Vocal development in a large‐scale crosslinguistic corpus

This study evaluates whether early vocalizations develop in similar ways in children across diverse cultural contexts. We analyze data from daylong audio recordings of 49 children (1–36 months) from five different language/cultural backgrounds. Citizen scientists annotated these recordings to determine if child vocalizations contained canonical transitions or not (e.g., “ba” vs. “ee”). Results revealed that the proportion of clips reported to contain canonical transitions increased with age. Furthermore, this proportion exceeded 0.15 by around 7 months, replicating and extending previous findings on canonical vocalization development but using data from the natural environments of a culturally and linguistically diverse sample. This work explores how crowdsourcing can be used to annotate corpora, helping establish developmental milestones relevant to multiple languages and cultures. Lower inter‐annotator reliability on the crowdsourcing platform, relative to more traditional in‐lab expert annotators, means that a larger number of unique annotators and/or annotations are required, and that crowdsourcing may not be a suitable method for more fine‐grained annotation decisions. Audio clips used for this project are compiled into a large‐scale infant vocalization corpus that is available for other researchers to use in future work

Effects of rapid prey evolution on predator-prey cycles

We study the qualitative properties of population cycles in a predator-prey system where genetic variability allows contemporary rapid evolution of the prey. Previous numerical studies have found that prey evolution in response to changing predation risk can have major quantitative and qualitative effects on predator-prey cycles, including: (i) large increases in cycle period, (ii) changes in phase relations (so that predator and prey are cycling exactly out of phase, rather than the classical quarter-period phase lag), and (iii) "cryptic" cycles in which total prey density remains nearly constant while predator density and prey traits cycle. Here we focus on a chemostat model motivated by our experimental system [Fussmann et al. 2000,Yoshida et al. 2003] with algae (prey) and rotifers (predators), in which the prey exhibit rapid evolution in their level of defense against predation. We show that the effects of rapid prey evolution are robust and general, and furthermore that they occur in a specific but biologically relevant region of parameter space: when traits that greatly reduce predation risk are relatively cheap (in terms of reductions in other fitness components), when there is coexistence between the two prey types and the predator, and when the interaction between predators and undefended prey alone would produce cycles. Because defense has been shown to be inexpensive, even cost-free, in a number of systems [Andersson and Levin 1999, Gagneux et al. 2006,Yoshida et al. 2004], our discoveries may well be reproduced in other model systems, and in nature. Finally, some of our key results are extended to a general model in which functional forms for the predation rate and prey birth rate are not specified.Comment: 35 pages, 8 figure

Balancing Selection at the Tomato RCR3 Guardee Gene Family Maintains Variation in Strength of Pathogen Defense

Coevolution between hosts and pathogens is thought to occur between interacting molecules of both species. This results in the maintenance of genetic diversity at pathogen antigens (or so-called effectors) and host resistance genes such as the major histocompatibility complex (MHC) in mammals or resistance (R) genes in plants. In plant-pathogen interactions, the current paradigm posits that a specific defense response is activated upon recognition of pathogen effectors via interaction with their corresponding R proteins. According to the''Guard-Hypothesis,'' R proteins (the ``guards'') can sense modification of target molecules in the host (the ``guardees'') by pathogen effectors and subsequently trigger the defense response. Multiple studies have reported high genetic diversity at R genes maintained by balancing selection. In contrast, little is known about the evolutionary mechanisms shaping the guardee, which may be subject to contrasting evolutionary forces. Here we show that the evolution of the guardee RCR3 is characterized by gene duplication, frequent gene conversion, and balancing selection in the wild tomato species Solanum peruvianum. Investigating the functional characteristics of 54 natural variants through in vitro and in planta assays, we detected differences in recognition of the pathogen effector through interaction with the guardee, as well as substantial variation in the strength of the defense response. This variation is maintained by balancing selection at each copy of the RCR3 gene. Our analyses pinpoint three amino acid polymorphisms with key functional consequences for the coevolution between the guardee (RCR3) and its guard (Cf-2). We conclude that, in addition to coevolution at the ``guardee-effector'' interface for pathogen recognition, natural selection acts on the ``guard-guardee'' interface. Guardee evolution may be governed by a counterbalance between improved activation in the presence and prevention of auto-immune responses in the absence of the corresponding pathogen

Microparticle-mediated transfer of the viral receptors CAR and CD46, and the CFTR channel in a CHO cell model confers new functions to target cells

Cell microparticles (MPs) released in the extracellular milieu can embark plasma membrane and intracellular components which are specific of their cellular origin, and transfer them to target cells. The MP-mediated, cell-to-cell transfer of three human membrane glycoproteins of different degrees of complexity was investigated in the present study, using a CHO cell model system. We first tested the delivery of CAR and CD46, two monospanins which act as adenovirus receptors, to target CHO cells. CHO cells lack CAR and CD46, high affinity receptors for human adenovirus serotype 5 (HAdV5), and serotype 35 (HAdV35), respectively. We found that MPs derived from CHO cells (MP-donor cells) constitutively expressing CAR (MP-CAR) or CD46 (MP-CD46) were able to transfer CAR and CD46 to target CHO cells, and conferred selective permissiveness to HAdV5 and HAdV35. In addition, target CHO cells incubated with MP-CD46 acquired the CD46-associated function in complement regulation. We also explored the MP-mediated delivery of a dodecaspanin membrane glycoprotein, the CFTR to target CHO cells. CFTR functions as a chloride channel in human cells and is implicated in the genetic disease cystic fibrosis. Target CHO cells incubated with MPs produced by CHO cells constitutively expressing GFP-tagged CFTR (MP-GFP-CFTR) were found to gain a new cellular function, the chloride channel activity associated to CFTR. Time-course analysis of the appearance of GFP-CFTR in target cells suggested that MPs could achieve the delivery of CFTR to target cells via two mechanisms: the transfer of mature, membrane-inserted CFTR glycoprotein, and the transfer of CFTR-encoding mRNA. These results confirmed that cell-derived MPs represent a new class of promising therapeutic vehicles for the delivery of bioactive macromolecules, proteins or mRNAs, the latter exerting the desired therapeutic effect in target cells via de novo synthesis of their encoded proteins

Anticancer Gene Transfer for Cancer Gene Therapy

Gene therapy vectors are among the treatments currently used to treat malignant tumors. Gene therapy vectors use a specific therapeutic transgene that causes death in cancer cells. In early attempts at gene therapy, therapeutic transgenes were driven by non-specific vectors which induced toxicity to normal cells in addition to the cancer cells. Recently, novel cancer specific viral vectors have been developed that target cancer cells leaving normal cells unharmed. Here we review such cancer specific gene therapy systems currently used in the treatment of cancer and discuss the major challenges and future directions in this field

Evaluation of CD46 re-targeted adenoviral vectors for clinical ovarian cancer intraperitoneal therapy

Ovarian cancer accounts for >140 000 deaths globally each year. Typically, disease is asymptomatic until an advanced, incurable stage. Although response to cytotoxic chemotherapy is frequently observed, resistance to conventional platinum-based therapies develop rapidly. Improved treatments are therefore urgently required. Virotherapy offers great potential for ovarian cancer, where the application of local, intraperitoneal delivery circumvents some of the limitations of intravenous strategies. To develop effective, adenovirus (Ad)-based platforms for ovarian cancer, we profiled the fluid and cellular components of patient ascites for factors known to influence adenoviral transduction. Levels of factor X (FX) and neutralizing antibodies (nAbs) in ascitic fluid were quantified and tumor cells were assessed for the expression of coxsackie virus and adenovirus receptor (CAR) and CD46. We show that clinical ascites contains significant levels of FX but consistently high CD46 expression. We therefore evaluated in vitro the relative transduction of epithelial ovarian cancers (EOCs) by Ad5 (via CAR) and Ad5 pseudotyped with the fiber of Ad35 (Ad5T*F35++) via CD46. Ad5T*F35++ achieved significantly increased transduction in comparison to Ad5 (P<0.001), independent of FX and nAb levels. We therefore propose selective transduction of CD46 over-expressing EOCs using re-targeted, Ad35-pseudotyped Ad vectors may represent a promising virotherapy for ovarian cance

Development of novel adenoviral vectors to overcome challenges observed with HAdV-5 based constructs

Recombinant vectors based on human adenovirus serotype 5 (HAdV-5) have been extensively studied in pre-clinical models and clinical trials over the last two decades. However, the thorough understanding of the HAdV-5 interaction with human subjects has uncovered major concerns about its product applicability. High vector-associated toxicity and widespread pre-existing immunity have been shown to significantly impede the effectiveness of HAdV-5 mediated gene transfer. It is therefore that the in depth knowledge attained working on HAdV-5 is currently being used to develop alternative vectors. Here, we provide a comprehensive overview of data obtained in recent years disqualifying the HAdV-5 vector for systemic gene delivery as well as novel strategies being pursued to overcome the limitations observed with particular emphasis on the ongoing vectorization efforts to obtain vectors based on alternative serotypes

Recurrence properties of hypercyclic operators

[EN] We generalize the notions of hypercyclic operators, U-frequently hypercyclic operators and frequently hypercyclic operators by introducing a new concept in linear dynamics, namely A-hypercyclicity. We then state an A-hypercyclicity criterion, inspired by the hypercyclicity criterion and the frequent hypercyclicity criterion, and we show that this criterion characterizes the A-hypercyclicity for weighted shifts. We also investigate which density properties can the sets N(x, U) = {n is an element of N; T-n x is an element of U} have for a given hypercyclic operator, and we study the new notion of reiteratively hypercyclic operators.This work is supported in part by MEC and FEDER, Project MTM2013-47093-P, and by GVA, Projects PROMETEOII/2013/013 and ACOMP/2015/005. The second author was a postdoctoral researcher of the Belgian FNRS.Bès, JP.; Menet, Q.; Peris Manguillot, A.; Puig-De Dios, Y. (2016). Recurrence properties of hypercyclic operators. Mathematische Annalen. 366(1):545-572. https://doi.org/10.1007/s00208-015-1336-3S5455723661Badea, C., Grivaux, S.: Unimodular eigenvalues, uniformly distributed sequences and linear dynamics. Adv. Math. 211, 766–793 (2007)Bayart, F., Grivaux, S.: Frequently hypercyclic operators. Trans. Amer. Math. Soc. 358, 5083–5117 (2006)Bayart, F., Grivaux, S.: Invariant Gaussian measures for operators on Banach spaces and linear dynamics. Proc. Lond. Math. Soc. 94, 181–210 (2007)Bayart, F., Matheron, É.: Dynamics of linear operators, Cambridge Tracts in Mathematics, 179. Cambridge University Press, Cambridge (2009)Bayart, F., Matheron, É.: (Non-)weakly mixing operators and hypercyclicity sets. Ann. Inst. Fourier 59, 1–35 (2009)Bayart, F., Ruzsa, I.: Difference sets and frequently hypercyclic weighted shifts. Ergodic Theory Dynam. Syst. 35, 691–709 (2015)Bergelson, V.: Ergodic Ramsey Theory- an update, Ergodic Theory of $$\mathbb{Z}^d$$ Z d -actions. Lond. Math. Soc. Lecture Note Ser. 28, 1–61 (1996)Bernal-González, L., Grosse-Erdmann, K.-G.: The Hypercyclicity Criterion for sequences of operators. Studia Math. 157, 17–32 (2003)Bès, J., Peris, A.: Hereditarily hypercyclic operators. J. Funct. Anal. 167, 94–112 (1999)Bonilla, A., Grosse-Erdmann, K.-G.: Frequently hypercyclic operators and vectors. Ergodic Theory Dynam. Syst. 27, 383–404 (2007)Bonilla, A., Grosse-Erdmann, K.-G.: Erratum: Ergodic Theory Dynam. Systems 29, 1993–1994 (2009)Chan, K., Seceleanu, I.: Hypercyclicity of shifts as a zero-one law of orbital limit points. J. Oper. Theory 67, 257–277 (2012)Costakis, G., Sambarino, M.: Topologically mixing hypercyclic operators. Proc. Amer. Math. Soc. 132, 385–389 (2004)Furstenberg, H.: Recurrence in ergodic theory and combinatorial number theory. Princeton University Press, Princeton (1981)Giuliano, R., Grekos, G., Mišík, L.: Open problems on densities II, Diophantine Analysis and Related Fields 2010. AIP Conf. Proc. 1264, 114–128 (2010)Grosse-Erdmann, K.-G.: Hypercyclic and chaotic weighted shifts. Studia Math. 139, 47–68 (2000)Grosse-Erdmann, K.-G., Peris, A.: Frequently dense orbits. C. R. Math. Acad. Sci. Paris 341, 123–128 (2005)Grosse-Erdmann, K.G., Peris, A.: Weakly mixing operators on topological vector spaces, Rev. R. Acad. Cienc. Exactas Fís. Nat. Ser. A Math. RACSAM, 104, 413–426 (2010)Grosse-Erdmann, K.G., Peris Manguillot, A.: Linear chaos, Universitext. Springer, London (2011)Menet, Q.: Linear chaos and frequent hypercyclicity. Trans. Amer. Math. Soc. arXiv:1410.7173Puig, Y.: Linear dynamics and recurrence properties defined via essential idempotents of $$\beta {\mathbb{N}}$$ β N (2014) arXiv:1411.7729 (preprint)Salas, H.N.: Hypercyclic weighted shifts. Trans. Amer. Math. Soc. 347, 993–1004 (1995)Salat, T., Toma, V.: A classical Olivier’s theorem and statistical convergence. Ann. Math. Blaise Pascal 10, 305–313 (2003)Shkarin, S.: On the spectrum of frequently hypercyclic operators. Proc. Am. Math. Soc. 137, 123–134 (2009

Enhanced Transduction and Replication of RGD-Fiber Modified Adenovirus in Primary T Cells

Background: Adenoviruses are often used as vehicles to mediate gene delivery for therapeutic purposes, but their research scope in hematological cells remains limited due to a narrow choice of host cells that express the adenoviral receptor (CAR). T cells, which are attractive targets for gene therapy of numerous diseases, remain resistant to adenoviral infection because of the absence of CAR expression. Here, we demonstrate that this resistance can be overcome when murine or human T cells are transduced with an adenovirus incorporating the RGD-fiber modification (Ad-RGD). Methodology/Principal Finding: A luciferase-expressing replication-deficient Ad-RGD infected 3-fold higher number of activated primary T cells than an adenovirus lacking the RGD-fiber modification in vitro. Infection with replicationcompetent Ad-RGD virus also caused increased cell cycling, higher E1A copy number and enriched hexon antigen expression in both human and murine T cells. Transduction with oncolytic Ad-RGD also resulted in higher titers of progeny virus and enhanced the killing of T cells. In vivo, 35–45 % of splenic T cells were transduced by Ad-RGD. Conclusions: Collectively, our results prove that a fiber modified Ad-RGD successfully transduces and replicates in primary