717 research outputs found
Structure and Reactivity of Halogenated GC PNA Base Pairs – A DFT Approach
The present study explored the structural and reactivity relationship of halogenated G-C PNA base pairs using density functional theory (DFT) calculations. The halogens such as F, Cl, and Br are substituted by replacing H atoms involved in H-bonds of the base pairs. All structures were optimized using the B3LYP/6-311++G** theory level, and positive frequencies confirmed their equilibrium states. To understand the structural variations of the considered halogenated systems, the bond distances of R─X, R─H, and X/H•••Y and the bond angles of R─X•••Y were analyzed. The obtained structural parameters and interaction energies are comparable with the previous theoretical reports. In addition, the interaction energies (Eint) and quantum molecular descriptors (QMD) are also calculated to understand the difference between halogenated PNA systems and their non-halogenated counterparts. In this study, the enhancement in the reactivity properties of halogenated PNA systems has been demonstrated, which indicates their improved responsive characteristics in various chemical reactions. Based on the available results, the halogenated PNA systems, carefully considering their substitutional position, facilitate better accommodation for the triplex formation of dsDNA/dsRNA. Therefore, it is concluded that the improved reactivity properties of halogenated PNA base pairs would make them potential candidates for various biological applications
Modelling semi-attributable toxicity in dual-agent phase I trials with non-concurrent drug administration.
In oncology, combinations of drugs are often used to improve treatment efficacy and/or reduce harmful side effects. Dual-agent phase I clinical trials assess drug safety and aim to discover a maximum tolerated dose combination via dose-escalation; cohorts of patients are given set doses of both drugs and monitored to see if toxic reactions occur. Dose-escalation decisions for subsequent cohorts are based on the number and severity of observed toxic reactions, and an escalation rule. In a combination trial, drugs may be administered concurrently or non-concurrently over a treatment cycle. For two drugs given non-concurrently with overlapping toxicities, toxicities occurring after administration of the first drug yet before administration of the second may be attributed directly to the first drug, whereas toxicities occurring after both drugs have been given some present ambiguity; toxicities may be attributable to the first drug only, the second drug only or the synergistic combination of both. We call this mixture of attributable and non-attributable toxicity semi-attributable toxicity. Most published methods assume drugs are given concurrently, which may not be reflective of trials with non-concurrent drug administration. We incorporate semi-attributable toxicity into Bayesian modelling for dual-agent phase I trials with non-concurrent drug administration and compare the operating characteristics to an approach where this detail is not considered. Simulations based on a trial for non-concurrent administration of intravesical Cabazitaxel and Cisplatin in early-stage bladder cancer patients are presented for several scenarios and show that including semi-attributable toxicity data reduces the number of patients given overly toxic combinations. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.G.M. Wheeler and A.P. Mander are supported by the Medical Research Council (grant number G0800860). M.J. Sweeting is supported by a European Research Council Advanced Investigator Award: EPIC-Heart (grant number 268834), the UK Medical Research Council (grant number MR/L003120/1), the British Heart Foundation and the Cambridge National Institute for Health Research Biomedical Research Centre. S.M. Lee is supported by the American Cancer Society (grant number MRSG-13-146-01-CPHPS).This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/sim.691
Period Integrals of CY and General Type Complete Intersections
We develop a global Poincar\'e residue formula to study period integrals of
families of complex manifolds. For any compact complex manifold equipped
with a linear system of generically smooth CY hypersurfaces, the formula
expresses period integrals in terms of a canonical global meromorphic top form
on . Two important ingredients of our construction are the notion of a CY
principal bundle, and a classification of such rank one bundles. We also
generalize our construction to CY and general type complete intersections. When
is an algebraic manifold having a sufficiently large automorphism group
and is a linear representation of , we construct a holonomic D-module
that governs the period integrals. The construction is based in part on the
theory of tautological systems we have developed in the paper \cite{LSY1},
joint with R. Song. The approach allows us to explicitly describe a
Picard-Fuchs type system for complete intersection varieties of general types,
as well as CY, in any Fano variety, and in a homogeneous space in particular.
In addition, the approach provides a new perspective of old examples such as CY
complete intersections in a toric variety or partial flag variety.Comment: An erratum is included to correct Theorem 3.12 (Uniqueness of CY
structure
Proteomics biomarker discovery for individualized prevention of familial pancreatic cancer using statistical learning
BACKGROUND: The low five-year survival rate of pancreatic ductal adenocarcinoma (PDAC) and the low diagnostic rate of early-stage PDAC via imaging highlight the need to discover novel biomarkers and improve the current screening procedures for early diagnosis. Familial pancreatic cancer (FPC) describes the cases of PDAC that are present in two or more individuals within a circle of first-degree relatives. Using innovative high-throughput proteomics, we were able to quantify the protein profiles of individuals at risk from FPC families in different potential pre-cancer stages. However, the high-dimensional proteomics data structure challenges the use of traditional statistical analysis tools. Hence, we applied advanced statistical learning methods to enhance the analysis and improve the results’ interpretability. METHODS: We applied model-based gradient boosting and adaptive lasso to deal with the small, unbalanced study design via simultaneous variable selection and model fitting. In addition, we used stability selection to identify a stable subset of selected biomarkers and, as a result, obtain even more interpretable results. In each step, we compared the performance of the different analytical pipelines and validated our approaches via simulation scenarios. RESULTS: In the simulation study, model-based gradient boosting showed a more accurate prediction performance in the small, unbalanced, and high-dimensional datasets than adaptive lasso and could identify more relevant variables. Furthermore, using model-based gradient boosting, we discovered a subset of promising serum biomarkers that may potentially improve the current screening procedure of FPC. CONCLUSION: Advanced statistical learning methods helped us overcome the shortcomings of an unbalanced study design in a valuable clinical dataset. The discovered serum biomarkers provide us with a clear direction for further investigations and more precise clinical hypotheses regarding the development of FPC and optimal strategies for its early detection
Geometric Aspects of the Moduli Space of Riemann Surfaces
This is a survey of our recent results on the geometry of moduli spaces and
Teichmuller spaces of Riemann surfaces appeared in math.DG/0403068 and
math.DG/0409220. We introduce new metrics on the moduli and the Teichmuller
spaces of Riemann surfaces with very good properties, study their curvatures
and boundary behaviors in great detail. Based on the careful analysis of these
new metrics, we have a good understanding of the Kahler-Einstein metric from
which we prove that the logarithmic cotangent bundle of the moduli space is
stable. Another corolary is a proof of the equivalences of all of the known
classical complete metrics to the new metrics, in particular Yau's conjectures
in the early 80s on the equivalences of the Kahler-Einstein metric to the
Teichmuller and the Bergman metric.Comment: Survey article of our recent results on the subject. Typoes
corrrecte
Trust as a mediator in the relationship between childhood sexual abuse and IL-6 level in adulthood
Childhood sexual abuse (CSA) has been shown to predict the coupling of depression and inflammation in adulthood. Trust within intimate relationships, a core element in marital relations, has been shown to predict positive physical and mental health outcomes, but the mediating role of trust in partners in the association between CSA and inflammation in adulthood requires further study. The present study aimed to examine the impact of CSA on inflammatory biomarkers (IL-6 and IL-1β) in adults with depression and the mediating role of trust. A cross-sectional survey data set of adults presenting with mood and sleep disturbance was used in the analysis. CSA demonstrated a significant negative correlation with IL-6 level (r = -0.28, p<0. 01) in adults with clinically significant depression, while trust showed a significant positive correlation with IL-6 level (r = 0.36, p < .01). Sobel test and bootstrapping revealed a significant mediating role for trust between CSA and IL-6 level. CSA and trust in partners were revealed to have significant associations with IL-6 level in adulthood. Counterintuitively, the directions of association were not those expected. Trust played a mediating role between CSA and adulthood levels of IL-6. Plausible explanations for these counterintuitive findings are discussed
Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer
The underpinnings of STAT3 hyperphosphorylation resulting in enhanced signaling and cancer progression are incompletely understood. Loss-of-function mutations of enzymes that dephosphorylate STAT3, such as receptor protein tyrosine phosphatases, which are encoded by the PTPR gene family, represent a plausible mechanism of STAT3 hyperactivation. We analyzed whole exome sequencing (n = 374) and reverse-phase protein array data (n = 212) from head and neck squamous cell carcinomas (HNSCCs). PTPR mutations are most common and are associated with significantly increased phospho-STAT3 expression in HNSCC tumors. Expression of receptor-like protein tyrosine phosphatase T (PTPRT) mutant proteins induces STAT3 phosphorylation and cell survival, consistent with a “driver” phenotype. Computational modeling reveals functional consequences of PTPRT mutations on phospho-tyrosine–substrate interactions. A high mutation rate (30%) of PTPRs was found in HNSCC and 14 other solid tumors, suggesting that PTPR alterations, in particular PTPRT mutations, may define a subset of patients where STAT3 pathway inhibitors hold particular promise as effective therapeutic agents.Fil: Lui, Vivian Wai Yan. University of Pittsburgh; Estados UnidosFil: Peyser, Noah D.. University of Pittsburgh; Estados UnidosFil: Ng, Patrick Kwok-Shing. University Of Texas Md Anderson Cancer Center;Fil: Hritz, Jozef. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos. Masaryk University; República ChecaFil: Zeng, Yan. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Lu, Yiling. University Of Texas Md Anderson Cancer Center;Fil: Li, Hua. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Wang, Lin. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Gilbert, Breean R.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: General, Ignacio. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Bahar, Ivet. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Ju, Zhenlin. University Of Texas Md Anderson Cancer Center;Fil: Wang, Zhenghe. Case Western Reserve University; Estados UnidosFil: Pendleton, Kelsey P.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Xiao, Xiao. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Du, Yu. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Vries, John K.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Hammerman, Peter S.. Harvard Medical School; Estados UnidosFil: Garraway, Levi A.. Harvard Medical School; Estados UnidosFil: Mills, Gordon B.. University Of Texas Md Anderson Cancer Center;Fil: Johnson, Daniel E.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Grandis, Jennifer R.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unido
Phase-field modeling of microstructural pattern formation during directional solidification of peritectic alloys without morphological instability
During the directional solidification of peritectic alloys, two stable solid
phases (parent and peritectic) grow competitively into a metastable liquid
phase of larger impurity content than either solid phase. When the parent or
both solid phases are morphologically unstable, i.e., for a small temperature
gradient/growth rate ratio (), one solid phase usually outgrows and
covers the other phase, leading to a cellular-dendritic array structure closely
analogous to the one formed during monophase solidification of a dilute binary
alloy. In contrast, when is large enough for both phases to be
morphologically stable, the formation of the microstructurebecomes controlled
by a subtle interplay between the nucleation and growth of the two solid
phases. The structures that have been observed in this regime (in small samples
where convection effect are suppressed) include alternate layers (bands) of the
parent and peritectic phases perpendicular to the growth direction, which are
formed by alternate nucleation and lateral spreading of one phase onto the
other as proposed in a recent model [R. Trivedi, Metall. Mater. Trans. A 26, 1
(1995)], as well as partially filled bands (islands), where the peritectic
phase does not fully cover the parent phase which grows continuously. We
develop a phase-field model of peritectic solidification that incorporates
nucleation processes in order to explore the formation of these structures.
Simulations of this model shed light on the morphology transition from islands
to bands, the dynamics of spreading of the peritectic phase on the parent phase
following nucleation, which turns out to be characterized by a remarkably
constant acceleration, and the types of growth morphology that one might expect
to observe in large samples under purely diffusive growth conditions.Comment: Final version, minor revisions, 16 pages, 14 EPS figures, RevTe
Magnetism, Critical Fluctuations and Susceptibility Renormalization in Pd
Some of the most popular ways to treat quantum critical materials, that is,
materials close to a magnetic instability, are based on the Landau functional.
The central quantity of such approaches is the average magnitude of spin
fluctuations, which is very difficult to measure experimentally or compute
directly from the first principles. We calculate the parameters of the Landau
functional for Pd and use these to connect the critical fluctuations beyond the
local-density approximation and the band structure.Comment: Replaced with the revised version accepted for publication.
References updated, errors corrected, other change
Nanoantennas for visible and infrared radiation
Nanoantennas for visible and infrared radiation can strongly enhance the
interaction of light with nanoscale matter by their ability to efficiently link
propagating and spatially localized optical fields. This ability unlocks an
enormous potential for applications ranging from nanoscale optical microscopy
and spectroscopy over solar energy conversion, integrated optical
nanocircuitry, opto-electronics and density-ofstates engineering to
ultra-sensing as well as enhancement of optical nonlinearities. Here we review
the current understanding of optical antennas based on the background of both
well-developed radiowave antenna engineering and the emerging field of
plasmonics. In particular, we address the plasmonic behavior that emerges due
to the very high optical frequencies involved and the limitations in the choice
of antenna materials and geometrical parameters imposed by nanofabrication.
Finally, we give a brief account of the current status of the field and the
major established and emerging lines of investigation in this vivid area of
research.Comment: Review article with 76 pages, 21 figure
- …