Andrey Zuskov, Renato V. Iozzo, David E. Birk, Louis J. Soslowsky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Achilles tendons are a common source of pain and injury, and their pathology may originate from aberrant structure function relationships. Small leucine rich proteoglycans (SLRPs) influence mechanical and structural properties in a tendon-specific manner. However, their roles in the Achilles tendon have not been defined. The objective of this study was to evaluate the mechanical and structural differences observed in mouse Achilles tendons lacking class I SLRPs; either decorin or biglycan. In addition, empirical modeling techniques based on mechanical and image-based measures were employed. Achilles tendons from decorin-null (Dcn(-/-)) and biglycan-null (Bgn(-/-)) C57BL/6 female mice (N=102) were used. Each tendon …


Registered Report: Biomechanical Remodeling Of The Microenvironment By Stromal Caveolin-1 Favors Tumor Invasion And Metastasis, Steven Fiering, Lay-Hong Ang, Judith Lacoste, Tim D. Smith, Erin Griner Jul 2015

Registered Report: Biomechanical Remodeling Of The Microenvironment By Stromal Caveolin-1 Favors Tumor Invasion And Metastasis, Steven Fiering, Lay-Hong Ang, Judith Lacoste, Tim D. Smith, Erin Griner

Dartmouth Scholarship

The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replicating selected results from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012 were selected on the basis of citations and Altimetric scores (Errington et al., 2014). This Registered report describes the proposed replication plan of key experiments from ‘Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis’ by Goetz and colleagues, published in Cell in 2011 (Goetz et al., 2011). The key experiments …


Neuronal Interferon Signaling Is Required For Protection Against Herpes Simplex Virus Replication And Pathogenesis, Pamela C. Rosato, David A. Leib Jul 2015

Neuronal Interferon Signaling Is Required For Protection Against Herpes Simplex Virus Replication And Pathogenesis, Pamela C. Rosato, David A. Leib

Dartmouth Scholarship

Interferon (IFN) responses are critical for controlling herpes simplex virus 1 (HSV-1). The importance of neuronal IFN signaling in controlling acute and latent HSV-1 infection remains unclear. Compartmentalized neuron cultures revealed that mature sensory neurons respond to IFNβ at both the axon and cell body through distinct mechanisms, resulting in control of HSV-1. Mice specifically lacking neural IFN signaling succumbed rapidly to HSV-1 corneal infection, demonstrating that IFN responses of the immune system and non-neuronal tissues are insufficient to confer survival following virus challenge. Furthermore, neurovirulence was restored to an HSV strain lacking the IFN-modulating gene, γ34.5, despite its expected …


Selenoprotein P Influences Colitis-Induced Tumorigenesis By Mediating Stemness And Oxidative Damage., C. W. Barrett, V. K. Reddy, S. P. Short, A. K. Motley, M. K. Lintel, A. M. Bradley, T. Freeman, J. Vallance, W. Ning, B. Parang, Shenika Poindexter Toliver Jul 2015

Selenoprotein P Influences Colitis-Induced Tumorigenesis By Mediating Stemness And Oxidative Damage., C. W. Barrett, V. K. Reddy, S. P. Short, A. K. Motley, M. K. Lintel, A. M. Bradley, T. Freeman, J. Vallance, W. Ning, B. Parang, Shenika Poindexter Toliver

Faculty and Staff Publications

Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and …


Coupling Between Cytoplasmic Concentration Gradients Through Local Control Of Protein Mobility In The Caenorhabditis Elegans Zygote, Youjun Wu, Huaiying Zhang, Erik E. Griffin Jun 2015

Coupling Between Cytoplasmic Concentration Gradients Through Local Control Of Protein Mobility In The Caenorhabditis Elegans Zygote, Youjun Wu, Huaiying Zhang, Erik E. Griffin

Dartmouth Scholarship

Cell polarity is characterized by the asymmetric distribution of factors at the cell cortex and in the cytoplasm. Although mechanisms that establish cortical asymmetries have been characterized, less is known about how persistent cytoplasmic asymmetries are generated. During the asymmetric division of the Caenorhabditis elegans zygote, the PAR proteins orchestrate the segregation of the cytoplasmic RNA-binding proteins MEX-5/6 to the anterior cytoplasm and PIE-1, POS-1, and MEX-1 to the posterior cytoplasm. In this study, we find that MEX-5/6 control the segregation of GFP::PIE-1, GFP::POS-1, and GFP::MEX-1 by locally increasing their mobility in the anterior cytoplasm. Remarkably, PIE-1, POS-1, and MEX-1 …


Taranis Functions With Cyclin A And Cdk1 In A Novel Arousal Center To Control Sleep In Drosophila., Dinis J.S. Afonso, Die Liu, Daniel R. Machado, Huihui Pan, James E.C. Jepson, Dragana Rogulja, Kyunghee Koh Jun 2015

Taranis Functions With Cyclin A And Cdk1 In A Novel Arousal Center To Control Sleep In Drosophila., Dinis J.S. Afonso, Die Liu, Daniel R. Machado, Huihui Pan, James E.C. Jepson, Dragana Rogulja, Kyunghee Koh

Department of Neuroscience Faculty Papers

Sleep is an essential and conserved behavior whose regulation at the molecular and anatomical level remains to be elucidated. Here, we identify TARANIS (TARA), a Drosophila homolog of the Trip-Br (SERTAD) family of transcriptional coregulators, as a molecule that is required for normal sleep patterns. Through a forward-genetic screen, we isolated tara as a novel sleep gene associated with a marked reduction in sleep amount. Targeted knockdown of tara suggests that it functions in cholinergic neurons to promote sleep. tara encodes a conserved cell-cycle protein that contains a Cyclin A (CycA)-binding homology domain. TARA regulates CycA protein levels and genetically …


Reformed Approach To The Interactions Of Science And Religion, Tony N. Jelsma Jun 2015

Reformed Approach To The Interactions Of Science And Religion, Tony N. Jelsma

Faculty Work Comprehensive List

"Sometimes, despite our best theological and scientific study, religion and science still seem to be in conflict."

Posting about the interactions between religion and science from In All Things - an online hub committed to the claim that the life, death, and resurrection of Jesus Christ has implications for the entire world.

http://inallthings.org/a-reformed-approach-to-the-interactions-of-science-and-religion