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Urban G,Tripathi P,Alkayali T,Mittal M,Jalali F,Karnes W,Baldi P
Deep Learning Localizes and Identifies Polyps in Real Time with 96% Accuracy in Screening Colonoscopy.
Gastroenterology. 2018 Jun 18;
The benefit of colonoscopy for colorectal cancer prevention depends on the adenoma detection rate (ADR). The ADR should reflect adenoma prevalence rate, estimated to be greater than 50% among the screening-age population. Yet the rate of adenoma detection by colonoscopists varies from 7% to 53%. It is estimated that every 1% increase in ADR reduces the risk of interval colorectal cancers by 3-6%. New strategies are needed to increase the ADR during colonoscopy. We tested the ability of computer-assisted image analysis, with convolutional neural networks (a deep learning model for image analysis), to improve polyp detection, a surrogate of ADR.
PMID: 29928897
Bruckner TA,Catalano R
Selection and population health: Theory and typology of research.
SSM Popul Health. 2018 Aug;5:101-113
Public health researchers may assume, based on the fetal origins literature, that "scarring" of birth cohorts describes the population response to modern-day stressors. We contend, based on extensive literature concerned with selection , that this assumption remains questionable. At least a third and likely many more of human conceptions fail to yield a live birth. Those that survive to birth, moreover, do not represent their conception cohort. Increasing data availability has led to an improved understanding of selection and its implications for population health. The literature describing selection , however, receives relatively little attention from social scientists. We aim to draw attention to the rich theoretical and empirical literature on selection by offering a typology that organizes this diverse work along dimensions we think important, if not familiar, to those studying population health. We further use the typology to identify important gaps in the literature. This work should interest social scientists for two reasons. First, phenomena of broad scholarly interest (i.e., social connectivity, bereavement) affect the extent and timing of selection . Second, the life-course health of a cohort depends in part on the strength of such selection. We conclude by identifying new research directions and with a reconciliation of the apparent contradiction between the "fetal origins" literature and that describing selection .
PMID: 29928686
Monto MA,McRee N,Deryck FS
Nonsuicidal Self-Injury Among a Representative Sample of US Adolescents, 2015.
Am J Public Health. 2018 Jun 21;:e1-e7
To provide prevalence estimates of adolescent nonsuicidal self-injury (NSSI) based on large, representative, nonclinical samples of high-school students, and to explore gender differences in health risks associated with NSSI.
PMID: 29927642
Van Doorslaer K,Chen Z,Bernard HU,Chan PKS,DeSalle R,Dillner J,Forslund O,Haga T,McBride AA,Villa LL,Burk RD,Ictv Report Consortium
ICTV Virus Taxonomy Profile: Papillomaviridae.
J Gen Virol. 2018 Jun 21;
The Papillomaviridae is a family of small, non-enveloped viruses with double-stranded DNA genomes of 5?748 to 8?607?bp. Their classification is based on pairwise nucleotide sequence identity across the L1 open reading frame. Members of the Papillomaviridae primarily infect mucosal and keratinised epithelia, and have been isolated from fish, reptiles, birds and mammals. Despite a long co-evolutionary history with their hosts, some papillomaviruses are pathogens of their natural host species. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Papillomaviridae, which is available at http://www.ictv.global/report/papillomaviridae.
PMID: 29927370
Hirshberg B,Rossich Molina E,Götz AW,Hammerich AD,Nathanson GM,Bertram TH,Johnson MA,Gerber RB
NO at water surfaces: binding forces, charge separation, energy accommodation and atmospheric implications.
Phys Chem Chem Phys. 2018 Jun 21;
Interactions of N2O5 with water media are of great importance in atmospheric chemistry and have been the topic of extensive research for over two decades. Nevertheless, many physical and chemical properties of N2O5 at the surface or in bulk water are unknown or not microscopically understood. This study presents extensive new results on the physical properties of N2O5 in water and at the surface of water, with a focus on their microscopic basis. The main results are obtained using ab initio molecular dynamics and calculations of a potential of mean force. These include: (1) collisions of N2O5 with water at 300 K lead to trapping at the surface for at least 20 ps and with 95% probability. (2) During that time, there is no N2O5 hydrolysis, evaporation, or entry into the bulk. (3) Charge separation between the NO2 and NO3 groups of N2O5, fluctuates significantly with time. (4) Energy accommodation of the colliding N2O5 at the surface takes place within picoseconds. (5) The binding energy of N2O5 to a nanosize amorphous ice particle at 0 K is on the order of 15 kcal mol-1 for the main surface site. N2O5 binding to the cluster is due to one weak hydrogen bond and to interactions between partial charges on the N2O5 and on water. (6) The free-energy profile was calculated for transporting N2O5 from the gas phase through the interface and into bulk water. The corresponding concentration profile exhibits a propensity for N2O5 at the aqueous surface. The free energy barrier for entry from the surface into the bulk was determined to be 1.8 kcal mol-1. These findings are used to interpret recent experiments. We conclude with implications of this study for atmospheric chemistry.
PMID: 29926059
Vapniarsky N,Huwe LW,Arzi B,Houghton MK,Wong ME,Wilson JW,Hatcher DC,Hu JC,Athanasiou KA
Tissue engineering toward temporomandibular joint disc regeneration.
Sci Transl Med. 2018 Jun 20;10(446)
Treatments for temporomandibular joint (TMJ) disc thinning and perforation, conditions prevalent in TMJ pathologies, are palliative but not reparative. To address this, scaffold-free tissue-engineered implants were created using allogeneic, passaged costal chondrocytes. A combination of compressive and bioactive stimulation regimens produced implants with mechanical properties akin to those of the native disc. Efficacy in repairing disc thinning was examined in minipigs. Compared to empty controls, treatment with tissue-engineered implants restored disc integrity by inducing 4.4 times more complete defect closure, formed 3.4-fold stiffer repair tissue, and promoted 3.2-fold stiffer intralaminar fusion. The osteoarthritis score (indicative of degenerative changes) of the untreated group was 3.0-fold of the implant-treated group. This tissue engineering strategy paves the way for developing tissue-engineered implants as clinical treatments for TMJ disc thinning.
PMID: 29925634
Tsai SS
The Structural Enzymology of Iterative Aromatic Polyketide Synthases: A Critical Comparison with Fatty Acid Synthases.
Annu Rev Biochem. 2018 Jun 20;87:503-531
Polyketides are a large family of structurally complex natural products including compounds with important bioactivities. Polyketides are biosynthesized by polyketide synthases (PKSs), multienzyme complexes derived evolutionarily from fatty acid synthases (FASs). The focus of this review is to critically compare the properties of FASs with iterative aromatic PKSs, including type II PKSs and fungal type I nonreducing PKSs whose chemical logic is distinct from that of modular PKSs. This review focuses on structural and enzymological studies that reveal both similarities and striking differences between FASs and aromatic PKSs. The potential application of FAS and aromatic PKS structures for bioengineering future drugs and biofuels is highlighted.
PMID: 29925265
Traboulsi W,Sergent F,Boufettal H,Brouillet S,Slim R,Hoffmann P,Benlahfid M,Zhou QY,Balboni G,Onnis V,Bolze PA,Salomon A,Sauthier P,Mallet F,Aboussaouira T,Feige JJ,Benharouga M,Alfaidy N
Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression and .
Clin Cancer Res. 2017 Nov 15;23(22):7130-7140
Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We recently identified endocrine gland-derived vascular endothelial growth factor (EG-VEGF) as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors, PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy. Three approaches were used: (i) a clinical investigation comparing circulating EG-VEGF in control ( = 20) and in distinctive CHM ( = 38) and CC ( = 9) cohorts, (ii) an study investigating EG-VEGF effects on the CC cell line JEG3, and (iii) an study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice. Both placental and circulating EG-VEGF levels were increased in CHM and CC (×5) patients. EG-VEGF increased JEG3 proliferation, migration, and invasion in two-dimensional (2D) and three-dimensional (3D) culture systems. JEG3 injection in the placenta caused CC development with large metastases compared with their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions. Our work describes a novel preclinical animal model of CC and presents evidence that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared with the currently used multi-agent chemotherapies. .
PMID: 28899975
Michalska K,Nhan DQ,Willett JLE,Stols LM,Eschenfeldt WH,Jones AM,Nguyen JY,Koskiniemi S,Low DA,Goulding CW,Joachimiak A,Hayes CS
Functional plasticity of antibacterial EndoU toxins.
Mol Microbiol. 2018 Jun 20;
Bacteria use several different secretion systems to deliver toxic EndoU ribonucleases into neighboring cells. Here, we present the first structure of a prokaryotic EndoU toxin in complex with its cognate immunity protein. The contact-dependent growth inhibition toxin CdiA-CT from Escherichia coli STEC_O31 adopts the eukaryotic EndoU fold and shares greatest structural homology with the nuclease domain of coronavirus Nsp15. The toxin contains a canonical His-His-Lys catalytic triad in the same arrangement as eukaryotic EndoU domains, but lacks the uridylate-specific ribonuclease activity that characterizes the superfamily. Comparative sequence analysis indicates that bacterial EndoU domains segregate into at least three major clades based on structural variations in the N-terminal subdomain. Representative EndoU nucleases from clades I and II degrade tRNA molecules with little specificity. In contrast, CdiA-CT and other clade III toxins are specific anticodon nucleases that cleave tRNA between nucleotides C37 and m A38. These findings suggest that the EndoU fold is a versatile scaffold for the evolution of novel substrate specificities. Such functional plasticity may account for the widespread use of EndoU effectors by diverse inter-bacterial toxin delivery systems. This article is protected by copyright. All rights reserved.
PMID: 29923643
Britton J,Majumdar S,Weiss GA
Continuous flow biocatalysis.
Chem Soc Rev. 2018 Jun 20;
The continuous flow synthesis of active pharmaceutical ingredients, value-added chemicals, and materials has grown tremendously over the past ten years. This revolution in chemical manufacturing has resulted from innovations in both new methodology and technology. This field, however, has been predominantly focused on synthetic organic chemistry, and the use of biocatalysts in continuous flow systems is only now becoming popular. Although immobilized enzymes and whole cells in batch systems are common, their continuous flow counterparts have grown rapidly over the past two years. With continuous flow systems offering improved mixing, mass transfer, thermal control, pressurized processing, decreased variation, automation, process analytical technology, and in-line purification, the combination of biocatalysis and flow chemistry opens powerful new process windows. This Review explores continuous flow biocatalysts with emphasis on new technology, enzymes, whole cells, co-factor recycling, and immobilization methods for the synthesis of pharmaceuticals, value-added chemicals, and materials.
PMID: 29922795
Dai B,Chen C,Long Y,Zheng L,Zhao H,Bai X,Liu W,Zhang Y,Liu L,Guo T,Ding G,Lu C
Neural mechanisms for selectively tuning in to the target speaker in a naturalistic noisy situation.
Nat Commun. 2018 Jun 19;9(1):2405
The neural mechanism for selectively tuning in to a target speaker while tuning out the others in a multi-speaker situation (i.e., the cocktail-party effect) remains elusive. Here we addressed this issue by measuring brain activity simultaneously from a listener and from multiple speakers while they were involved in naturalistic conversations. Results consistently show selectively enhanced interpersonal neural synchronization (INS) between the listener and the attended speaker at left temporal-parietal junction, compared with that between the listener and the unattended speaker across different multi-speaker situations. Moreover, INS increases significantly prior to the occurrence of verbal responses, and even when the listener's brain activity precedes that of the speaker. The INS increase is independent of brain-to-speech synchronization in both the anatomical location and frequency range. These findings suggest that INS underlies the selective process in a multi-speaker situation through neural predictions at the content level but not the sensory level of speech.
PMID: 29921937
Fishbane S,Singh B,Kumbhat S,Wisemandle WA,Martin NE
Intravenous Epoetin Alfa-epbx versus Epoetin Alfa for Treatment of Anemia in End-Stage Kidney Disease.
Clin J Am Soc Nephrol. 2018 Jun 19;
This study was conducted to compare the safety and efficacy of intravenous epoetin alfa-epbx, an epoetin alfa biosimilar, to epoetin alfa in patients on hemodialysis with ESKD and anemia.
PMID: 29921734
Tunnicliffe RB,Collins RF,Ruiz Nivia HD,Sandri-Goldin RM,Golovanov AP
The ICP27 Homology Domain of the Human Cytomegalovirus Protein UL69 Adopts a Dimer-of-Dimers Structure.
MBio. 2018 Jun 19;9(3)
The UL69 protein from human cytomegalovirus (HCMV) is a multifunctional regulatory protein and a member of the ICP27 protein family conserved throughout herpesviruses. UL69 plays many roles during productive infection, including the regulation of viral gene expression, nuclear export of intronless viral RNAs, and control of host cell cycle progression. Throughout the ICP27 protein family, an ability to self-associate is correlated with the functions of these proteins in transactivating certain viral genes. Here, we determined the domain boundaries of a globular ICP27 homology domain of UL69, which mediates self-association, and characterized the oligomeric state of the isolated domain. Size exclusion chromatography coupled with multiangle light scattering (SEC-MALS) revealed that residues 200 to 540 form a stable homo-tetramer, whereas a shorter region comprising residues 248 to 536 forms a homo-dimer. Structural analysis of the UL69 tetramer by transmission electron microscopy (TEM) revealed a dimer-of-dimers three-dimensional envelope with bridge features likely from a region of the protein unique to betaherpesviruses. The data provide a structural template for tetramerization and improve our understanding of the structural diversity and features necessary for self-association within UL69 and the ICP27 family. Human cytomegalovirus (HCMV) infection is widespread in the human population but typically remains dormant in an asymptomatic latent state. HCMV causes disease in neonates and adults with suppressed or impaired immune function, as the virus is activated into a lytic state. All species of herpesvirus express a protein from the ICP27 family which functions as a posttranscriptional activator in the lytic state. In HCMV, this protein is called UL69. The region of sequence conservation in the ICP27 family is a folded domain that mediates protein interactions, including self-association and functions in transactivation. All members thus far analyzed homo-dimerize, with the exception of UL69, which forms higher-order oligomers. Here, we use biochemical and structural data to reveal that UL69 forms stable tetramers composed of a dimer of dimers and determine a region essential for cross-dimer stabilization.
PMID: 29921674
Oertel FC,Havla J,Roca-Fernández A,Lizak N,Zimmermann H,Motamedi S,Borisow N,White OB,Bellmann-Strobl J,Albrecht P,Ruprecht K,Jarius S,Palace J,Leite MI,Kuempfel T,Paul F,Brandt AU
Retinal ganglion cell loss in neuromyelitis optica: a longitudinal study.
J Neurol Neurosurg Psychiatry. 2018 Jun 19;
Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory conditions of the central nervous system and an important differential diagnosis of multiple sclerosis (MS). Unlike MS, the course is usually relapsing, and it is unclear, if progressive neurodegeneration contributes to disability. Therefore, we aimed to investigate if progressive retinal neuroaxonal damage occurs in aquaporin4-antibody-seropositive NMOSD.
PMID: 29921610
Issaian A,Faizi DJ,Bailey JO,Mayer P,Berionni G,Singleton DA,Blum SA
Mechanistic Studies of Formal Thioboration Reactions of Alkynes.
J Org Chem. 2017 08 04;82(15):8165-8178
Several formal heteroborylative cyclization reactions have been recently reported, but little physical-organic and mechanistic data are known. We now investigate the catalyst-free formal thioboration reaction of alkynes to gain mechanistic insight into B-chlorocatecholborane (ClBcat) in its new role as an alkynophilic Lewis acid in electrophilic cyclization/dealkylation reactions. In kinetic studies, the reaction is second-order globally and first-order with respect to both the 2-alkynylthioanisole substrate and the ClBcat electrophile, with activation parameters of ?G = 27.1 ± 0.1 kcal mol at 90 °C, ?H = 13.8 ± 1.0 kcal mol, and ?S = -37 ± 3 cal mol K, measured over the range 70-90 °C. Carbon kinetic isotope effects supported a rate-determining Ad3 mechanism wherein alkyne activation by neutral ClBcat is concerted with cyclative attack by nucleophilic sulfur. A Hammett study found a ? of -1.7, suggesting cationic charge buildup during the cyclization and supporting rate-determining concerted cyclization. Studies of the reaction with tris(pentafluorophenyl)borane (B(CF)), an activating agent capable of cyclization but not dealkylation, resulted in the isolation of a postcyclization zwitterionic intermediate. Kinetic studies via UV-vis spectroscopy with this boron reagent found second-order kinetics, supporting the likely relevancy of intermediates in this system to the ClBcat system. Computational studies comparing ClBcat with BCl as an activating agent showed why BCl, in contrast to ClBcat, failed to mediate the complete the cyclization/demethylation reaction sequence by itself. Overall, the results support a mechanism in which the ClBcat reagent serves a bifunctional role by sequentially activating the alkyne, despite being less electrophilic than other known alkyne-activating reagents and then providing chloride for post-rate-determining demethylation/neutralization of the resulting zwitterionic intermediate.
PMID: 28671461
Wang Y,Kreutzer AG,Truex NL,Nowick JS
A Tetramer Derived from Islet Amyloid Polypeptide.
J Org Chem. 2017 08 04;82(15):7905-7912
Aggregation of the islet amyloid polypeptide (IAPP) to form fibrils and oligomers is important in the progression of type 2 diabetes. This article describes X-ray crystallographic and solution-state NMR studies of peptides derived from residues 11-17 of IAPP that assemble to form tetramers. Incorporation of residues 11-17 of IAPP (RLANFLV) into a macrocyclic ß-sheet peptide results in a monomeric peptide that does not self-assemble to form oligomers. Mutation of Arg to the uncharged isostere citrulline gives peptide homologues that assemble to form tetramers in both the crystal state and in aqueous solution. The tetramers consist of hydrogen-bonded dimers that sandwich together through hydrophobic interactions. The tetramers share several features with structures reported for IAPP fibrils and demonstrate the importance of hydrogen bonding and hydrophobic interactions in the oligomerization of IAPP-derived peptides.
PMID: 28661686
Khambhati J,Allard-Ratick M,Dhindsa D,Lee S,Chen J,Sandesara PB,Quyyumi AA,Wong ND,Blumenthal RS,Sperling L
The Art of Cardiovascular Risk Assessment.
Clin Cardiol. 2018 Jun 19;
The authors would like to submit two corrections on the recently published manuscript, Art of Cardiovascular Risk Assessment. In section 4, the original sentence states: "However, the SCCT does not recommend use of a CAC score in low-risk patients with an ASCVD risk of < 10%." We would like to correct this to "Furthermore, the SCCT recommends consideration of a CAC score in those with a risk score of 5-20% and selectively in those with lower predicted risk who have a family history of premature ASCVD or other risk conditions." This article is protected by copyright. All rights reserved.
PMID: 29920711
Rosenbaum M,Goldsmith RL,Haddad F,Baldwin KM,Smiley R,Gallagher D,Leibel RL
Triiodothyronine and leptin repletion in humans similarly reverse weight-loss induced changes in skeletal muscle.
Am J Physiol Endocrinol Metab. 2018 Jun 19;
Subjects maintaining a 10% or greater dietary weight loss exhibit decreased circulating concentrations of bioactive thyroid hormones and increased skeletal muscle work efficiency largely due to increased expression of more efficient myosin heavy chain isoforms (MHCI) and significantly mediated by the adipocyte-derived hormone leptin. The primary purpose of this study was to examine the effects of triiodothyronine (T3) repletion on energy homeostasis and skeletal muscle physiology in weight-reduced subjects and to compare these results with the effects of leptin repletion. Nine healthy inpatient subjects with obesity were studied at usual weight (Wt) and following a 10% dietary weight loss while receiving 5 weeks of a placebo (Wt) of T3 (Wt) in a single blind crossover design. Primary outcome variables were skeletal muscle work efficiency and vastus lateralis muscle mRNA expression. These results were compared to the effects of leptin repletion in a population of 22 subjects some of whom were previously reported. At Wt there were significant increases in skeletal muscle work efficiency and in the relative expression of the more efficient/less efficient MHCI/MHCII isoforms, and a decrease in the ratio of the less efficient/more efficient SERCA1/SERCA2 isoforms. These changes were largely reversed by T3 repletion to a degree similar to that occurring with leptin repletion. These data support the hypothesis that the effects of leptin on energy expenditure in weight-reduced individuals are largely mediated by T3 and suggest that further study of the possible role of thyroid hormone repletion as adjunctive therapy to help sustain weight loss.
PMID: 29920214
Robinson JL,Corrada MM,Kovacs GG,Dominique M,Caswell C,Xie SX,Lee VM,Kawas CH,Trojanowski JQ
Non-Alzheimer's contributions to dementia and cognitive resilience in The 90+ Study.
Acta Neuropathol. 2018 Jun 18;
The diagnosis of Alzheimer's disease (AD) in the oldest-old is complicated by the increasing prevalence of age-related neurofibrillary tangles, plaques and non-AD pathologies such as cerebrovascular disease (CVD), hippocampal sclerosis (HS), aging-related tau astrogliopathy (ARTAG), as well as TDP-43 and Lewy pathology. The contribution of these non-AD pathologies to dementia and cognitive resilience is unclear. We assessed the level of AD neuropathologic change (ADNPC) and non-AD pathology in 185 participants enrolled in The 90+?Study with available cognitive assessments and brain tissue. Logistic regression models-adjusting for age, sex and education-determined the association between each pathology and dementia or between subgroups. 53% had dementia, primarily AD or mixed AD; 23% had cognitive impairment without dementia (CIND); 23% were not impaired. Both AD and non-AD pathology was prevalent. 100% had tangles, 81% had plaques, and both tangles and plaques associated with dementia. ARTAG distributed across limbic (70%), brainstem (39%) and cortical regions (24%). 49% had possible CVD and 26% had definite CVD, while HS was noted in 15%. Cortical ARTAG, CVD and HS were each associated with dementia, but limbic and brainstem ARTAGs were not. TDP-43 and Lewy pathologies were found in 36 and 17% and both associated with dementia. No pathology distinguished CIND and the not impaired. By NIA-AA criteria and dementia status, the cohort was subdivided into four groups: those with minimal ADNPC included the not dementia (ND) and Not AD dementia groups; and those with significant ADNPC included the Resilient without dementia and AD dementia groups. Compared to the ND group, the Not AD dementia group had more HS, cortical ARTAG, TDP-43, and Lewy pathology. Compared to the AD dementia group, the Resilient group had less CVD, no HS and less cortical ARTAG, TDP-43 and Lewy pathology. Our findings imply that reductions in non-AD pathologies including CVD contribute to cognitive resilience in the oldest-old.
PMID: 29916037
Orabi NA,Quint LE,Watcharotone K,Nan B,Williams DM,Kim KM
Distinguishing acute from chronic aortic dissections using CT imaging features.
Int J Cardiovasc Imaging. 2018 Jun 18;
The aim was to compare computed tomography (CT) features in acute and chronic aortic dissections (AADs and CADs) and determine if a certain combination of imaging features was reliably predictive of the acute versus chronic nature of disease in individual patients. Consecutive patients with aortic dissection and a chest CT scan were identified, and 120 CT scans corresponding to 105 patients were reviewed for a variety of imaging features. Statistical tests assessed for differences in the frequency of these features. A predictive model was created and tested on an additional 120 CT scans from 115 patients. Statistically significant features of AAD included periaortic confluent soft tissue opacity, curved dissection flap, and highly mobile dissection flap, and features of CAD included thick dissection flap, false lumen (FL) outer wall calcification, FL thrombus, dilated FL, and tear edges curling into the FL. The model predicted the chronicity of a dissection with an area under the curve of 0.98 (CI 0.98-1.00). AADs and CADs demonstrated significantly different CT imaging features.
PMID: 29915877
Gearhart AS,Batra AS
Isolated left bundle branch block progressing to complete heart block and asystole: A novel presentation of a desmin mutation.
HeartRhythm Case Rep. 2018 May;4(5):184-186
PMID: 29915714
Amber KT,Valdebran M,Grando SA
Non-Desmoglein Antibodies in Patients With Pemphigus Vulgaris.
Front Immunol. 2018;9:1190
Pemphigus vulgaris (PV) is a potentially life-threatening mucocutaneous autoimmune blistering disease. Patients develop non-healing erosions and blisters due to cell-cell detachment of keratinocytes (acantholysis), with subsequent suprabasal intraepidermal splitting. Identified almost 30?years ago, desmoglein-3 (Dsg3), a Ca-dependent cell adhesion molecule belonging to the cadherin family, has been considered the "primary" autoantigen in PV. Proteomic studies have identified numerous autoantibodies in patients with PV that have known roles in the physiology and cell adhesion of keratinocytes. Antibodies to these autoantibodies include desmocollins 1 and 3, several muscarinic and nicotinic acetylcholine receptor subtypes, mitochondrial proteins, human leukocyte antigen molecules, thyroid peroxidase, and hSPCA1-the Ca/Mn-ATPase encoded by ATP2C1, which is mutated in Hailey-Hailey disease. Several studies have identified direct pathogenic roles of these proteins, or synergistic roles when combined with Dsg3. We review the role of these direct and indirect mechanisms of non-desmoglein autoantibodies in the pathogenesis of PV.
PMID: 29915578
Wu L,Shi W,Long J,Guo X,Michailidou K,Beesley J,Bolla MK,Shu XO,Lu Y,Cai Q,Al-Ejeh F,Rozali E,Wang Q,Dennis J,Li B,Zeng C,Feng H,Gusev A,Barfield RT,Andrulis IL,Anton-Culver H,Arndt V,Aronson KJ,Auer PL,Barrdahl M,Baynes C,Beckmann MW,Benitez J,Bermisheva M,Blomqvist C,Bogdanova NV,Bojesen SE,Brauch H,Brenner H,Brinton L,Broberg P,Brucker SY,Burwinkel B,Caldés T,Canzian F,Carter BD,Castelao JE,Chang-Claude J,Chen X,Cheng TD,Christiansen H,Clarke CL, ,Collée M,Cornelissen S,Couch FJ,Cox D,Cox A,Cross SS,Cunningham JM,Czene K,Daly MB,Devilee P,Doheny KF,Dörk T,Dos-Santos-Silva I,Dumont M,Dwek M,Eccles DM,Eilber U,Eliassen AH,Engel C,Eriksson M,Fachal L,Fasching PA,Figueroa J,Flesch-Janys D,Fletcher O,Flyger H,Fritschi L,Gabrielson M,Gago-Dominguez M,Gapstur SM,García-Closas M,Gaudet MM,Ghoussaini M,Giles GG,Goldberg MS,Goldgar DE,González-Neira A,Guénel P,Hahnen E,Haiman CA,Håkansson N,Hall P,Hallberg E,Hamann U,Harrington P,Hein A,Hicks B,Hillemanns P,Hollestelle A,Hoover RN,Hopper JL,Huang G,Humphreys K,Hunter DJ,Jakubowska A,Janni W,John EM,Johnson N,Jones K,Jones ME,Jung A,Kaaks R,Kerin MJ,Khusnutdinova E,Kosma VM,Kristensen VN,Lambrechts D,Le Marchand L,Li J,Lindström S,Lissowska J,Lo WY,Loibl S,Lubinski J,Luccarini C,Lux MP,MacInnis RJ,Maishman T,Kostovska IM,Mannermaa A,Manson JE,Margolin S,Mavroudis D,Meijers-Heijboer H,Meindl A,Menon U,Meyer J,Mulligan AM,Neuhausen SL,Nevanlinna H,Neven P,Nielsen SF,Nordestgaard BG,Olopade OI,Olson JE,Olsson H,Peterlongo P,Peto J,Plaseska-Karanfilska D,Prentice R,Presneau N,Pylkäs K,Rack B,Radice P,Rahman N,Rennert G,Rennert HS,Rhenius V,Romero A,Romm J,Rudolph A,Saloustros E,Sandler DP,Sawyer EJ,Schmidt MK,Schmutzler RK,Schneeweiss A,Scott RJ,Scott CG,Seal S,Shah M,Shrubsole MJ,Smeets A,Southey MC,Spinelli JJ,Stone J,Surowy H,Swerdlow AJ,Tamimi RM,Tapper W,Taylor JA,Terry MB,Tessier DC,Thomas A,Thöne K,Tollenaar RAEM,Torres D,Truong T,Untch M,Vachon C,Van Den Berg D,Vincent D,Waisfisz Q,Weinberg CR,Wendt C,Whittemore AS,Wildiers H,Willett WC,Winqvist R,Wolk A,Xia L,Yang XR,Ziogas A,Ziv E, ,Dunning AM,Pharoah PDP,Simard J,Milne RL,Edwards SL,Kraft P,Easton DF,Chenevix-Trench G,Zheng W
A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.
Nat Genet. 2018 Jun 18;
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P?
PMID: 29915430
Jiang L,Johnson A,Pratte K,Beals J,Bullock A,Manson SM,
Long-term Outcomes of Lifestyle Intervention to Prevent Diabetes in American Indian and Alaska Native Communities: The Special Diabetes Program for Indians Diabetes Prevention Program.
Diabetes Care. 2018 Jun 18;
Evidence for long-term translational effectiveness of lifestyle interventions in minority populations is scarce. This article reports long-term outcomes, for up to 10 years, of such an intervention to prevent diabetes in American Indian and Alaska Native (AI/AN) communities.
PMID: 29915128
Morgan TR
Is Granulocyte Colony Stimulating Factor a New Treatment for Alcoholic Hepatitis?
Clin Gastroenterol Hepatol. 2018 Jun 15;
PMID: 29913276
Deep Learning Localizes and Identifies Polyps in Real Time with 96% Accuracy in Screening Colonoscopy.
Gastroenterology. 2018 Jun 18;
The benefit of colonoscopy for colorectal cancer prevention depends on the adenoma detection rate (ADR). The ADR should reflect adenoma prevalence rate, estimated to be greater than 50% among the screening-age population. Yet the rate of adenoma detection by colonoscopists varies from 7% to 53%. It is estimated that every 1% increase in ADR reduces the risk of interval colorectal cancers by 3-6%. New strategies are needed to increase the ADR during colonoscopy. We tested the ability of computer-assisted image analysis, with convolutional neural networks (a deep learning model for image analysis), to improve polyp detection, a surrogate of ADR.
PMID: 29928897
Bruckner TA,Catalano R
Selection and population health: Theory and typology of research.
SSM Popul Health. 2018 Aug;5:101-113
Public health researchers may assume, based on the fetal origins literature, that "scarring" of birth cohorts describes the population response to modern-day stressors. We contend, based on extensive literature concerned with selection , that this assumption remains questionable. At least a third and likely many more of human conceptions fail to yield a live birth. Those that survive to birth, moreover, do not represent their conception cohort. Increasing data availability has led to an improved understanding of selection and its implications for population health. The literature describing selection , however, receives relatively little attention from social scientists. We aim to draw attention to the rich theoretical and empirical literature on selection by offering a typology that organizes this diverse work along dimensions we think important, if not familiar, to those studying population health. We further use the typology to identify important gaps in the literature. This work should interest social scientists for two reasons. First, phenomena of broad scholarly interest (i.e., social connectivity, bereavement) affect the extent and timing of selection . Second, the life-course health of a cohort depends in part on the strength of such selection. We conclude by identifying new research directions and with a reconciliation of the apparent contradiction between the "fetal origins" literature and that describing selection .
PMID: 29928686
Monto MA,McRee N,Deryck FS
Nonsuicidal Self-Injury Among a Representative Sample of US Adolescents, 2015.
Am J Public Health. 2018 Jun 21;:e1-e7
To provide prevalence estimates of adolescent nonsuicidal self-injury (NSSI) based on large, representative, nonclinical samples of high-school students, and to explore gender differences in health risks associated with NSSI.
PMID: 29927642
Van Doorslaer K,Chen Z,Bernard HU,Chan PKS,DeSalle R,Dillner J,Forslund O,Haga T,McBride AA,Villa LL,Burk RD,Ictv Report Consortium
ICTV Virus Taxonomy Profile: Papillomaviridae.
J Gen Virol. 2018 Jun 21;
The Papillomaviridae is a family of small, non-enveloped viruses with double-stranded DNA genomes of 5?748 to 8?607?bp. Their classification is based on pairwise nucleotide sequence identity across the L1 open reading frame. Members of the Papillomaviridae primarily infect mucosal and keratinised epithelia, and have been isolated from fish, reptiles, birds and mammals. Despite a long co-evolutionary history with their hosts, some papillomaviruses are pathogens of their natural host species. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Papillomaviridae, which is available at http://www.ictv.global/report/papillomaviridae.
PMID: 29927370
Hirshberg B,Rossich Molina E,Götz AW,Hammerich AD,Nathanson GM,Bertram TH,Johnson MA,Gerber RB
NO at water surfaces: binding forces, charge separation, energy accommodation and atmospheric implications.
Phys Chem Chem Phys. 2018 Jun 21;
Interactions of N2O5 with water media are of great importance in atmospheric chemistry and have been the topic of extensive research for over two decades. Nevertheless, many physical and chemical properties of N2O5 at the surface or in bulk water are unknown or not microscopically understood. This study presents extensive new results on the physical properties of N2O5 in water and at the surface of water, with a focus on their microscopic basis. The main results are obtained using ab initio molecular dynamics and calculations of a potential of mean force. These include: (1) collisions of N2O5 with water at 300 K lead to trapping at the surface for at least 20 ps and with 95% probability. (2) During that time, there is no N2O5 hydrolysis, evaporation, or entry into the bulk. (3) Charge separation between the NO2 and NO3 groups of N2O5, fluctuates significantly with time. (4) Energy accommodation of the colliding N2O5 at the surface takes place within picoseconds. (5) The binding energy of N2O5 to a nanosize amorphous ice particle at 0 K is on the order of 15 kcal mol-1 for the main surface site. N2O5 binding to the cluster is due to one weak hydrogen bond and to interactions between partial charges on the N2O5 and on water. (6) The free-energy profile was calculated for transporting N2O5 from the gas phase through the interface and into bulk water. The corresponding concentration profile exhibits a propensity for N2O5 at the aqueous surface. The free energy barrier for entry from the surface into the bulk was determined to be 1.8 kcal mol-1. These findings are used to interpret recent experiments. We conclude with implications of this study for atmospheric chemistry.
PMID: 29926059
Vapniarsky N,Huwe LW,Arzi B,Houghton MK,Wong ME,Wilson JW,Hatcher DC,Hu JC,Athanasiou KA
Tissue engineering toward temporomandibular joint disc regeneration.
Sci Transl Med. 2018 Jun 20;10(446)
Treatments for temporomandibular joint (TMJ) disc thinning and perforation, conditions prevalent in TMJ pathologies, are palliative but not reparative. To address this, scaffold-free tissue-engineered implants were created using allogeneic, passaged costal chondrocytes. A combination of compressive and bioactive stimulation regimens produced implants with mechanical properties akin to those of the native disc. Efficacy in repairing disc thinning was examined in minipigs. Compared to empty controls, treatment with tissue-engineered implants restored disc integrity by inducing 4.4 times more complete defect closure, formed 3.4-fold stiffer repair tissue, and promoted 3.2-fold stiffer intralaminar fusion. The osteoarthritis score (indicative of degenerative changes) of the untreated group was 3.0-fold of the implant-treated group. This tissue engineering strategy paves the way for developing tissue-engineered implants as clinical treatments for TMJ disc thinning.
PMID: 29925634
Tsai SS
The Structural Enzymology of Iterative Aromatic Polyketide Synthases: A Critical Comparison with Fatty Acid Synthases.
Annu Rev Biochem. 2018 Jun 20;87:503-531
Polyketides are a large family of structurally complex natural products including compounds with important bioactivities. Polyketides are biosynthesized by polyketide synthases (PKSs), multienzyme complexes derived evolutionarily from fatty acid synthases (FASs). The focus of this review is to critically compare the properties of FASs with iterative aromatic PKSs, including type II PKSs and fungal type I nonreducing PKSs whose chemical logic is distinct from that of modular PKSs. This review focuses on structural and enzymological studies that reveal both similarities and striking differences between FASs and aromatic PKSs. The potential application of FAS and aromatic PKS structures for bioengineering future drugs and biofuels is highlighted.
PMID: 29925265
Traboulsi W,Sergent F,Boufettal H,Brouillet S,Slim R,Hoffmann P,Benlahfid M,Zhou QY,Balboni G,Onnis V,Bolze PA,Salomon A,Sauthier P,Mallet F,Aboussaouira T,Feige JJ,Benharouga M,Alfaidy N
Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression and .
Clin Cancer Res. 2017 Nov 15;23(22):7130-7140
Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We recently identified endocrine gland-derived vascular endothelial growth factor (EG-VEGF) as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors, PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy. Three approaches were used: (i) a clinical investigation comparing circulating EG-VEGF in control ( = 20) and in distinctive CHM ( = 38) and CC ( = 9) cohorts, (ii) an study investigating EG-VEGF effects on the CC cell line JEG3, and (iii) an study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice. Both placental and circulating EG-VEGF levels were increased in CHM and CC (×5) patients. EG-VEGF increased JEG3 proliferation, migration, and invasion in two-dimensional (2D) and three-dimensional (3D) culture systems. JEG3 injection in the placenta caused CC development with large metastases compared with their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions. Our work describes a novel preclinical animal model of CC and presents evidence that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared with the currently used multi-agent chemotherapies. .
PMID: 28899975
Michalska K,Nhan DQ,Willett JLE,Stols LM,Eschenfeldt WH,Jones AM,Nguyen JY,Koskiniemi S,Low DA,Goulding CW,Joachimiak A,Hayes CS
Functional plasticity of antibacterial EndoU toxins.
Mol Microbiol. 2018 Jun 20;
Bacteria use several different secretion systems to deliver toxic EndoU ribonucleases into neighboring cells. Here, we present the first structure of a prokaryotic EndoU toxin in complex with its cognate immunity protein. The contact-dependent growth inhibition toxin CdiA-CT from Escherichia coli STEC_O31 adopts the eukaryotic EndoU fold and shares greatest structural homology with the nuclease domain of coronavirus Nsp15. The toxin contains a canonical His-His-Lys catalytic triad in the same arrangement as eukaryotic EndoU domains, but lacks the uridylate-specific ribonuclease activity that characterizes the superfamily. Comparative sequence analysis indicates that bacterial EndoU domains segregate into at least three major clades based on structural variations in the N-terminal subdomain. Representative EndoU nucleases from clades I and II degrade tRNA molecules with little specificity. In contrast, CdiA-CT and other clade III toxins are specific anticodon nucleases that cleave tRNA between nucleotides C37 and m A38. These findings suggest that the EndoU fold is a versatile scaffold for the evolution of novel substrate specificities. Such functional plasticity may account for the widespread use of EndoU effectors by diverse inter-bacterial toxin delivery systems. This article is protected by copyright. All rights reserved.
PMID: 29923643
Britton J,Majumdar S,Weiss GA
Continuous flow biocatalysis.
Chem Soc Rev. 2018 Jun 20;
The continuous flow synthesis of active pharmaceutical ingredients, value-added chemicals, and materials has grown tremendously over the past ten years. This revolution in chemical manufacturing has resulted from innovations in both new methodology and technology. This field, however, has been predominantly focused on synthetic organic chemistry, and the use of biocatalysts in continuous flow systems is only now becoming popular. Although immobilized enzymes and whole cells in batch systems are common, their continuous flow counterparts have grown rapidly over the past two years. With continuous flow systems offering improved mixing, mass transfer, thermal control, pressurized processing, decreased variation, automation, process analytical technology, and in-line purification, the combination of biocatalysis and flow chemistry opens powerful new process windows. This Review explores continuous flow biocatalysts with emphasis on new technology, enzymes, whole cells, co-factor recycling, and immobilization methods for the synthesis of pharmaceuticals, value-added chemicals, and materials.
PMID: 29922795
Dai B,Chen C,Long Y,Zheng L,Zhao H,Bai X,Liu W,Zhang Y,Liu L,Guo T,Ding G,Lu C
Neural mechanisms for selectively tuning in to the target speaker in a naturalistic noisy situation.
Nat Commun. 2018 Jun 19;9(1):2405
The neural mechanism for selectively tuning in to a target speaker while tuning out the others in a multi-speaker situation (i.e., the cocktail-party effect) remains elusive. Here we addressed this issue by measuring brain activity simultaneously from a listener and from multiple speakers while they were involved in naturalistic conversations. Results consistently show selectively enhanced interpersonal neural synchronization (INS) between the listener and the attended speaker at left temporal-parietal junction, compared with that between the listener and the unattended speaker across different multi-speaker situations. Moreover, INS increases significantly prior to the occurrence of verbal responses, and even when the listener's brain activity precedes that of the speaker. The INS increase is independent of brain-to-speech synchronization in both the anatomical location and frequency range. These findings suggest that INS underlies the selective process in a multi-speaker situation through neural predictions at the content level but not the sensory level of speech.
PMID: 29921937
Fishbane S,Singh B,Kumbhat S,Wisemandle WA,Martin NE
Intravenous Epoetin Alfa-epbx versus Epoetin Alfa for Treatment of Anemia in End-Stage Kidney Disease.
Clin J Am Soc Nephrol. 2018 Jun 19;
This study was conducted to compare the safety and efficacy of intravenous epoetin alfa-epbx, an epoetin alfa biosimilar, to epoetin alfa in patients on hemodialysis with ESKD and anemia.
PMID: 29921734
Tunnicliffe RB,Collins RF,Ruiz Nivia HD,Sandri-Goldin RM,Golovanov AP
The ICP27 Homology Domain of the Human Cytomegalovirus Protein UL69 Adopts a Dimer-of-Dimers Structure.
MBio. 2018 Jun 19;9(3)
The UL69 protein from human cytomegalovirus (HCMV) is a multifunctional regulatory protein and a member of the ICP27 protein family conserved throughout herpesviruses. UL69 plays many roles during productive infection, including the regulation of viral gene expression, nuclear export of intronless viral RNAs, and control of host cell cycle progression. Throughout the ICP27 protein family, an ability to self-associate is correlated with the functions of these proteins in transactivating certain viral genes. Here, we determined the domain boundaries of a globular ICP27 homology domain of UL69, which mediates self-association, and characterized the oligomeric state of the isolated domain. Size exclusion chromatography coupled with multiangle light scattering (SEC-MALS) revealed that residues 200 to 540 form a stable homo-tetramer, whereas a shorter region comprising residues 248 to 536 forms a homo-dimer. Structural analysis of the UL69 tetramer by transmission electron microscopy (TEM) revealed a dimer-of-dimers three-dimensional envelope with bridge features likely from a region of the protein unique to betaherpesviruses. The data provide a structural template for tetramerization and improve our understanding of the structural diversity and features necessary for self-association within UL69 and the ICP27 family. Human cytomegalovirus (HCMV) infection is widespread in the human population but typically remains dormant in an asymptomatic latent state. HCMV causes disease in neonates and adults with suppressed or impaired immune function, as the virus is activated into a lytic state. All species of herpesvirus express a protein from the ICP27 family which functions as a posttranscriptional activator in the lytic state. In HCMV, this protein is called UL69. The region of sequence conservation in the ICP27 family is a folded domain that mediates protein interactions, including self-association and functions in transactivation. All members thus far analyzed homo-dimerize, with the exception of UL69, which forms higher-order oligomers. Here, we use biochemical and structural data to reveal that UL69 forms stable tetramers composed of a dimer of dimers and determine a region essential for cross-dimer stabilization.
PMID: 29921674
Oertel FC,Havla J,Roca-Fernández A,Lizak N,Zimmermann H,Motamedi S,Borisow N,White OB,Bellmann-Strobl J,Albrecht P,Ruprecht K,Jarius S,Palace J,Leite MI,Kuempfel T,Paul F,Brandt AU
Retinal ganglion cell loss in neuromyelitis optica: a longitudinal study.
J Neurol Neurosurg Psychiatry. 2018 Jun 19;
Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory conditions of the central nervous system and an important differential diagnosis of multiple sclerosis (MS). Unlike MS, the course is usually relapsing, and it is unclear, if progressive neurodegeneration contributes to disability. Therefore, we aimed to investigate if progressive retinal neuroaxonal damage occurs in aquaporin4-antibody-seropositive NMOSD.
PMID: 29921610
Issaian A,Faizi DJ,Bailey JO,Mayer P,Berionni G,Singleton DA,Blum SA
Mechanistic Studies of Formal Thioboration Reactions of Alkynes.
J Org Chem. 2017 08 04;82(15):8165-8178
Several formal heteroborylative cyclization reactions have been recently reported, but little physical-organic and mechanistic data are known. We now investigate the catalyst-free formal thioboration reaction of alkynes to gain mechanistic insight into B-chlorocatecholborane (ClBcat) in its new role as an alkynophilic Lewis acid in electrophilic cyclization/dealkylation reactions. In kinetic studies, the reaction is second-order globally and first-order with respect to both the 2-alkynylthioanisole substrate and the ClBcat electrophile, with activation parameters of ?G = 27.1 ± 0.1 kcal mol at 90 °C, ?H = 13.8 ± 1.0 kcal mol, and ?S = -37 ± 3 cal mol K, measured over the range 70-90 °C. Carbon kinetic isotope effects supported a rate-determining Ad3 mechanism wherein alkyne activation by neutral ClBcat is concerted with cyclative attack by nucleophilic sulfur. A Hammett study found a ? of -1.7, suggesting cationic charge buildup during the cyclization and supporting rate-determining concerted cyclization. Studies of the reaction with tris(pentafluorophenyl)borane (B(CF)), an activating agent capable of cyclization but not dealkylation, resulted in the isolation of a postcyclization zwitterionic intermediate. Kinetic studies via UV-vis spectroscopy with this boron reagent found second-order kinetics, supporting the likely relevancy of intermediates in this system to the ClBcat system. Computational studies comparing ClBcat with BCl as an activating agent showed why BCl, in contrast to ClBcat, failed to mediate the complete the cyclization/demethylation reaction sequence by itself. Overall, the results support a mechanism in which the ClBcat reagent serves a bifunctional role by sequentially activating the alkyne, despite being less electrophilic than other known alkyne-activating reagents and then providing chloride for post-rate-determining demethylation/neutralization of the resulting zwitterionic intermediate.
PMID: 28671461
Wang Y,Kreutzer AG,Truex NL,Nowick JS
A Tetramer Derived from Islet Amyloid Polypeptide.
J Org Chem. 2017 08 04;82(15):7905-7912
Aggregation of the islet amyloid polypeptide (IAPP) to form fibrils and oligomers is important in the progression of type 2 diabetes. This article describes X-ray crystallographic and solution-state NMR studies of peptides derived from residues 11-17 of IAPP that assemble to form tetramers. Incorporation of residues 11-17 of IAPP (RLANFLV) into a macrocyclic ß-sheet peptide results in a monomeric peptide that does not self-assemble to form oligomers. Mutation of Arg to the uncharged isostere citrulline gives peptide homologues that assemble to form tetramers in both the crystal state and in aqueous solution. The tetramers consist of hydrogen-bonded dimers that sandwich together through hydrophobic interactions. The tetramers share several features with structures reported for IAPP fibrils and demonstrate the importance of hydrogen bonding and hydrophobic interactions in the oligomerization of IAPP-derived peptides.
PMID: 28661686
Khambhati J,Allard-Ratick M,Dhindsa D,Lee S,Chen J,Sandesara PB,Quyyumi AA,Wong ND,Blumenthal RS,Sperling L
The Art of Cardiovascular Risk Assessment.
Clin Cardiol. 2018 Jun 19;
The authors would like to submit two corrections on the recently published manuscript, Art of Cardiovascular Risk Assessment. In section 4, the original sentence states: "However, the SCCT does not recommend use of a CAC score in low-risk patients with an ASCVD risk of < 10%." We would like to correct this to "Furthermore, the SCCT recommends consideration of a CAC score in those with a risk score of 5-20% and selectively in those with lower predicted risk who have a family history of premature ASCVD or other risk conditions." This article is protected by copyright. All rights reserved.
PMID: 29920711
Rosenbaum M,Goldsmith RL,Haddad F,Baldwin KM,Smiley R,Gallagher D,Leibel RL
Triiodothyronine and leptin repletion in humans similarly reverse weight-loss induced changes in skeletal muscle.
Am J Physiol Endocrinol Metab. 2018 Jun 19;
Subjects maintaining a 10% or greater dietary weight loss exhibit decreased circulating concentrations of bioactive thyroid hormones and increased skeletal muscle work efficiency largely due to increased expression of more efficient myosin heavy chain isoforms (MHCI) and significantly mediated by the adipocyte-derived hormone leptin. The primary purpose of this study was to examine the effects of triiodothyronine (T3) repletion on energy homeostasis and skeletal muscle physiology in weight-reduced subjects and to compare these results with the effects of leptin repletion. Nine healthy inpatient subjects with obesity were studied at usual weight (Wt) and following a 10% dietary weight loss while receiving 5 weeks of a placebo (Wt) of T3 (Wt) in a single blind crossover design. Primary outcome variables were skeletal muscle work efficiency and vastus lateralis muscle mRNA expression. These results were compared to the effects of leptin repletion in a population of 22 subjects some of whom were previously reported. At Wt there were significant increases in skeletal muscle work efficiency and in the relative expression of the more efficient/less efficient MHCI/MHCII isoforms, and a decrease in the ratio of the less efficient/more efficient SERCA1/SERCA2 isoforms. These changes were largely reversed by T3 repletion to a degree similar to that occurring with leptin repletion. These data support the hypothesis that the effects of leptin on energy expenditure in weight-reduced individuals are largely mediated by T3 and suggest that further study of the possible role of thyroid hormone repletion as adjunctive therapy to help sustain weight loss.
PMID: 29920214
Robinson JL,Corrada MM,Kovacs GG,Dominique M,Caswell C,Xie SX,Lee VM,Kawas CH,Trojanowski JQ
Non-Alzheimer's contributions to dementia and cognitive resilience in The 90+ Study.
Acta Neuropathol. 2018 Jun 18;
The diagnosis of Alzheimer's disease (AD) in the oldest-old is complicated by the increasing prevalence of age-related neurofibrillary tangles, plaques and non-AD pathologies such as cerebrovascular disease (CVD), hippocampal sclerosis (HS), aging-related tau astrogliopathy (ARTAG), as well as TDP-43 and Lewy pathology. The contribution of these non-AD pathologies to dementia and cognitive resilience is unclear. We assessed the level of AD neuropathologic change (ADNPC) and non-AD pathology in 185 participants enrolled in The 90+?Study with available cognitive assessments and brain tissue. Logistic regression models-adjusting for age, sex and education-determined the association between each pathology and dementia or between subgroups. 53% had dementia, primarily AD or mixed AD; 23% had cognitive impairment without dementia (CIND); 23% were not impaired. Both AD and non-AD pathology was prevalent. 100% had tangles, 81% had plaques, and both tangles and plaques associated with dementia. ARTAG distributed across limbic (70%), brainstem (39%) and cortical regions (24%). 49% had possible CVD and 26% had definite CVD, while HS was noted in 15%. Cortical ARTAG, CVD and HS were each associated with dementia, but limbic and brainstem ARTAGs were not. TDP-43 and Lewy pathologies were found in 36 and 17% and both associated with dementia. No pathology distinguished CIND and the not impaired. By NIA-AA criteria and dementia status, the cohort was subdivided into four groups: those with minimal ADNPC included the not dementia (ND) and Not AD dementia groups; and those with significant ADNPC included the Resilient without dementia and AD dementia groups. Compared to the ND group, the Not AD dementia group had more HS, cortical ARTAG, TDP-43, and Lewy pathology. Compared to the AD dementia group, the Resilient group had less CVD, no HS and less cortical ARTAG, TDP-43 and Lewy pathology. Our findings imply that reductions in non-AD pathologies including CVD contribute to cognitive resilience in the oldest-old.
PMID: 29916037
Orabi NA,Quint LE,Watcharotone K,Nan B,Williams DM,Kim KM
Distinguishing acute from chronic aortic dissections using CT imaging features.
Int J Cardiovasc Imaging. 2018 Jun 18;
The aim was to compare computed tomography (CT) features in acute and chronic aortic dissections (AADs and CADs) and determine if a certain combination of imaging features was reliably predictive of the acute versus chronic nature of disease in individual patients. Consecutive patients with aortic dissection and a chest CT scan were identified, and 120 CT scans corresponding to 105 patients were reviewed for a variety of imaging features. Statistical tests assessed for differences in the frequency of these features. A predictive model was created and tested on an additional 120 CT scans from 115 patients. Statistically significant features of AAD included periaortic confluent soft tissue opacity, curved dissection flap, and highly mobile dissection flap, and features of CAD included thick dissection flap, false lumen (FL) outer wall calcification, FL thrombus, dilated FL, and tear edges curling into the FL. The model predicted the chronicity of a dissection with an area under the curve of 0.98 (CI 0.98-1.00). AADs and CADs demonstrated significantly different CT imaging features.
PMID: 29915877
Gearhart AS,Batra AS
Isolated left bundle branch block progressing to complete heart block and asystole: A novel presentation of a desmin mutation.
HeartRhythm Case Rep. 2018 May;4(5):184-186
PMID: 29915714
Amber KT,Valdebran M,Grando SA
Non-Desmoglein Antibodies in Patients With Pemphigus Vulgaris.
Front Immunol. 2018;9:1190
Pemphigus vulgaris (PV) is a potentially life-threatening mucocutaneous autoimmune blistering disease. Patients develop non-healing erosions and blisters due to cell-cell detachment of keratinocytes (acantholysis), with subsequent suprabasal intraepidermal splitting. Identified almost 30?years ago, desmoglein-3 (Dsg3), a Ca-dependent cell adhesion molecule belonging to the cadherin family, has been considered the "primary" autoantigen in PV. Proteomic studies have identified numerous autoantibodies in patients with PV that have known roles in the physiology and cell adhesion of keratinocytes. Antibodies to these autoantibodies include desmocollins 1 and 3, several muscarinic and nicotinic acetylcholine receptor subtypes, mitochondrial proteins, human leukocyte antigen molecules, thyroid peroxidase, and hSPCA1-the Ca/Mn-ATPase encoded by ATP2C1, which is mutated in Hailey-Hailey disease. Several studies have identified direct pathogenic roles of these proteins, or synergistic roles when combined with Dsg3. We review the role of these direct and indirect mechanisms of non-desmoglein autoantibodies in the pathogenesis of PV.
PMID: 29915578
Wu L,Shi W,Long J,Guo X,Michailidou K,Beesley J,Bolla MK,Shu XO,Lu Y,Cai Q,Al-Ejeh F,Rozali E,Wang Q,Dennis J,Li B,Zeng C,Feng H,Gusev A,Barfield RT,Andrulis IL,Anton-Culver H,Arndt V,Aronson KJ,Auer PL,Barrdahl M,Baynes C,Beckmann MW,Benitez J,Bermisheva M,Blomqvist C,Bogdanova NV,Bojesen SE,Brauch H,Brenner H,Brinton L,Broberg P,Brucker SY,Burwinkel B,Caldés T,Canzian F,Carter BD,Castelao JE,Chang-Claude J,Chen X,Cheng TD,Christiansen H,Clarke CL, ,Collée M,Cornelissen S,Couch FJ,Cox D,Cox A,Cross SS,Cunningham JM,Czene K,Daly MB,Devilee P,Doheny KF,Dörk T,Dos-Santos-Silva I,Dumont M,Dwek M,Eccles DM,Eilber U,Eliassen AH,Engel C,Eriksson M,Fachal L,Fasching PA,Figueroa J,Flesch-Janys D,Fletcher O,Flyger H,Fritschi L,Gabrielson M,Gago-Dominguez M,Gapstur SM,García-Closas M,Gaudet MM,Ghoussaini M,Giles GG,Goldberg MS,Goldgar DE,González-Neira A,Guénel P,Hahnen E,Haiman CA,Håkansson N,Hall P,Hallberg E,Hamann U,Harrington P,Hein A,Hicks B,Hillemanns P,Hollestelle A,Hoover RN,Hopper JL,Huang G,Humphreys K,Hunter DJ,Jakubowska A,Janni W,John EM,Johnson N,Jones K,Jones ME,Jung A,Kaaks R,Kerin MJ,Khusnutdinova E,Kosma VM,Kristensen VN,Lambrechts D,Le Marchand L,Li J,Lindström S,Lissowska J,Lo WY,Loibl S,Lubinski J,Luccarini C,Lux MP,MacInnis RJ,Maishman T,Kostovska IM,Mannermaa A,Manson JE,Margolin S,Mavroudis D,Meijers-Heijboer H,Meindl A,Menon U,Meyer J,Mulligan AM,Neuhausen SL,Nevanlinna H,Neven P,Nielsen SF,Nordestgaard BG,Olopade OI,Olson JE,Olsson H,Peterlongo P,Peto J,Plaseska-Karanfilska D,Prentice R,Presneau N,Pylkäs K,Rack B,Radice P,Rahman N,Rennert G,Rennert HS,Rhenius V,Romero A,Romm J,Rudolph A,Saloustros E,Sandler DP,Sawyer EJ,Schmidt MK,Schmutzler RK,Schneeweiss A,Scott RJ,Scott CG,Seal S,Shah M,Shrubsole MJ,Smeets A,Southey MC,Spinelli JJ,Stone J,Surowy H,Swerdlow AJ,Tamimi RM,Tapper W,Taylor JA,Terry MB,Tessier DC,Thomas A,Thöne K,Tollenaar RAEM,Torres D,Truong T,Untch M,Vachon C,Van Den Berg D,Vincent D,Waisfisz Q,Weinberg CR,Wendt C,Whittemore AS,Wildiers H,Willett WC,Winqvist R,Wolk A,Xia L,Yang XR,Ziogas A,Ziv E, ,Dunning AM,Pharoah PDP,Simard J,Milne RL,Edwards SL,Kraft P,Easton DF,Chenevix-Trench G,Zheng W
A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.
Nat Genet. 2018 Jun 18;
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P?
PMID: 29915430
Jiang L,Johnson A,Pratte K,Beals J,Bullock A,Manson SM,
Long-term Outcomes of Lifestyle Intervention to Prevent Diabetes in American Indian and Alaska Native Communities: The Special Diabetes Program for Indians Diabetes Prevention Program.
Diabetes Care. 2018 Jun 18;
Evidence for long-term translational effectiveness of lifestyle interventions in minority populations is scarce. This article reports long-term outcomes, for up to 10 years, of such an intervention to prevent diabetes in American Indian and Alaska Native (AI/AN) communities.
PMID: 29915128
Morgan TR
Is Granulocyte Colony Stimulating Factor a New Treatment for Alcoholic Hepatitis?
Clin Gastroenterol Hepatol. 2018 Jun 15;
PMID: 29913276
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