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Cellular and Molecular Physiology

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Articles 1 - 30 of 217

Full-Text Articles in Molecular Biology

A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout Jan 2019

A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout

Open Access Articles

Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental inputs. Caenorhabditis elegans has two breakdown pathways for the short-chain fatty acid propionate: a canonical, vitamin B12-dependent pathway and a propionate shunt that is used when vitamin B12 levels are low. The shunt pathway is kept off when there is sufficient flux through the canonical pathway, likely to avoid generating shunt-specific toxic intermediates. Here, we discovered a transcriptional regulatory circuit that activates shunt gene expression upon propionate buildup. Nuclear hormone receptor 10 (NHR-10) and NHR-68 function together as a "persistence detector" in a type 1, coherent feed-forward loop ...


Orbit: A New Paradigm For Genetic Engineering Of Mycobacterial Chromosomes, Kenan C. Murphy, Samantha J. Nelson, Subhalaxmi Nambi, Kadamba Papavinasasundaram, Christina E. Baer, Christopher M. Sassetti Dec 2018

Orbit: A New Paradigm For Genetic Engineering Of Mycobacterial Chromosomes, Kenan C. Murphy, Samantha J. Nelson, Subhalaxmi Nambi, Kadamba Papavinasasundaram, Christina E. Baer, Christopher M. Sassetti

Open Access Articles

Two efficient recombination systems were combined to produce a versatile method for chromosomal engineering that obviates the need to prepare double-stranded DNA (dsDNA) recombination substrates. A synthetic "targeting oligonucleotide" is incorporated into the chromosome via homologous recombination mediated by the phage Che9c RecT annealase. This oligonucleotide contains a site-specific recombination site for the directional Bxb1 integrase (Int), which allows the simultaneous integration of a "payload plasmid" that contains a cognate recombination site and a selectable marker. The targeting oligonucleotide and payload plasmid are cotransformed into a RecT- and Int-expressing strain, and drug-resistant homologous recombinants are selected in a single step ...


Potent Cas9 Inhibition In Bacterial And Human Cells By Acriic4 And Acriic5 Anti-Crispr Proteins, Jooyoung Lee, Aamir Mir, Alireza Edraki, Bianca Garcia, Nadia Amrani, Hannah E. Lou, Ildar Gainetdinov, April Pawluk, Raed Ibraheim, Xin D. Gao, Pengpeng Liu, Alan R. Davidson, Karen L. Maxwell, Erik J. Sontheimer Dec 2018

Potent Cas9 Inhibition In Bacterial And Human Cells By Acriic4 And Acriic5 Anti-Crispr Proteins, Jooyoung Lee, Aamir Mir, Alireza Edraki, Bianca Garcia, Nadia Amrani, Hannah E. Lou, Ildar Gainetdinov, April Pawluk, Raed Ibraheim, Xin D. Gao, Pengpeng Liu, Alan R. Davidson, Karen L. Maxwell, Erik J. Sontheimer

Open Access Articles

In their natural settings, CRISPR-Cas systems play crucial roles in bacterial and archaeal adaptive immunity to protect against phages and other mobile genetic elements, and they are also widely used as genome engineering technologies. Previously we discovered bacteriophage-encoded Cas9-specific anti-CRISPR (Acr) proteins that serve as countermeasures against host bacterial immunity by inactivating their CRISPR-Cas systems (A. Pawluk, N. Amrani, Y. Zhang, B. Garcia, et al., Cell 167:1829-1838.e9, 2016, https://doi.org/10.1016/j.cell.2016.11.017). We hypothesized that the evolutionary advantages conferred by anti-CRISPRs would drive the widespread occurrence of these proteins in nature (K ...


A Population Of Gut Epithelial Enterochromaffin Cells Is Mechanosensitive And Requires Piezo2 To Convert Force Into Serotonin Release, Constanza Alcaino, Kaitlyn R. Knutson, Anthony J. Treichel, Gulcan Yildiz, Peter R. Strege, David R. Linden, Joyce H. Li, Andrew B. Leiter, Joseph H. Szurszewski, Gianrico Farrugia, Arthur Beyder Aug 2018

A Population Of Gut Epithelial Enterochromaffin Cells Is Mechanosensitive And Requires Piezo2 To Convert Force Into Serotonin Release, Constanza Alcaino, Kaitlyn R. Knutson, Anthony J. Treichel, Gulcan Yildiz, Peter R. Strege, David R. Linden, Joyce H. Li, Andrew B. Leiter, Joseph H. Szurszewski, Gianrico Farrugia, Arthur Beyder

Open Access Articles

Enterochromaffin (EC) cells constitute the largest population of intestinal epithelial enteroendocrine (EE) cells. EC cells are proposed to be specialized mechanosensory cells that release serotonin in response to epithelial forces, and thereby regulate intestinal fluid secretion. However, it is unknown whether EE and EC cells are directly mechanosensitive, and if so, what the molecular mechanism of their mechanosensitivity is. Consequently, the role of EE and EC cells in gastrointestinal mechanobiology is unclear. Piezo2 mechanosensitive ion channels are important for some specialized epithelial mechanosensors, and they are expressed in mouse and human EC cells. Here, we use EC and EE cell ...


Activities And Classroom Demonstrations In Biological Physics: A Resource Document, Philip C. Nelson, William Berner Jul 2018

Activities And Classroom Demonstrations In Biological Physics: A Resource Document, Philip C. Nelson, William Berner

Department of Physics Papers

We give detailed recipes for a number of classroom demonstrations relevant to biological physics instruction. We developed them mainly for use in 2nd-3rd year undergraduate Physics courses. But you can (and we do) use them for primary school, through high school, up to PhD candidates. You adapt the words for each audience, but a phenomenon is a phenomenon.

We also outline a 1-hour introduction to Python for undergraduate scientific computing.

Finally we document some outcomes from courses taught at U Pennsylvania using these resources and others cited here. This material was presented at a workshop at the AAPT meeting in ...


Llc Tumor Cells-Derivated Factors Reduces Adipogenesis In Co-Culture System, Magno Alves Lopes, Felipe Oliveira Franco, Felipe Henriques, Sidney Barnabe Peres, Miguel Luiz Batista Jr. Jul 2018

Llc Tumor Cells-Derivated Factors Reduces Adipogenesis In Co-Culture System, Magno Alves Lopes, Felipe Oliveira Franco, Felipe Henriques, Sidney Barnabe Peres, Miguel Luiz Batista Jr.

Open Access Articles

Cancer cachexia (CC) is a multifactorial syndrome with an unknown etiology. The primary symptom is the progressive reduction of the body weight. Recently, down-regulation of adipogenic and lipogenic genes were demonstrated to be early affected during cachexia progression in adipose tissue (AT), resulting in AT remodeling. Thus, this study aimed to evaluate in a co-culture system the influence of the Lewis Lung Carcinoma (LLC) tumor cells (c/c-LLC) in an established pre-adipocyte cell line 3T3-L1 adipogenic capacity. c/c-LLC in the presence of 3T3-L1 caused a reduction in lipids accumulation, suggesting that secretory tumor cells products may affect adipogenesis. Interestingly ...


Role Of The Mapk/Cjun Nh2-Terminal Kinase Signaling Pathway In Starvation-Induced Autophagy, Seda Barutcu, Nomeda Girnius, Santiago Vernia, Roger J. Davis Jun 2018

Role Of The Mapk/Cjun Nh2-Terminal Kinase Signaling Pathway In Starvation-Induced Autophagy, Seda Barutcu, Nomeda Girnius, Santiago Vernia, Roger J. Davis

Davis Lab Publications

Autophagy is required for cellular homeostasis and can determine cell viability in response to stress. It is established that MTOR is a master regulator of starvation-induced macroautophagy/autophagy, but recent studies have also implicated an essential role for the MAPK8/cJun NH2-terminal kinase 1 signal transduction pathway. We found that MAPK8/JNK1 and MAPK9/JNK2 were not required for autophagy caused by starvation or MTOR inhibition in murine fibroblasts and epithelial cells. These data demonstrate that MAPK8/9 has no required role in starvation-induced autophagy. We conclude that the role of MAPK8/9 in autophagy may be context-dependent and more ...


Neuronal Modulation Of Brown Adipose Activity Through Perturbation Of White Adipocyte Lipogenesis, Adilson L. Guilherme, David J. Pedersen, Felipe Henriques, Alexander H. Bedard, Elizabeth Henchey, Mark Kelly, Donald A. Morgan, Kamal Rahmouni, Michael P. Czech Jun 2018

Neuronal Modulation Of Brown Adipose Activity Through Perturbation Of White Adipocyte Lipogenesis, Adilson L. Guilherme, David J. Pedersen, Felipe Henriques, Alexander H. Bedard, Elizabeth Henchey, Mark Kelly, Donald A. Morgan, Kamal Rahmouni, Michael P. Czech

Open Access Articles

OBJECTIVE: Crosstalk between adipocytes and local neurons may be an important regulatory mechanism to control energy homeostasis. We previously reported that perturbation of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) expands sympathetic neurons within white adipose tissue (WAT) and stimulates the appearance of "beige" adipocytes. Here we tested whether WAT DNL activity can also influence neuronal regulation and thermogenesis in brown adipose tissue (BAT).

METHODS AND RESULTS: Induced deletion of FASN in all adipocytes in mature mice (iAdFASNKO) enhanced sympathetic innervation and neuronal activity as well as UCP1 expression in both WAT and BAT. This ...


Biology Of Exosomes And Their Microrna Cargos In Human And Bovine Milk, Amy Lynn Leiferman Jun 2018

Biology Of Exosomes And Their Microrna Cargos In Human And Bovine Milk, Amy Lynn Leiferman

Public Access Theses and Dissertations from the College of Education and Human Sciences

Exosomes are small, cargo-containing vesicles secreted by cells to facilitate intercellular communication. Of exosome cargos, microRNAs are especially interesting because of their involvement in gene regulation. Recently, our lab has shown that exosomes and their microRNA cargo are absorbed through the diet and elicit effects exogenously. Human and animal milk contain exosomes, which may have implications in infant and adult nutrition. There is evidence that bovine milk exosomes enhance growth of murine C2C12 myotube cell cultures, but whether this translates to muscle in vivo is unknown. The USDA National Nutrient Database for Standard Reference is lacking up-to-date information about human ...


Regulation Of Juvenile Hormone Synthesis By 20-Hydroxyecdysone In The Yellow-Fever Mosquito, Aedes Aegypti, Maria Areiza May 2018

Regulation Of Juvenile Hormone Synthesis By 20-Hydroxyecdysone In The Yellow-Fever Mosquito, Aedes Aegypti, Maria Areiza

FIU Electronic Theses and Dissertations

In Aedes aegypti, development and reproduction are regulated by juvenile hormone III (JH). This master regulatory hormone is synthesized by the corpora allata (CA), a pair of endocrine glands with neural connections to the brain. JH titers are largely determined by the rate of biosynthetic activity of the CA and are regulated by inhibitory and stimulatory factors. Like JH, the ecdysteroid 20-hydroxyecdysone (20E) is a key hormonal regulator and has been proposed as an allatoregulator in other insects. However, its part in the regulation of JH biosynthesis of mosquitoes was unknown. The specific aims of this dissertation were to (1 ...


A Microtubule-Dynein Tethering Complex Regulates The Axonemal Inner Dynein F (I1), Tomohiro Kubo, Yuqing Hou, Deborah A. Cochran, George B. Witman, Toshiyuki Oda May 2018

A Microtubule-Dynein Tethering Complex Regulates The Axonemal Inner Dynein F (I1), Tomohiro Kubo, Yuqing Hou, Deborah A. Cochran, George B. Witman, Toshiyuki Oda

Radiology Publications and Presentations

Motility of cilia/flagella is generated by a coordinated activity of thousands of dyneins. Inner dynein arms (IDAs) are particularly important for the formation of ciliary/flagellar waveforms, but the molecular mechanism of IDA regulation is poorly understood. Here, we show using cryo-electron tomography and biochemical analyses of Chlamydomonas flagella that a conserved protein FAP44 forms a complex that tethers IDA f (I1 dynein) head domains to the A-tubule of the axonemal outer doublet microtubule. In wild-type flagella, IDA f showed little nucleotide-dependent movement except for a tilt in the fbeta head perpendicular to the microtubule-sliding direction. In the absence ...


Reconstitution Of Gabaergic Postsynapses In Host Cells, Karthik Kanamalla Apr 2018

Reconstitution Of Gabaergic Postsynapses In Host Cells, Karthik Kanamalla

Honors Scholar Theses

Type A GABA receptors (GABAARs) can be found embedded in postsynaptic membranes or in a variety of extrasynaptic locations. Receptors with synaptic function are recruited to the postsynapse by submembranous scaffolds composed of gephyrin and collybistin (CB). This study was aimed at assessing whether the ability to interact with the scaffold differentiates synaptic from non-synaptic receptors. Using HEK293 cells as an expression system, and indirect immunofluorescence (IF), co-localization of extrasynaptic receptors α1β3δ and α4β3δ with the CB-gephyrin scaffold was assessed and compared with that of the synaptic receptor α1β3γ2. Results indicated that both extrasynaptic receptors were able to colocalize with ...


Jip1-Mediated Jnk Activation Negatively Regulates Synaptic Plasticity And Spatial Memory, Caroline Morel, Tessi Sherrin, Norman J. Kennedy, Kelly H. Forest, Seda Barutcu, Michael Robles, Ezekiel Carpenter-Hyland, Naghum Alfulaij, Claire L. Standen, Robert A. Nichols, Morris Benveniste, Roger J. Davis, Cedomir Todorovic Apr 2018

Jip1-Mediated Jnk Activation Negatively Regulates Synaptic Plasticity And Spatial Memory, Caroline Morel, Tessi Sherrin, Norman J. Kennedy, Kelly H. Forest, Seda Barutcu, Michael Robles, Ezekiel Carpenter-Hyland, Naghum Alfulaij, Claire L. Standen, Robert A. Nichols, Morris Benveniste, Roger J. Davis, Cedomir Todorovic

University of Massachusetts Medical School Faculty Publications

The c-Jun N-terminal kinase (JNK) signal transduction pathway is implicated in learning and memory. Here, we examined the role of JNK activation mediated by the JIP1 scaffold protein. We compared male wild-type mice with a mouse model harboring a point mutation in the Jip1 gene that selectively blocks JIP1-mediated JNK activation. These male mutant mice exhibited increased NMDA receptor currents, increased NMDA receptor-mediated gene expression, and a lower threshold for induction of hippocampal long-term potentiation. The JIP1 mutant mice also displayed improved hippocampus-dependent spatial memory and enhanced associative fear conditioning. These results were confirmed using a second JIP1 mutant mouse ...


Multiple Molecular Mechanisms Rescue Mtdna Disease In C. Elegans, Suraiya Haroon, Annie Li, Jaye L. Weinert, Clark Fritsch, Nolan G. Ericson, Jasmine Alexander-Floyd, Bart P. Braeckman, Cole M. Haynes, Jason H. Bielas, Tali Gidalevitz, Marc Vermulst Mar 2018

Multiple Molecular Mechanisms Rescue Mtdna Disease In C. Elegans, Suraiya Haroon, Annie Li, Jaye L. Weinert, Clark Fritsch, Nolan G. Ericson, Jasmine Alexander-Floyd, Bart P. Braeckman, Cole M. Haynes, Jason H. Bielas, Tali Gidalevitz, Marc Vermulst

University of Massachusetts Medical School Faculty Publications

Genetic instability of the mitochondrial genome (mtDNA) plays an important role in human aging and disease. Thus far, it has proven difficult to develop successful treatment strategies for diseases that are caused by mtDNA instability. To address this issue, we developed a model of mtDNA disease in the nematode C. elegans, an animal model that can rapidly be screened for genes and biological pathways that reduce mitochondrial pathology. These worms recapitulate all the major hallmarks of mtDNA disease in humans, including increased mtDNA instability, loss of respiration, reduced neuromuscular function, and a shortened lifespan. We found that these phenotypes could ...


Cbx4 Sumoylates Prdm16 To Regulate Adipose Tissue Thermogenesis, Qingbo Chen, Lei Huang, Dongning Pan, Lihua (Julie) Zhu, Yong-Xu Wang Mar 2018

Cbx4 Sumoylates Prdm16 To Regulate Adipose Tissue Thermogenesis, Qingbo Chen, Lei Huang, Dongning Pan, Lihua (Julie) Zhu, Yong-Xu Wang

Open Access Articles

Transcriptional co-activator Prdm16 controls brown fat development and white fat browning, but how this thermogenic function is modulated post-translationally is poorly understood. Here, we report that Cbx4, a Polycomb group protein, is a SUMO E3 ligase for Prdm16 and that Cbx4-mediated sumoylation of Prdm16 is required for thermogenic gene expression. Cbx4 expression is enriched in brown fat and is induced in adipose tissue by acute cold exposure. Sumoylation of Prdm16 at lysine 917 by Cbx4 blocks its ubiquitination-mediated degradation, thereby augmenting its stability and thermogenic function. Moreover, this sumoylation event primes Prdm16 to be further stabilized by methyltransferase Ehmt1. Heterozygous ...


Distinct Adipocyte Progenitor Cells Are Associated With Regional Phenotypes Of Perivascular Aortic Fat In Mice, Khanh-Van T. Tran, Timothy P. Fitzgibbons, So Yun Min, Tiffany Desouza, Silvia Corvera Mar 2018

Distinct Adipocyte Progenitor Cells Are Associated With Regional Phenotypes Of Perivascular Aortic Fat In Mice, Khanh-Van T. Tran, Timothy P. Fitzgibbons, So Yun Min, Tiffany Desouza, Silvia Corvera

University of Massachusetts Medical School Faculty Publications

OBJECTIVE: Perivascular adipose tissue depots around the aorta are regionally distinct and have specific functional properties. Thoracic aorta perivascular adipose tissue (tPVAT) expresses higher levels of thermogenic genes and lower levels of inflammatory genes than abdominal aorta perivascular adipose tissue (aPVAT). It is not known whether this distinction is due to the in-vivo functional environment or to cell-autonomous traits that persist outside the in-vivo setting. In this study, we asked whether the progenitor cells in tPVAT and aPVAT have cell-autonomous traits that lead to formation of regionally distinct PVAT.

METHODS: We performed microarray analysis of thoracic and abdominal peri-aortic adipose ...


Molecular Mechanisms Of Cell Death: Recommendations Of The Nomenclature Committee On Cell Death 2018, Lorenzo Galluzzi, Eric H. Baehrecke, Francis Ka-Ming Chan, Guido Kroemer Mar 2018

Molecular Mechanisms Of Cell Death: Recommendations Of The Nomenclature Committee On Cell Death 2018, Lorenzo Galluzzi, Eric H. Baehrecke, Francis Ka-Ming Chan, Guido Kroemer

Open Access Articles

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell ...


Characterization Of The Roles Of Muscle-Synthesized Brain-Derived Neurotrophic Factor And Presynaptic Tyrosine Receptor Kinase B In Motor Neuron Axonal Transport, Luke A. Vanosdol Mar 2018

Characterization Of The Roles Of Muscle-Synthesized Brain-Derived Neurotrophic Factor And Presynaptic Tyrosine Receptor Kinase B In Motor Neuron Axonal Transport, Luke A. Vanosdol

All NMU Master's Theses

Brain-derived neurotrophic factor (BDNF) is a small, diffusible protein essential for the development and function of neurons. It is synthesized by many types of tissue, including muscle. BDNF actions are mediated via binding to its receptor, tyrosine receptor kinase B (TrkB). The BDNF-TrkB complex is endocytosed into a specialized vesicle, which induces downstream signaling cascades locally in the dendrites, or, more often, is delivered to the cell soma via retrograde axonal transport, where it modulates gene expression. BDNF activation of TrkB is critical for the initiation of axonal transport, and this cellular process relies on the interaction of numerous adaptor ...


Upr(Mt) Regulation And Output: A Stress Response Mediated By Mitochondrial-Nuclear Communication, Andrew Melber, Cole M. Haynes Feb 2018

Upr(Mt) Regulation And Output: A Stress Response Mediated By Mitochondrial-Nuclear Communication, Andrew Melber, Cole M. Haynes

University of Massachusetts Medical School Faculty Publications

The mitochondrial network is not only required for the production of energy, essential cofactors and amino acids, but also serves as a signaling hub for innate immune and apoptotic pathways. Multiple mechanisms have evolved to identify and combat mitochondrial dysfunction to maintain the health of the organism. One such pathway is the mitochondrial unfolded protein response (UPR(mt)), which is regulated by the mitochondrial import efficiency of the transcription factor ATFS-1 in C. elegans and potentially orthologous transcription factors in mammals (ATF4, ATF5, CHOP). Upon mitochondrial dysfunction, import of ATFS-1 into mitochondria is reduced, allowing it to be trafficked to ...


Mrub_1325, Mrub_1326, Mrub_1327, And Mrub_1328 Are Orthologs Of B_3454, B_3455, B_3457, B_3458, Respectively Found In Escherichia Coli Coding For A Branched Chain Amino Acid Atp Binding Cassette (Abc) Transporter System, Bennett Tomlin, Adam Buric, Dr. Lori Scott Jan 2018

Mrub_1325, Mrub_1326, Mrub_1327, And Mrub_1328 Are Orthologs Of B_3454, B_3455, B_3457, B_3458, Respectively Found In Escherichia Coli Coding For A Branched Chain Amino Acid Atp Binding Cassette (Abc) Transporter System, Bennett Tomlin, Adam Buric, Dr. Lori Scott

Meiothermus ruber Genome Analysis Project

In this project we investigated the biological function of the genes Mrub_1325, Mrub_1326, Mrub_1327, and Mrub_1328 (KEGG map number 02010). We predict these genes encode components of a Branched Chain Amino Acid ATP Binding Cassette (ABC) transporter: 1) Mrub_1325 (DNA coordinates 1357399-1358130 on the reverse strand) encodes the ATP binding domain; 2) Mrub_1326 (DNA coordinates 1358127-1359899 on the reverse strand) encodes the ATP-binding domain and permease domain; 3) Mrub_1327 (DNA coordinates 1359899-1360930 on the reverse strand) encodes a permease domain; and 4)Mrub_1328 (DNA coordinates 1711022-1712185 on the reverse strand) encodes the substrate binding domain. This system is not predicted ...


Confirmation That Mrub_1751 Is Homologous To E. Coli Xylf, Mrub_1752 Is Homologous To E. Coli Xylh, And Mrub_1753 Is Homologous To E. Coli Xylg, Ben Price, Dr. Lori Scott Jan 2018

Confirmation That Mrub_1751 Is Homologous To E. Coli Xylf, Mrub_1752 Is Homologous To E. Coli Xylh, And Mrub_1753 Is Homologous To E. Coli Xylg, Ben Price, Dr. Lori Scott

Meiothermus ruber Genome Analysis Project

In this project we investigated the biological function of the genes Mrub_1751, Mrub_1752 and Mrub_1753 (KEGG map number 02010). We predict these genes encode components of a D-xylose ATP Binding Cassette (ABC) transporter: 1) Mrub_1752 (DNA coordinates 1809004-1810224 on the forward strand) encodes the permease component (aka transmembrane domain), predicted to be an ortholog and 2) Mrub_1753 (DNA coordinates 1810227-1811000 on the forward strand) encodes the ATP-binding domain (aka nucleotide binding domain); and 3) Mrub_1751 (DNA coordinates 1807855-1808892 on the forward strand) encodes the solute binding protein. The ABC-transporter for M. ruber to transport D-xylose is homologous with the transporter ...


Understanding Exportin-1 As An Anti-Cancer Target, Russell Thomas Burke Jan 2018

Understanding Exportin-1 As An Anti-Cancer Target, Russell Thomas Burke

Molecular, Cellular, and Developmental Biology Graduate Theses & Dissertations

Exportin-1 is a promising new anti-cancer target for selective inhibitors of nuclear export (SINE) molecules. Selinexor is a first-in-class SINE molecule in clinical trials for a variety of different cancers. Selinexor and other SINE molecules covalently bind exportin-1 and prevent nuclear export of cargo proteins. Over 200 Exportin-1 protein cargoes have been identified, including p53, pRB, IκB, and BRCA1. While early clinical success with inhibitors of Exportin-1 has been observed, the molecular mechanisms of response are still being examined. Previous studies have shown a variety of cell cycle effects and cell death. Here we show that inhibition of Exportin-1 causes ...


Thermophilic Adaptation In Prokaryotes Is Constrained By Metabolic Costs Of Proteostasis, Sergey V. Venev, Konstantin B. Zeldovich Jan 2018

Thermophilic Adaptation In Prokaryotes Is Constrained By Metabolic Costs Of Proteostasis, Sergey V. Venev, Konstantin B. Zeldovich

Open Access Articles

Prokaryotes evolved to thrive in an extremely diverse set of habitats, and their proteomes bear signatures of environmental conditions. Although correlations between amino acid usage and environmental temperature are well-documented, understanding of the mechanisms of thermal adaptation remains incomplete. Here, we couple the energetic costs of protein folding and protein homeostasis to build a microscopic model explaining both the overall amino acid composition and its temperature trends. Low biosynthesis costs lead to low diversity of physical interactions between amino acid residues, which in turn makes proteins less stable and drives up chaperone activity to maintain appropriate levels of folded, functional ...


Chronic Clozapine Treatment Impairs Functional Activation Of Metabotropic Glutamate Receptor 2 Via An Hdac2-Depedent Mechanism, Travis M. Cuddy Jan 2018

Chronic Clozapine Treatment Impairs Functional Activation Of Metabotropic Glutamate Receptor 2 Via An Hdac2-Depedent Mechanism, Travis M. Cuddy

Theses and Dissertations

Schizophrenia is a chronic mental disorder affecting millions worldwide. It has no known cure. Current pharmaceutical treatments have shown efficacy in only one of the three symptom clusters of schizophrenia, providing little or no benefit in the other two. Furthermore, the current standard-of-care drugs, known as atypical antipsychotics, carry risks of severe side effects affecting multiple body systems. Most patients opt to discontinue drug therapy within two years of initiation due to lack of efficacy and/or preponderance of adverse effects. Previous findings have shown that chronic usage of atypical antipsychotics causes a 5-HT2A-dependent upregulation of histone deacetylase ...


Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres Dec 2017

Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres

University of Massachusetts Medical School Faculty Publications

Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer. Although tumors and mammalian aneuploid cells, including several cancer cell lines, show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here, we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness ...


Reconciling Contradictory Findings: Glucose Transporter 1 (Glut1) Functions As An Oligomer Of Allosteric, Alternating Access Transporters, Kenneth P. Lloyd, Ogooluwa A. Ojelabi, Julie K. De Zutter, Anthony Carruthers Dec 2017

Reconciling Contradictory Findings: Glucose Transporter 1 (Glut1) Functions As An Oligomer Of Allosteric, Alternating Access Transporters, Kenneth P. Lloyd, Ogooluwa A. Ojelabi, Julie K. De Zutter, Anthony Carruthers

UMass Metabolic Network Publications

Recent structural studies suggest that glucose transporter 1 (GLUT1)-mediated sugar transport is mediated by an alternating access transporter that successively presents exofacial (e2) and endofacial (e1) substrate-binding sites. Transport studies, however, indicate multiple, interacting (allosteric), and co-existent, exo- and endofacial GLUT1 ligand-binding sites. The present study asks whether these contradictory conclusions result from systematic analytical error or reveal a more fundamental relationship between transporter structure and function. Here, homology modeling supported the alternating access transporter model for sugar transport by confirming at least four GLUT1 conformations, the so-called outward, outward-occluded, inward-occluded, and inward GLUT1 conformations. Results from docking analysis ...


Loss Of The Cone-Enriched Caspase-7 Does Not Affect Secondary Cone Death In Retinitis Pigmentosa, Aditya Venkatesh, Shun-Yun Cheng, Claudio Punzo Dec 2017

Loss Of The Cone-Enriched Caspase-7 Does Not Affect Secondary Cone Death In Retinitis Pigmentosa, Aditya Venkatesh, Shun-Yun Cheng, Claudio Punzo

University of Massachusetts Medical School Faculty Publications

Purpose: The apoptotic mechanisms responsible for secondary cone death in retinitis pigmentosa (RP) remain largely unknown. The cone-enriched apoptotic protease caspase-7 (Casp7) is thought to be triggered by endoplasmic reticulum (ER) stress and plays a pivotal role in mice deficient in the cone cyclic nucleotide-gated channels, a deficiency that causes achromatopsia in humans and in mice with autosomal dominant rhodopsin mutations, in particular the T17M mutation. Thus, we tested in two mouse models of RP whether the cone-enriched Casp7 plays a role during secondary cone death.

Methods: Casp7 knockout mice were crossed to two different RP mouse models with significantly ...


Attaching-And-Effacing Pathogens Exploit Junction Regulatory Activities Of N-Wasp And Snx9 To Disrupt The Intestinal Barrier, John J. Garber, Emily M. Mallick, Karen M. Scanlon, Jerrold R. Turner, Michael S. Donnenberg, John M. Leong, Scott B. Snapper Dec 2017

Attaching-And-Effacing Pathogens Exploit Junction Regulatory Activities Of N-Wasp And Snx9 To Disrupt The Intestinal Barrier, John J. Garber, Emily M. Mallick, Karen M. Scanlon, Jerrold R. Turner, Michael S. Donnenberg, John M. Leong, Scott B. Snapper

Open Access Articles

Background and Aims: Neural Wiskott-Aldrich Syndrome protein (N-WASP) is a key regulator of the actin cytoskeleton in epithelial tissues and is poised to mediate cytoskeletal-dependent aspects of apical junction complex (AJC) homeostasis. Attaching-and-effacing (AE) pathogens disrupt this homeostasis through translocation of the effector molecule early secreted antigenic target-6 (ESX)-1 secretion-associated protein F (EspF). Although the mechanisms underlying AJC disruption by EspF are unknown, EspF contains putative binding sites for N-WASP and the endocytic regulator sorting nexin 9 (SNX9). We hypothesized that N-WASP regulates AJC integrity and AE pathogens use EspF to induce junction disassembly through an N-WASP- and SNX9-dependent ...


Hepatic Dysfunction Caused By Consumption Of A High-Fat Diet, Anthony R. Soltis, Norman J. Kennedy, Xiaofeng Xin, Feng Zhou, Scott B. Ficarro, Yoon Sing Yap, Bryan J. Matthews, Douglas A. Lauffenburger, Forest M. White, Jarrod A. Marto, Roger J. Davis, Ernest Fraenkel Dec 2017

Hepatic Dysfunction Caused By Consumption Of A High-Fat Diet, Anthony R. Soltis, Norman J. Kennedy, Xiaofeng Xin, Feng Zhou, Scott B. Ficarro, Yoon Sing Yap, Bryan J. Matthews, Douglas A. Lauffenburger, Forest M. White, Jarrod A. Marto, Roger J. Davis, Ernest Fraenkel

University of Massachusetts Medical School Faculty Publications

Obesity is a major human health crisis that promotes insulin resistance and, ultimately, type 2 diabetes. The molecular mechanisms that mediate this response occur across many highly complex biological regulatory levels that are incompletely understood. Here, we present a comprehensive molecular systems biology study of hepatic responses to high-fat feeding in mice. We interrogated diet-induced epigenomic, transcriptomic, proteomic, and metabolomic alterations using high-throughput omic methods and used a network modeling approach to integrate these diverse molecular signals. Our model indicated that disruption of hepatic architecture and enhanced hepatocyte apoptosis are among the numerous biological processes that contribute to early liver ...


The Alpha6beta4 Integrin Promotes Resistance To Ferroptosis, Caitlin W. Brown, John J. Amante, Hira Lal Goel, Arthur M. Mercurio Dec 2017

The Alpha6beta4 Integrin Promotes Resistance To Ferroptosis, Caitlin W. Brown, John J. Amante, Hira Lal Goel, Arthur M. Mercurio

UMass Metabolic Network Publications

Increases in lipid peroxidation can cause ferroptosis, a form of cell death triggered by inhibition of glutathione peroxidase 4 (GPX4), which catalyzes the reduction of lipid peroxides and is a target of ferroptosis inducers, such as erastin. The alpha6beta4 integrin protects adherent epithelial and carcinoma cells from ferroptosis induced by erastin. In addition, extracellular matrix (ECM) detachment is a physiologic trigger of ferroptosis, which is evaded by alpha6beta4. The mechanism that enables alpha6beta4 to evade ferroptosis involves its ability to protect changes in membrane lipids that are proferroptotic. Specifically, alpha6beta4-mediated activation of Src and STAT3 suppresses expression of ACSL4, an ...