Lysophosphatidylcholine as an adjuvant for lentiviral vector mediated gene transfer to airway epithelium: effect of acyl chain length

Extent: 11p.Background Poor gene transfer efficiency has been a major problem in developing an effective gene therapy for cystic fibrosis (CF) airway disease. Lysophosphatidylcholine (LPC), a natural airway surfactant, can enhance viral gene transfer in animal models. We examined the electrophysiological and physical effect of airway pre-treatment with variants of LPC on lentiviral (LV) vector gene transfer efficiency in murine nasal airways in vivo. Methods Gene transfer was assessed after 1 week following nasal instillations of a VSV-G pseudotype LV vector pre-treated with a low and high dose of LPC variants. The electrophysiological effects of a range of LPC variants were assessed by nasal transepithelial potential difference measurements (TPD) to determine tight junction permeability. Any physical changes to the epithelium from administration of the LPC variants were noted by histological methods in airway tissue harvested after 1 hour. Results Gene transduction was significantly greater compared to control (PBS) for our standard LPC (palmitoyl/stearoyl mixture) treatment and for the majority of the other LPC variants with longer acyl chain lengths. The LPC variant heptadecanoyl also produced significantly greater LV gene transfer compared to our standard LPC mixture. LV gene transfer and the transepithelial depolarization produced by the 0.1% LPC variants at 1 hour were strongly correlated (r2 = 0.94), but at the 1% concentration the correlation was less strong (r2 = 0.59). LPC variants that displayed minor to moderate levels of disruption to the airway epithelium were clearly associated with higher LV gene transfer. Conclusions These findings show the LPC variants effect on airway barrier function and their correlation to the effectiveness of gene expression. The enhanced expression produced by a number of LPC variants should provide new options for preclinical development of efficient airway gene transfer techniques.Patricia Cmielewski, Don S. Anson and David W. Parson

Role of Cellular Heparan Sulfate Proteoglycans in Infection of Human Adenovirus Serotype 3 and 35

Species B human adenoviruses (Ads) are increasingly associated with outbreaks of acute respiratory disease in U.S. military personnel and civil population. The initial interaction of Ads with cellular attachment receptors on host cells is via Ad fiber knob protein. Our previous studies showed that one species B Ad receptor is the complement receptor CD46 that is used by serotypes 11, 16, 21, 35, and 50 but not by serotypes 3, 7, and 14. In this study, we attempted to identify yet-unknown species B cellular receptors. For this purpose we used recombinant Ad3 and Ad35 fiber knobs in high-throughput receptor screening methods including mass spectrometry analysis and glycan arrays. Surprisingly, we found that the main interacting surface molecules of Ad3 fiber knob are cellular heparan sulfate proteoglycans (HSPGs). We subsequently found that HSPGs acted as low-affinity co-receptors for Ad3 but did not represent the main receptor of this serotype. Our study also revealed a new CD46-independent infection pathway of Ad35. This Ad35 infection mechanism is mediated by cellular HSPGs. The interaction of Ad35 with HSPGs is not via fiber knob, whereas Ad3 interacts with HSPGs via fiber knob. Both Ad3 and Ad35 interacted specifically with the sulfated regions within HSPGs that have also been implicated in binding physiologic ligands. In conclusion, our findings show that Ad3 and Ad35 directly utilize HSPGs as co-receptors for infection. Our data suggest that adenoviruses evolved to simulate the presence of physiologic HSPG ligands in order to increase infection

Mucin Variable Number Tandem Repeat Polymorphisms and Severity of Cystic Fibrosis Lung Disease: Significant Association with MUC5AC

Variability in cystic fibrosis (CF) lung disease is partially due to non-CFTR genetic modifiers. Mucin genes are very polymorphic, and mucins play a key role in the pathogenesis of CF lung disease; therefore, mucin genes are strong candidates as genetic modifiers. DNA from CF patients recruited for extremes of lung phenotype was analyzed by Southern blot or PCR to define variable number tandem repeat (VNTR) length polymorphisms for MUC1, MUC2, MUC5AC, and MUC7. VNTR length polymorphisms were tested for association with lung disease severity and for linkage disequilibrium (LD) with flanking single nucleotide polymorphisms (SNPs). No strong associations were found for MUC1, MUC2, or MUC7. A significant association was found between the overall distribution of MUC5AC VNTR length and CF lung disease severity (p = 0.025; n = 468 patients); plus, there was robust association of the specific 6.4 kb HinfI VNTR fragment with severity of lung disease (p = 6.2 x 10(-4) after Bonferroni correction). There was strong LD between MUC5AC VNTR length modes and flanking SNPs. The severity-associated 6.4 kb VNTR allele of MUC5AC was confirmed to be genetically distinct from the 6.3 kb allele, as it showed significantly stronger association with nearby SNPs. These data provide detailed respiratory mucin gene VNTR allele distributions in CF patients. Our data also show a novel link between the MUC5AC 6.4 kb VNTR allele and severity of CF lung disease. The LD pattern with surrounding SNPs suggests that the 6.4 kb allele contains, or is linked to, important functional genetic variation

Scalability approaches for causal multicast: a survey

The final publication is available at Springer via http://dx.doi.org/10.1007/s00607-015-0479-0Many distributed services need to be scalable: internet search, electronic commerce, e-government... In order to achieve scalability, high availability and fault tolerance, such applications rely on replicated components. Because of the dynamics of growth and volatility of customer markets, applications need to be hosted by adaptive, highly scalable systems. In particular, the scalability of the reliable multicast mechanisms used for supporting the consistency of replicas is of crucial importance. Reliable multicast might propagate updates in a pre-determined order (e.g., FIFO, total or causal). Since total order needs more communication rounds than causal order, the latter appears to be the preferable candidate for achieving multicast scalability, although the consistency guarantees based on causal order are weaker than those of total order. This paper provides a historical survey of different scalability approaches for reliable causal multicast protocols.This work was supported by European Regional Development Fund (FEDER) and Ministerio de Economia y Competitividad (MINECO) under research Grant TIN2012-37719-C03-01.Juan Marín, RD.; Decker, H.; Armendáriz Íñigo, JE.; Bernabeu Aubán, JM.; Muñoz Escoí, FD. (2016). Scalability approaches for causal multicast: a survey. Computing. 98(9):923-947. https://doi.org/10.1007/s00607-015-0479-0S923947989Adly N, Nagi M (1995) Maintaining causal order in large scale distributed systems using a logical hierarchy. In: IASTED Intnl Conf on Appl Inform, pp 214–219Aguilera MK, Chen W, Toueg S (1997) Heartbeat: a timeout-free failure detector for quiescent reliable communication. In: 11th Intnl Wshop on Distrib Alg (WDAG), Saarbrücken, pp 126–140Almeida JB, Almeida PS, Baquero C (2004) Bounded version vectors. In: 18th Intnl Conf Distrib Comput (DISC), Amsterdam, pp 102–116Almeida PS, Baquero C, Fonte V (2008) Interval tree clocks. In: 12th Intnl Conf Distrib Syst (OPODIS), Luxor, pp 259–274Almeida S, Leitão J, Rodrigues LET (2013) ChainReaction: a causal+ consistent datastore based on chain replication. In: 8th EuroSys Conf, Czech Republic, pp 85–98Álvarez A, Arévalo S, Cholvi V, Fernández A, Jiménez E (2008) On the interconnection of message passing systems. Inf Process Lett 105(6):249–254Amir Y, Stanton J (1998) The Spread wide area group communication system. Tech. rep., CDNS-98-4, The Center for Networking and Distributed Systems, The Johns Hopkins UnivAmir Y, Dolev D, Kramer S, Malki D (1992) Transis: a communication subsystem for high availability. In: 22nd Intnl Symp Fault-Tolerant Comp (FTCS), Boston, pp 76–84Anastasi G, Bartoli A, Spadoni F (2001) A reliable multicast protocol for distributed mobile systems: design and evaluation. IEEE Trans Parallel Distrib Syst 12(10):1009–1022Bailis P, Ghodsi A, Hellerstein JM, Stoica I (2013) Bolt-on causal consistency. In: Intnl Conf Mgmnt Data (SIGMOD), New York, pp 761–772Baldoni R, Raynal M, Prakash R, Singhal M (1996) Broadcast with time and causality constraints for multimedia applications. In: 22nd Intnl Euromicro Conf, Prague, pp 617–624Baldoni R, Friedman R, van Renesse R (1997) The hierarchical daisy architecture for causal delivery. In: 17th Intnl Conf Distrib Comput Syst (ICDCS), Maryland, pp 570–577Ban B (2002) JGroups—a toolkit for reliable multicast communication. http://www.jgroups.orgBaquero C, Almeida PS, Shoker A (2014) Making operation-based CRDTs operation-based. In: 14th Intnl Conf Distrib Appl Interop Syst (DAIS), Berlin, pp 126–140Benslimane A, Abouaissa A (2002) Dynamical grouping model for distributed real time causal ordering. Comput Commun 25:288–302Birman KP, Joseph TA (1987) Reliable communication in the presence of failures. ACM Trans Comput Syst 5(1):47–76Birman KP, Schiper A, Stephenson P (1991) Lightweigt causal and atomic group multicast. ACM Trans Comput Syst 9(3):272–314Cachin C, Guerraoui R, Rodrigues LET (2011) Introduction to reliable and secure distributed programming, 2nd edn. Springer, BerlinChandra P, Gambhire P, Kshemkalyani AD (2004) Performance of the optimal causal multicast algorithm: a statistical analysis. IEEE Trans Parall Distr 15(1):40–52Chandra TD, Toueg S (1996) Unreliable failure detectors for reliable distributed systems. J ACM 43(2):225–267de Juan-Marín R, Cholvi V, Jiménez E, Muñoz-Escoí FD (2009) Parallel interconnection of broadcast systems with multiple FIFO channels. In: 11th Intnl Symp on Distrib Obj, Middleware and Appl (DOA), Vilamoura, LNCS, vol 5870, pp 449–466Défago X, Schiper A, Urbán P (2004) Total order broadcast and multicast algorithms: taxonomy and survey. ACM Comput Surv 36(4):372–421Demers AJ, Greene DH, Hauser C, Irish W, Larson J, Shenker S, Sturgis HE, Swinehart DC, Terry DB (1987) Epidemic algorithms for replicated database maintenance. In: 6th ACM Symp on Princ of Distrib Comput (PODC), Canada, pp 1–12Du J, Elnikety S, Roy A, Zwaenepoel W (2013) Orbe: scalable causal consistency using dependency matrices and physical clocks. In: ACM Symp on Cloud Comput (SoCC), Santa Clara, pp 11:1–11:14Fernández A, Jiménez E, Cholvi V (2000) On the interconnection of causal memory systems. In: 19th Annual ACM Symp on Princ of Distrib Comput (PODC), Portland, pp 163–170Fidge CJ (1988) Timestamps in message-passing systems that preserve the partial ordering. In: 11th Australian Comput Conf, pp 56–66Friedman R, Vitenberg R, Chockler G (2003) On the composability of consistency conditions. Inf Process Lett 86(4):169–176Gilbert S, Lynch N (2002) Brewer’s conjecture and the feasibility of consistent, available, partition-tolerant web services. SIGACT News 33(2):51–59Gray J, Helland P, O’Neil PE, Shasha D (1996) The dangers of replication and a solution. In: SIGMOD Conf, pp 173–182Hadzilacos V, Toueg S (1993) Fault-tolerant broadcasts and related problems. In: Mullender S (ed) Distributed systems, chap 5, 2nd edn. ACM Press, pp 97–145Johnson S, Jahanian F, Shah J (1999) The inter-group router approach to scalable group composition. In: 19th Intnl Conf on Distrib Comput Syst (ICDCS), Austin, pp 4–14Kalantar MH, Birman KP (1999) Causally ordered multicast: the conservative approach. In: 19th Intnl Conf on Distrib Comput Syst (ICDCS), Austin, pp 36–44Kawanami S, Enokido T, Takizawa M (2004) A group communication protocol for scalable causal ordering. In: 18th Intnl Conf on Adv Inform Netw Appl (AINA), Fukuoka, pp 296–302Kawanami S, Nishimura T, Enokido T, Takizawa M (2005) A scalable group communication protocol with global clock. In: 19th Intnl Conf on Adv Inform Netw Appl (AINA), Taipei, pp 625–630Kshemkalyani AD, Singhal M (1998) Necessary and sufficient conditions on information for causal message ordering and their optimal implementation. Distrib Comput 11(2):91–111Kshemkalyani AD, Singhal M (2011) Distributed computing: principles, algorithms, and systems, 2nd edn. Cambridge University Press, New YorkLadin R, Liskov B, Shrira L, Ghemawat S (1992) Providing high availability using lazy replication. ACM Trans Comput Syst 10(4):360–391Lamport L (1978) Time, clocks, and the ordering of events in a distributed system. Commun ACM 21(7):558–565Laumay P, Bruneton E, de Palma N, Krakowiak S (2001) Preserving causality in a scalable message-oriented middleware. In: Intnl Conf on Distrib Syst Platf (Middleware), pp 311–328Liu N, Liu M, Cao J, Chen G, Lou W (2010) When transportation meets communication: V2P over VANETs. In: 30th Intnl Conf Distrib Comput Syst (ICDCS), GenovaLwin CH, Mohanty H, Ghosh RK (2004) Causal ordering in event notification service systems for mobile users. In: Intnl Conf Inform Tech: Coding Comput (ITCC), Las Vegas, pp 735–740Mahajan P, Alvisi L, Dahlin M (2011) Consistency, availability and covergence. Tech. rep., UTCS TR-11-22, The University of Texas at AustinMatos M, Sousa A, Pereira J, Oliveira R, Deliot E, Murray P (2009) CLON: overlay networks and gossip protocols for cloud environments. In: 11th Intnl Symp on Dist Obj, Middleware and Appl (DOA), Vilamoura, LNCS, vol 5870, pp 549–566Mattern F (1989) Virtual time and global states of distributed systems. In: Parallel and distributed algorithms, North-Holland, pp 215–226Mattern F, Fünfrocken S (1994) A non-blocking lightweight implementation of causal order message delivery. Lect Notes Comput Sci 938:197–213Meldal S, Sankar S, Vera J (1991) Exploiting locality in maintaining potential causality. In: 10th ACM Symp on Princ of Distrib Comp (PODC), Montreal, pp 231–239Meling H, Montresor A, Helvik BE, Babaoglu Ö (2008) Jgroup/ARM: a distributed object group platform with autonomous replication management. Softw Pract Exp 38(9):885–923Mosberger D (1993) Memory consistency models. Oper Syst Rev 27(1):18–26Mostéfaoui A, Raynal M (1993) Causal multicast in overlapping groups: towards a low cost approach. In: 4th Intnl Wshop on Future Trends of Distrib Comp Syst (FTDCS), Lisbon, pp 136–142Mostéfaoui A, Raynal M, Travers C, Patterson S, Agrawal D, El Abbadi A (2005) From static distributed systems to dynamic systems. In: 24th Symp on Rel Distrib Syst (SRDS), Orlando, pp 109–118Nishimura T, Hayashibara N, Takizawa M, Enokido T (2005) Causally ordered delivery with global clock in hierarchical group. In: ICPADS (2), Fukuoka, pp 560–564Parker DS Jr, Popek GJ, Rudisin G, Stoughton A, Walker BJ, Walton E, Chow JM, Edwards DA, Kiser S, Kline CS (1983) Detection of mutual inconsistency in distributed systems. IEEE Trans Softw Eng 9(3):240–247Pascual-Miret L (2014) Consistency models in modern distributed systems. An approach to eventual consistency. Master’s thesis, Depto. de Sistemas Informáticos y Computación, Univ. Politècnica de ValènciaPascual-Miret L, González de Mendívil JR, Bernabéu-Aubán JM, Muñoz-Escoí FD (2015) Widening CAP consistency. Tech. rep., IUMTI-SIDI-2015/003, Univ. Politècnica de València, ValenciaPeterson LL, Buchholz NC, Schlichting RD (1989) Preserving and using context information in interprocess communication. ACM Trans Comput Syst 7(3):217–246Pomares Hernández S, Fanchon J, Drira K, Diaz M (2001) Causal broadcast protocol for very large group communication systems. In: 5th Intnl Conf on Princ of Distrib Syst (OPODIS), Manzanillo, pp 175–188Prakash R, Baldoni R (2004) Causality and the spatial-temporal ordering in mobile systems. Mobile Netw Appl 9(5):507–516Prakash R, Raynal M, Singhal M (1997) An adaptive causal ordering algorithm suited to mobile computing environments. J Parallel Distrib Comput 41(2):190–204Raynal M, Schiper A, Toueg S (1991) The causal ordering abstraction and a simple way to implement it. Inf Process Lett 39(6):343–350Rodrigues L, Veríssimo P (1995a) Causal separators and topological timestamping: An approach to support causal multicast in large-scale systems. Tech. Rep. AR-05/95, Instituto de Engenharia de Sistemas e Computadores (INESC), LisbonRodrigues L, Veríssimo P (1995b) Causal separators for large-scale multicast communication. In: 15th Intnl Conf on Distrib Comput Syst (ICDCS), Vancouver, pp 83–91Schiper A, Eggli J, Sandoz A (1989) A new algorithm to implement causal ordering. In: 3rd Intnl Wshop on Distrib Alg (WDAG), Nice, pp 219–232Schiper N, Pedone F (2010) Fast, flexible and highly resilient genuine FIFO and causal multicast algorithms. In: 25th ACM Symp on Applied Comp (SAC), Sierre, pp 418–422Shapiro M, Preguiça NM, Baquero C, Zawirski M (2011) Convergent and commutative replicated data types. Bull EATCS 104:67–88Shen M, Kshemkalyani AD, Hsu TY (2015) Causal consistency for geo-replicated cloud storage under partial replication. In: Intnl Paral Distrib Proces Symp (IPDPS) Wshop, Hyderabad, pp 509–518Singhal M, Kshemkalyani AD (1992) An efficient implementation of vector clocks. Inf Process Lett 43(1):47–52Sotomayor B, Montero RS, Llorente IM, Foster IT (2009) Virtual infrastructure management in private and hybrid clouds. IEEE Internet Comput 13(5):14–22Stephenson P (1991) Fast ordered multicasts. PhD thesis, Dept. of Comp. Sc., Cornell Univ., IthacaStonebraker M (1986) The case for shared nothing. IEEE Database Eng Bull 9(1):4–9Vogels W (2009) Eventually consistent. Commun ACM 52(1):40–44Wischhof L, Ebner A, Rohling H (2005) Information dissemination in self-organizing intervehicle networks. IEEE Trans Intell Transp 6(1):90–101Yavatkar R (1992) MCP: a protocol for coordination and temporal synchronization in multimedia collaborative applications. In: 12th Intnl Conf on Distrib Comput Syst (ICDCS), Yokohama, pp 606–613Yen LH, Huang TL, Hwang SY (1997) A protocol for causally ordered message delivery in mobile computing systems. Mobile Netw Appl 2(4):365–372Zawirski M, Preguiça N, Duarte S, Bieniusa A, Balegas V, Shapiro M (2015) Write fast, read in the past: causal consistency for client-side applications. In: 16th Intnl Middleware Conf, VancouverZhou S, Cai W, Turner SJ, Lee BS, Wei J (2007) Critical causal order of events in distributed virtual environments. ACM Trans Mult Comp Commun Appl 3(3):1

Avian Influenza Virus Glycoproteins Restrict Virus Replication and Spread through Human Airway Epithelium at Temperatures of the Proximal Airways

Transmission of avian influenza viruses from bird to human is a rare event even though avian influenza viruses infect the ciliated epithelium of human airways in vitro and ex vivo. Using an in vitro model of human ciliated airway epithelium (HAE), we demonstrate that while human and avian influenza viruses efficiently infect at temperatures of the human distal airways (37°C), avian, but not human, influenza viruses are restricted for infection at the cooler temperatures of the human proximal airways (32°C). These data support the hypothesis that avian influenza viruses, ordinarily adapted to the temperature of the avian enteric tract (40°C), rarely infect humans, in part due to differences in host airway regional temperatures. Previously, a critical residue at position 627 in the avian influenza virus polymerase subunit, PB2, was identified as conferring temperature-dependency in mammalian cells. Here, we use reverse genetics to show that avianization of residue 627 attenuates a human virus, but does not account for the different infection between 32°C and 37°C. To determine the mechanism of temperature restriction of avian influenza viruses in HAE at 32°C, we generated recombinant human influenza viruses in either the A/Victoria/3/75 (H3N2) or A/PR/8/34 (H1N1) genetic background that contained avian or avian-like glycoproteins. Two of these viruses, A/Victoria/3/75 with L226Q and S228G mutations in hemagglutinin (HA) and neuraminidase (NA) from A/Chick/Italy/1347/99 and A/PR/8/34 containing the H7 and N1 from A/Chick/Italy/1347/99, exhibited temperature restriction approaching that of wholly avian influenza viruses. These data suggest that influenza viruses bearing avian or avian-like surface glycoproteins have a reduced capacity to establish productive infection at the temperature of the human proximal airways. This temperature restriction may limit zoonotic transmission of avian influenza viruses and suggests that adaptation of avian influenza viruses to efficient infection at 32°C may represent a critical evolutionary step enabling human-to-human transmission

Mucin impedes cytotoxic effect of 5-FU against growth of human pancreatic cancer cells: overcoming cellular barriers for therapeutic gain

Mucins are high molecular weight glycoproteins expressed on the apical surface of normal epithelial cells. In cancer disease mucins are overexpressed on the entire cellular surface. Overexpression of MUC1 mucin in pancreatic tumours has been correlated with poor patient survival. Current chemotherapeutic approaches such as 5-fluorouracil (5-FU) has produced limited clinical success. In this study we investigated the role of mucin in cytotoxic drug treatment to determine whether the extracellular domain of mucin impedes cytotoxic drug action of 5-FU. Human pancreatic cancer cells revealed high and relatively moderate MUC1 levels for Capan-1 and HPAF-II, respectively, compared to MUC1 negative control (U-87 MG glioblastoma) that showed relatively non-specific anti-MUC1 uptake. Benzyl-α-GalNAc (O-glycosylation inhibitor) was used to reduce mucin on cell surfaces, and neuraminidase was used to hydrolyse sialic acid at the distal end of carbohydrate chains. Benzyl-α-GalNAc had no effect on cell morphology or proliferation at the concentrations employed. The inhibition of O-glycosylation resulted in significant 5-FU antiproliferative activity against Capan-1 and HPAF-II, but not against U-87 MG. However, the exposure of cells to neuraminidase failed to improve the cytotoxic action of 5-FU. Our experimental findings suggest that the overexpression of mucin produced by human pancreatic tumours might limit the effectiveness of chemotherapy

Assessing the Effects of Responsible Leadership and Ethical Conflict on Behavioral Intention

[[abstract]]This study develops a research model that elaborates how responsible leadership and ethical conflict influence employees from the perspectives of role theory and attachment theory. Its empirical results reveal that turnover intention indirectly relates to ethical conflict and responsible leadership via the mediating mechanisms of organizational identification and organizational uncertainty. At the same time, helping intention indirectly relates to ethical conflict and responsible leadership only through organizational identification. Finally, the managerial implications for international business and research limitations based on the empirical results are discussed.[[notice]]補正完

Introduction: Applications of Business Information Literacy for Improved Decision Making

The article is the introduction to the special issue of the Journal of Business & Finance Librarianship that I edited. The introduction is co-written with my colleague Ilana Stonebraker. It focuses on the business information ecosystem to set a context for the articles focusing on applications of business information literacy for improved decision making