The large terminase DNA packaging motor grips DNA with its ATPase domain for cleavage by the flexible nuclease domain

Many viruses use a powerful terminase motor to pump their genome inside an empty procapsid shell during virus maturation. The large terminase (TerL) protein contains both enzymatic activities necessary for packaging in such viruses: the adenosine triphosphatase (ATPase) that powers DNA translocation and an endonuclease that cleaves the concatemeric genome at both initiation and completion of genome packaging. However, how TerL binds DNA during translocation and cleavage remains mysterious. Here we investigate DNA binding and cleavage using TerL from the thermophilic phage P74-26. We report the structure of the P74-26 TerL nuclease domain, which allows us to model DNA binding in the nuclease active site. We screened a large panel of TerL variants for defects in binding and DNA cleavage, revealing that the ATPase domain is the primary site for DNA binding, and is required for nuclease activity. The nuclease domain is dispensable for DNA binding but residues lining the active site guide DNA for cleavage. Kinetic analysis of DNA cleavage suggests flexible tethering of the nuclease domains during DNA cleavage. We propose that interactions with the procapsid during DNA translocation conformationally restrict the nuclease domain, inhibiting cleavage; TerL release from the capsid upon completion of packaging unlocks the nuclease domains to cleave DNA

Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein

The C-terminal binding protein (CtBP) is an NADH-dependent dimeric family of nuclear proteins that scaffold interactions between transcriptional regulators and chromatin-modifying complexes. Its association with poor survival in several cancers implicates CtBP as a promising target for pharmacological intervention. We employed computer-assisted drug design to search for CtBP inhibitors, using quantitative structure-activity relationship (QSAR) modeling and docking. Functional screening of these drugs identified 4 compounds with low toxicity and high water solubility. Micro molar concentrations of these CtBP inhibitors produces significant de-repression of epigenetically silenced pro-epithelial genes, preferentially in the triple-negative breast cancer cell line MDA-MB-231. This epigenetic reprogramming occurs through eviction of CtBP from gene promoters; disrupted recruitment of chromatin-modifying protein complexes containing LSD1, and HDAC1; and re-wiring of activating histone marks at targeted genes. In functional assays, CtBP inhibition disrupts CtBP dimerization, decreases cell migration, abolishes cellular invasion, and improves DNA repair. Combinatorial use of CtBP inhibitors with the LSD1 inhibitor pargyline has synergistic influence. Finally, integrated correlation of gene expression in breast cancer patients with nuclear levels of CtBP1 and LSD1, reveals new potential therapeutic vulnerabilities. These findings implicate a broad role for this class of compounds in strategies for epigenetically targeted therapeutic intervention

Multipliers of Dirichlet series and monomial series expansions of holomorphic functions in infinitely many variables

[EN] Let H-infinity be the set of all ordinary Dirichlet series D = Sigma(n) a(n)(n-1) ann-s representing bounded holomorphic functions on the right half plane. A completely multiplicative sequence (b(n)) of complex numbers is said to be an l(1)-multiplier for H-infinity whenever Sigma(n vertical bar)a(n)b(n vertical bar) < infinity for every D is an element of H-infinity. We study the problem of describing such sequences (b(n)) in terms of the asymptotic decay of the subsequence (b(pj)), where p(j) denotes the j th prime number. Given a completely multiplicative sequence b = (b(n)) we prove (among other results): b is an l(1)-multiplier for H-infinity provided vertical bar b(pj)vertical bar < 1 for all j and (lim(n)) over bar 1/log(n) Sigma(n)(j=1) b(p j)*(2) < 1, and conversely, if b is an l(1)-multiplier for H-infinity, then vertical bar b(pj)vertical bar < 1 for all j and (lim(n)) over bar 1/log(n) Sigma(n)(j=1) b(p j)*(2) <= 1 (here b* stands for the decreasing rearrangement of b). Following an ingenious idea of Harald Bohr it turns out that this problem is intimately related with the question of characterizing those sequences z in the infinite dimensional polydisk D-infinity (the open unit ball of l(infinity)) for which every bounded and holomorphic function f on D-infinity has an absolutely convergent monomial series expansion Sigma(alpha) partial derivative alpha f (0)/alpha! z alpha. Moreover, we study analogous problems in Hardy spaces of Dirichlet series and Hardy spaces of functions on the infinite dimensional polytorus T-infinity.The second, fourth and fifth authors were supported by MINECO and FEDER Project MTM2014-57838-C2-2-P. The fourth author was also supported by PrometeoII/2013/013. The fifth author was also supported by project SP-UPV20120700.Bayart, F.; Defant, A.; Frerick, L.; Maestre, M.; Sevilla Peris, P. (2017). Multipliers of Dirichlet series and monomial series expansions of holomorphic functions in infinitely many variables. Mathematische Annalen. 368(1-2):837-876. https://doi.org/10.1007/s00208-016-1511-1S8378763681-2Aleman, A., Olsen, J.-F., Saksman, E.: Fatou and brother Riesz theorems in the infinite-dimensional polydisc. arXiv:1512.01509Balasubramanian, R., Calado, B., Queffélec, H.: The Bohr inequality for ordinary Dirichlet series. Studia Math. 175(3), 285–304 (2006)Bayart, F.: Hardy spaces of Dirichlet series and their composition operators. Monatsh. Math. 136(3), 203–236 (2002)Bayart, F., Pellegrino, D., Seoane-Sepúlveda, J.B.: The Bohr radius of the $$n$$ n -dimensional polydisk is equivalent to $$\sqrt{(\log n)/n}$$ ( log n ) / n . Adv. Math. 264:726–746 (2014)Bohnenblust, H.F., Hille, E.: On the absolute convergence of Dirichlet series. Ann. Math. 32(3), 600–622 (1931)Bohr, H.: Über die Bedeutung der Potenzreihen unendlich vieler Variablen in der Theorie der Dirichlet–schen Reihen $$\sum \,\frac{a_n}{n^s}$$ ∑ a n n s . Nachr. Ges. Wiss. Göttingen, Math. Phys. Kl. 441–488 (1913)Bohr, H.: Über die gleichmäßige Konvergenz Dirichletscher Reihen. J. Reine Angew. Math. 143, 203–211 (1913)Cole, B.J., Gamelin., T.W.: Representing measures and Hardy spaces for the infinite polydisk algebra. Proc. Lond. Math. Soc. 53(1), 112–142 (1986)Davie, A.M., Gamelin, T.W.: A theorem on polynomial-star approximation. Proc. Am. Math. Soc. 106(2), 351–356 (1989)de la Bretèche, R.: Sur l’ordre de grandeur des polynômes de Dirichlet. Acta Arith. 134(2), 141–148 (2008)Defant, A., Frerick, L., Ortega-Cerdà, J., Ounaïes, M., Seip, K.: The Bohnenblust–Hille inequality for homogeneous polynomials is hypercontractive. Ann. Math. 174(1), 485–497 (2011)Defant, A., García, D., Maestre, M.: New strips of convergence for Dirichlet series. Publ. Mat. 54(2), 369–388 (2010)Defant, A., García, D., Maestre, M., Pérez-García, D.: Bohr’s strip for vector valued Dirichlet series. Math. Ann. 342(3), 533–555 (2008)Defant, A., Maestre, M., Prengel, C.: Domains of convergence for monomial expansions of holomorphic functions in infinitely many variables. J. Reine Angew. Math. 634, 13–49 (2009)Dineen, S.: Complex Analysis on Infinite-dimensional Spaces. Springer Monographs in Mathematics. Springer-Verlag London Ltd, London (1999)Floret, K.: Natural norms on symmetric tensor products of normed spaces. Note Mat. 17(153–188), 1997 (1999)Harris, L. A.: Bounds on the derivatives of holomorphic functions of vectors. In: Analyse fonctionnelle et applications (Comptes Rendus Colloq. Analyse, Inst. Mat., Univ. Federal Rio de Janeiro, Rio de Janeiro, 1972), pp. 145–163. Actualités Aci. Indust., No. 1367. Hermann, Paris (1975)Hedenmalm, H., Lindqvist, P., Seip, K.: A Hilbert space of Dirichlet series and systems of dilated functions in $$L^2(0,1)$$ L 2 ( 0 , 1 ) . Duke Math. J. 86(1), 1–37 (1997)Helson, H., Lowdenslager, D.: Prediction theory and Fourier series in several variables. Acta Math. 99, 165–202 (1958)Hibert, D.: Gesammelte Abhandlungen (Band 3). Verlag von Julius Springer, Berlin (1935)Hilbert, D.: Wesen und Ziele einer Analysis der unendlichvielen unabhängigen Variablen. Rend. del Circolo Mat. di Palermo 27, 59–74 (1909)Kahane, J.-P.: Some Random Series of Functions, Volume 5 of Cambridge Studies in Advanced Mathematics, second edn. Cambridge University Press, Cambridge (1985)Konyagin, S.V., Queffélec, H.: The translation $$\frac{1}{2}$$ 1 2 in the theory of Dirichlet series. Real Anal. Exchange 27(1):155–175 (2001/2002)Maurizi, B., Queffélec, H.: Some remarks on the algebra of bounded Dirichlet series. J. Fourier Anal. Appl. 16(5), 676–692 (2010)Queffélec, H.: H. Bohr’s vision of ordinary Dirichlet series; old and new results. J. Anal. 3, 43–60 (1995)Queffélec, H., Queffélec, M.: Diophantine Approximation and Dirichlet Series. HRI Lecture Notes Series, New Delhi (2013)Rudin, W.: Function Theory in Polydisks. W. A. Benjamin Inc, New York (1969)Toeplitz, O.: Über eine bei den Dirichletschen Reihen auftretende Aufgabe aus der Theorie der Potenzreihen von unendlichvielen Veränderlichen. Nachrichten von der Königlichen Gesellschaft der Wissenschaften zu Göttingen, pp. 417–432 (1913)Weissler, F.B.: Logarithmic Sobolev inequalities and hypercontractive estimates on the circle. J. Funct. Anal. 37(2), 218–234 (1980)Wojtaszczyk, P.: Banach Spaces for Analysts, Volume 25 of Cambridge Studies in Advanced Mathematics. Cambridge University Press, Cambridge (1991

Patient profiling for success after weight loss surgery (GO Bypass study): an interdisciplinary study protocol

Despite substantial research efforts, the mechanisms proposed to explain weight loss after gastric bypass (RYGB) and sleeve gastrectomy (SL) do not explain the large individual variation seen after these treatments. A complex set of factors are involved in the onset and development of obesity and these may also be relevant for the understanding of why success with treatments vary considerably between individuals. This calls for explanatory models that take into account not only biological determinants but also behavioral, affective and contextual factors. In this prospective study, we recruited 47 women and 8 men, aged 25–56 years old, with a BMI of 45.8 ± 7.1 kg/m2 from the waiting list for RYGB and SL at Køge hospital, Denmark. Pre-surgery and 1.5, 6 and 18 months after surgery we assessed various endpoints spanning multiple domains. Endpoints were selected on basis of previous studies and include: physiological measures: anthropometrics, vital signs, biochemical measures and appetite hormones, genetics, gut microbiota, appetite sensation, food and taste preferences, neural sensitivity, sensory perception and movement behaviors; psychological measures: general psychiatric symptom-load, depression, eating disorders, ADHD, personality disorder, impulsivity, emotion regulation, attachment pattern, general self-efficacy, alexithymia, internalization of weight bias, addiction, quality of life and trauma; and sociological and anthropological measures: sociodemographic measures, eating behavior, weight control practices and psycho-social factors. Joining these many endpoints and methodologies from different scientific disciplines and creating a multi-dimensional predictive model has not previously been attempted. Data on the primary endpoint are expected to be published in 2018

Transcriptome profiling of ontogeny in the acridid grasshopper Chorthippus biguttulus

Acridid grasshoppers (Orthoptera:Acrididae) are widely used model organisms for developmental, evolutionary, and neurobiological research. Although there has been recent influx of orthopteran transcriptomic resources, many use pooled ontogenetic stages obscuring information about changes in gene expression during development. Here we developed a de novo transcriptome spanning 7 stages in the life cycle of the acridid grasshopper Chorthippus biguttulus. Samples from different stages encompassing embryonic development through adults were used for transcriptomic profiling, revealing patterns of differential gene expression that highlight processes in the different life stages. These patterns were validated with semi-quantitative RT-PCR. Embryonic development showed a strongly differentiated expression pattern compared to all of the other stages and genes upregulated in this stage were involved in signaling, cellular differentiation, and organ development. Our study is one of the first to examine gene expression during post-embryonic development in a hemimetabolous insect and we found that only the fourth and fifth instars had clusters of genes upregulated during these stages. These genes are involved in various processes ranging from synthesis of biogenic amines to chitin binding. These observations indicate that post-embryonic ontogeny is not a continuous process and that some instars are differentiated. Finally, genes upregulated in the imago were generally involved in aging and immunity. Our study highlights the importance of looking at ontogeny as a whole and indicates promising directions for future research in orthopteran development

The Hemopoietic Stem Cell Niche Versus the Microenvironment of the Multiple Myeloma-Tumor Initiating Cell

Multiple myeloma cells are reminiscent of hemopoietic stem cells in their strict dependence upon the bone marrow microenvironment. However, from all other points of view, multiple myeloma cells differ markedly from stem cells. The cells possess a mature phenotype and secrete antibodies, and have thus made the whole journey to maturity, while maintaining a tumor phenotype. Not much credence was given to the possibility that the bulk of plasma-like multiple myeloma tumor cells is generated from tumor-initiating cells. Although interleukin-6 is a major contributor to the formation of the tumor’s microenvironment in multiple myeloma, it is not a major factor within hemopoietic stem cell niches. The bone marrow niche for myeloma cells includes the activity of inflammatory cytokines released through osteoclastogenesis. These permit maintenance of myeloma cells within the bone marrow. In contrast, osteoclastogenesis constitutes a signal that drives hemopoietic stem cells away from their bone marrow niches. The properties of the bone marrow microenvironment, which supports myeloma cell maintenance and proliferation, is therefore markedly different from the characteristics of the hemopoietic stem cell niche. Thus, multiple myeloma presents an example of a hemopoietic tumor microenvironment that does not resemble the corresponding stem cell renewal niche

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

S