Factors influencing the fracture of nickel-titanium rotary instruments

Abstract Mart|¤ n B, Zelada G, Varela P, Bahillo JG, Maga¤ n F, Ahn S, Rodr|¤ guez C

How large dimension guarantees a given angle

Abstract We study the following two problems: (1) Given n ≥ 2 and α, how large Hausdorff dimension can a compact set A ⊂ R n have if A does not contain three points that form an angle α? (2) Given α and δ, how large Hausdorff dimension can a compact subset A of a Euclidean space have if A does not contain three points that form an angle in the δ-neighborhood of α? Some angles (0, 60 • ) turn out to behave differently than other α ∈ [0, 180 • ]

Multitarget CFTR Modulators Endowed with Multiple Beneficial Side Effects for Cystic Fibrosis Patients: Toward a Simplified Therapeutic Approach

Cystic fibrosis (CF) is a multiorgan disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR). In addition to respiratory impairment due to mucus accumulation, viruses and bacteria trigger acute pulmonary exacerbations, accelerating disease progression and mortality rate. Treatment complexity increases with patients’ age, and simplifying the therapeutic regimen represents one of the key priorities in CF. We have recently reported the discovery of multitarget compounds able to “kill two birds with one stone” by targeting F508del-CFTR and PI4KIIIβ and thus acting simultaneously as CFTR correctors and broad-spectrum enterovirus (EV) inhibitors. Starting from these preliminary results, we report herein a hit-to-lead optimization and multidimensional structure–activity relationship (SAR) study that led to compound 23a. This compound showed good antiviral and F508del-CFTR correction potency, additivity/synergy with lumacaftor, and a promising in vitro absorption, distribution, metabolism, and excretion (ADME) profile. It was well tolerated in vivo with no sign of acute toxicity and histological alterations in key biodistribution organs

A Motif Unique to the Human Dead-Box Protein DDX3 Is Important for Nucleic Acid Binding, ATP Hydrolysis, RNA/DNA Unwinding and HIV-1 Replication

DEAD-box proteins are enzymes endowed with nucleic acid-dependent ATPase, RNA translocase and unwinding activities. The human DEAD-box protein DDX3 has been shown to play important roles in tumor proliferation and viral infections. In particular, DDX3 has been identified as an essential cofactor for HIV-1 replication. Here we characterized a set of DDX3 mutants biochemically with respect to nucleic acid binding, ATPase and helicase activity. In particular, we addressed the functional role of a unique insertion between motifs I and Ia of DDX3 and provide evidence for its implication in nucleic acid binding and HIV-1 replication. We show that human DDX3 lacking this domain binds HIV-1 RNA with lower affinity. Furthermore, a specific peptide ligand for this insertion selected by phage display interferes with HIV-1 replication after transduction into HelaP4 cells. Besides broadening our understanding of the structure-function relationships of this important protein, our results identify a specific domain of DDX3 which may be suited as target for antiviral drugs designed to inhibit cellular cofactors for HIV-1 replication

Human PrimPol is a highly error-prone polymerase regulated by single-stranded DNA binding proteins

PrimPol is a recently identified polymerase involved in eukaryotic DNA damage tolerance, employed in both re-priming and translesion synthesis mechanisms to bypass nuclear and mitochondrial DNA lesions. In this report, we investigate how the enzymatic activities of human PrimPol are regulated. We show that, unlike other TLS polymerases, PrimPol is not stimulated by PCNA and does not interact with it in vivo. We identify that PrimPol interacts with both of the major single-strand binding proteins, RPA and mtSSB in vivo. Using NMR spectroscopy, we characterize the domains responsible for the PrimPol-RPA interaction, revealing that PrimPol binds directly to the N-terminal domain of RPA70. In contrast to the established role of SSBs in stimulating replicative polymerases, we find that SSBs significantly limit the primase and polymerase activities of PrimPol. To identify the requirement for this regulation, we employed two forward mutation assays to characterize PrimPol's replication fidelity. We find that PrimPol is a mutagenic polymerase, with a unique error specificity that is highly biased towards insertion-deletion errors. Given the error-prone disposition of PrimPol, we propose a mechanism whereby SSBs greatly restrict the contribution of this enzyme to DNA replication at stalled forks, thus reducing the mutagenic potential of PrimPol during genome replication

Lakeside Cemeteries in the Sahara: 5000 Years of Holocene Population and Environmental Change

Background: Approximately two hundred human burials were discovered on the edge of a paleolake in Niger that providea uniquely preserved record of human occupation in the Sahara during the Holocene (,8000 B.C.E. to the present). CalledGobero, this suite of closely spaced sites chronicles the rapid pace of biosocial change in the southern Sahara in response tosevere climatic fluctuation.Methodology/Principal Findings: Two main occupational phases are identified that correspond with humid intervals in theearly and mid-Holocene, based on 78 direct AMS radiocarbon dates on human remains, fauna and artifacts, as well as 9 OSLdates on paleodune sand. The older occupants have craniofacial dimensions that demonstrate similarities with mid-Holocene occupants of the southern Sahara and Late Pleistocene to early Holocene inhabitants of the Maghreb. Theirhyperflexed burials compose the earliest cemetery in the Sahara dating to ,7500 B.C.E. These early occupants abandon thearea under arid conditions and, when humid conditions return ,4600 B.C.E., are replaced by a more gracile people withelaborated grave goods including animal bone and ivory ornaments.Conclusions/Significance: The principal significance of Gobero lies in its extraordinary human, faunal, and archaeologicalrecord, from which we conclude the following:(1) The early Holocene occupants at Gobero (7700–6200 B.C.E.) were largely sedentary hunter-fisher-gatherers withlakeside funerary sites that include the earliest recorded cemetery in the Sahara.(2) Principal components analysis of craniometric variables closely allies the early Holocene occupants at Gobero with askeletally robust, trans-Saharan assemblage of Late Pleistocene to mid-Holocene human populations from the Maghreband southern Sahara.(3) Gobero was abandoned during a period of severe aridification possibly as long as one millennium (6200–5200 B.C.E).(4) More gracile humans arrived in the mid-Holocene (5200–2500 B.C.E.) employing a diversified subsistence economybased on clams, fish, and savanna vertebrates as well as some cattle husbandry.(5) Population replacement after a harsh arid hiatus is the most likely explanation for the occupational sequence at Gobero.(6) We are just beginnin

Search for the standard model Higgs boson decaying to a bb pair in events with one charged lepton and large missing transverse energy using the full CDF data set

We present a search for the standard model Higgs boson produced in association with a W boson in sqrt(s) = 1.96 TeV p-pbar collision data collected with the CDF II detector at the Tevatron corresponding to an integrated luminosity of 9.45 fb-1. In events consistent with the decay of the Higgs boson to a bottom-quark pair and the W boson to an electron or muon and a neutrino, we set 95% credibility level upper limits on the WH production cross section times the H->bb branching ratio as a function of Higgs boson mass. At a Higgs boson mass of 125 GeV/c2 we observe (expect) a limit of 4.9 (2.8) times the standard model value.Comment: Submitted to Phys. Rev. Lett (v2 contains clarifications suggested by PRL

Search for the standard model Higgs boson decaying to a bbˉb\bar{b} pair in events with no charged leptons and large missing transverse energy using the full CDF data set

We report on a search for the standard model Higgs boson produced in association with a vector boson in the full data set of proton-antiproton collisions at $\sqrt{s} = 1.96$ TeV recorded by the CDF II detector at the Tevatron, corresponding to an integrated luminosity of 9.45 fb$^{-1}$. We consider events having no identified charged lepton, a transverse energy imbalance, and two or three jets, of which at least one is consistent with originating from the decay of a $b$ quark. We place 95% credibility level upper limits on the production cross section times standard model branching fraction for several mass hypotheses between 90 and $150 \mathrm{GeV}/c^2$. For a Higgs boson mass of $125 \mathrm{GeV}/c^2$, the observed (expected) limit is 6.7 (3.6) times the standard model prediction.Comment: Accepted by Phys. Rev. Let

Search for the standard model Higgs boson decaying to a bb pair in events with two oppositely-charged leptons using the full CDF data set

We present a search for the standard model Higgs boson produced in association with a Z boson in data collected with the CDF II detector at the Tevatron, corresponding to an integrated luminosity of 9.45/fb. In events consistent with the decay of the Higgs boson to a bottom-quark pair and the Z boson to electron or muon pairs, we set 95% credibility level upper limits on the ZH production cross section times the H -> bb branching ratio as a function of Higgs boson mass. At a Higgs boson mass of 125 GeV/c^2 we observe (expect) a limit of 7.1 (3.9) times the standard model value.Comment: To be submitted to Phys. Rev. Let

Expression of the RNA helicase DDX3 and the hypoxia response in breast cancer

<p>Aims: DDX3 is an RNA helicase that has antiapoptotic properties, and promotes proliferation and transformation. In addition, DDX3 was shown to be a direct downstream target of HIF-1α (the master regulatory of the hypoxia response) in breast cancer cell lines. However, the relation between DDX3 and hypoxia has not been addressed in human tumors. In this paper, we studied the relation between DDX3 and the hypoxic responsive proteins in human breast cancer.</p> <p>Methods and Results: DDX3 expression was investigated by immunohistochemistry in breast cancer in comparison with hypoxia related proteins HIF-1α, GLUT1, CAIX, EGFR, HER2, Akt1, FOXO4, p53, ERα, COMMD1, FER kinase, PIN1, E-cadherin, p21, p27, Transferrin receptor, FOXO3A, c-Met and Notch1. DDX3 was overexpressed in 127 of 366 breast cancer patients, and was correlated with overexpression of HIF-1α and its downstream genes CAIX and GLUT1. Moreover, DDX3 expression correlated with hypoxia-related proteins EGFR, HER2, FOXO4, ERα and c-Met in a HIF-1α dependent fashion, and with COMMD1, FER kinase, Akt1, E-cadherin, TfR and FOXO3A independent of HIF-1α.</p> <p>Conclusions: In invasive breast cancer, expression of DDX3 was correlated with overexpression of HIF-1α and many other hypoxia related proteins, pointing to a distinct role for DDX3 under hypoxic conditions and supporting the oncogenic role of DDX3 which could have clinical implication for current development of DDX3 inhibitors.</p&gt