Interactions Between Spermine-Derivatized Tentacle Porphyrins And The Human Telomeric DNA G-Quadruplex

G-rich DNA sequences have the potential to fold into non-canonical G-Quadruplex (GQ) structures implicated in aging and human diseases, notably cancers. Because stabilization of GQs at telomeres and oncogene promoters may prevent cancer, there is an interest in developing small molecules that selectively target GQs. Herein, we investigate the interactions of meso-tetrakis-(4-carboxysperminephenyl)porphyrin (TCPPSpm4) and its Zn(II) derivative (ZnTCPPSpm4) with human telomeric DNA (Tel22) via UV-Vis, circular dichroism (CD), and fluorescence spectroscopies, resonance light scattering (RLS), and fluorescence resonance energy transfer (FRET) assays. UV-Vis titrations reveal binding constants of 4.7 × 10⁶ and 1.4 × 10⁷ M⁻¹ and binding stoichiometry of 2–4:1 and 10–12:1 for TCPPSpm4 and ZnTCPPSpm4, respectively. High stoichiometry is supported by the Job plot data, CD titrations, and RLS data. FRET melting indicates that TCPPSpm4 stabilizes Tel22 by 36 ± 2 °C at 7.5 eq., and that ZnTCPPSpm4 stabilizes Tel22 by 33 ± 2 °C at ~20 eq.; at least 8 eq. of ZnTCPPSpm4 are required to achieve significant stabilization of Tel22, in agreement with its high binding stoichiometry. FRET competition studies show that both porphyrins are mildly selective for human telomeric GQ vs duplex DNA. Spectroscopic studies, combined, point to end-stacking and porphyrin self-association as major binding modes. This work advances our understanding of ligand interactions with GQ DNA

Chylous Leak During Posterior Approach to Juvenile Scoliosis Surgery: A Case Report.

CaseWe report the first documented case of chylous leak recognized intraoperatively during posterior spinal instrumentation and fusion for juvenile scoliosis in a female patient with a history of thoracotomy and decortication for an empyema.ConclusionsThoracic duct injury can lead to severe morbidity and mortality because of chylothorax formation. Although chylous leaks are a well-documented complication of the anterior approach to spine surgery, leaks during the posterior approach are rarely reported. When these chylous leaks are recognized intraoperatively, the likelihood of serious complications may be minimized by drain placement before closure

Interference management with mismatched partial channel state information

We study the fundamental limits of communications over multi-layer wireless networks where each node has only limited knowledge of the channel state information. In particular, we consider the scenario in which each source-destination pair has only enough information to perform optimally when other pairs do not interfere. Beyond that, the only other information available at each node is the global network connectivity. We propose a transmission strategy that solely relies on the available limited knowledge and combines coding with interference avoidance. We show that our proposed strategy goes well beyond the performance of interference avoidance techniques. We present an algebraic framework for the proposed transmission strategy based on which we provide a guarantee of the achievable rate. For several network topologies, we prove the optimality of our proposed strategy by providing information-theoretic outer-bounds

Proximal femoral excision with interposition myoplasty for cerebral palsy patients with painful chronic hip dislocation

Purpose: Proximal femoral excision is a salvage procedure for painful chronic hip dislocation in cerebral palsy (CP) patients. The primary objective of this article is to describe our experience of an amplified interposition myoplasty, with appropriate peri-operative pain and tone management strategies, in a cohort of non-ambulatory CP patients with painful chronic hip dislocation. Our secondary objective is to present the clinical outcomes of these patients. Methods: We describe our experience in 20 CP patients (25 procedures) at mean 54-month (range 27–169) follow-up with a surgical technique that includes an augmented interposition myoplasty and tone management. The indications for surgery were pain (21 hips), poor sitting tolerance (11) and difficulty with perineal care (8). Results: The mean age was 22 years (range 10–40) with 11 patients Gross Motor Function Classification Scale (GMFCS) IV and 9 patients GMFCS V. Mean length of stay was 13 days (3–35). One procedure required revision at 12 months. Mean pain score improved from 7.8 (5–10) pre-operatively to 2.8 (1–5) post-operatively (p  <  0.001). Sitting tolerance improved in all patients and in 75 % (15) perineal care was easier. Conclusions: Our interposition myoplasty technique with individualised pain/tone management has good outcomes in this cohort of patients with multiple co-morbidities

N-Methylmesoporphyrin IX Fluorescence As A Reporter Of Strand Orientation In Guanine Quadruplexes

Guanine quadruplexes (GQ) are four-stranded DNA structures formed by guanine-rich DNA sequences. The formation of GQs inhibits cancer cell growth, although the detection of GQs invivo has proven difficult, in part because of their structural diversity. The development of GQ-selective fluorescent reporters would enhance our ability to quantify the number and location of GQs, ultimately advancing biological studies of quadruplex relevance and function. N-methylmesoporphyrin IX (NMM) interacts selectively with parallel-stranded GQs; in addition, its fluorescence is sensitive to the presence of DNA, making this ligand a possible candidate for a quadruplex probe. In the present study, we investigated the effect of DNA secondary structure on NMM fluorescence. We found that NMM fluorescence increases by about 60-fold in the presence of parallel-stranded GQs and by about 40-fold in the presence of hybrid GQs. Antiparallel GQs lead to lower than 10-fold increases in NMM fluorescence. Single-stranded DNA, duplex, or i-motif, induce no change in NMM fluorescence. We conclude that NMM shows promise as a turn-on\u27 fluorescent probe for detecting quadruplex structures, as well as for differentiating them on the basis of strand orientation

Investigation Of The Interactions Between Pt(II) And Pd(II) Derivatives Of 5,10,15,20-Tetrakis (N-Methyl-4-Pyridyl) Porphyrin And G-Quadruplex DNA

G-quadruplexes are non-canonical DNA structures formed by guanine-rich DNA sequences that are implicated in cancer and aging. Understanding how small molecule ligands interact with quadruplexes is essential both to the development of novel anticancer therapeutics and to the design of new quadruplex-selective probes needed for elucidation of quadruplex biological functions. In this work, UV–visible, fluorescence, and circular dichroism spectroscopies, fluorescence resonance energy transfer (FRET) melting assays, and resonance light scattering were used to investigate how the Pt(II) and Pd(II) derivatives of the well-studied 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4) interact with quadruplexes formed by the human telomeric DNA, Tel22, and by the G-rich sequences from oncogene promoters. Our results suggest that Pt- and PdTMPyP4 interact with Tel22 via efficient π–π stacking with a binding affinity of 106–107 M−1. Under porphyrin excess, PtTMPyP4 aggregates using Tel22 as a template; the aggregates reach maximum size at [PtTMPyP4]/[Tel22] ~8 and dissolve at [PtTMPyP4]/[Tel22] ≤ 2. FRET assays reveal that both porphyrins are excellent stabilizers of human telomeric DNA, with stabilization temperature of 30.7 ± 0.6 °C for PtTMPyP4 and 30.9 ± 0.4 °C for PdTMPyP4 at [PtTMPyP4]/[Tel22] = 2 in K+ buffer, values significantly higher as compared to those for TMPyP4. The porphyrins display modest selectivity for quadruplex vs. duplex DNA, with selectivity ratios of 150 and 330 for Pt- and PdTMPyP4, respectively. This selectivity was confirmed by observed ‘light switch’ effect: fluorescence of PtTMPyP4 increases significantly in the presence of a variety of DNA secondary structures, yet the strongest effect is produced by quadruplex DNA

Numerical loop quantum cosmology: an overview

A brief review of various numerical techniques used in loop quantum cosmology and results is presented. These include the way extensive numerical simulations shed insights on the resolution of classical singularities, resulting in the key prediction of the bounce at the Planck scale in different models, and the numerical methods used to analyze the properties of the quantum difference operator and the von Neumann stability issues. Using the quantization of a massless scalar field in an isotropic spacetime as a template, an attempt is made to highlight the complementarity of different methods to gain understanding of the new physics emerging from the quantum theory. Open directions which need to be explored with more refined numerical methods are discussed.Comment: 33 Pages, 4 figures. Invited contribution to appear in Classical and Quantum Gravity special issue on Non-Astrophysical Numerical Relativit

Traumatic Retrobulbar Haemorrhage: Aetio-pathology and management

Retrobulbar haematoma following blunt orbital trauma is a rare,but potentially serious complication, since it can evolve rapidly from visual impairment to permanent loss of vision. This sight-threatening situation most commonly arises from orbital bleeding accompanying undisplaced fractures of the orbital walls, an event that increases the pressure inside theorbit and results in vascular damage to the optic nerve. The clinical presentation includes pain, exophthalmos with proptosis, and internal ophthalmoplegia, with impairment or loss of the pupillary reXex. A thin-layer orbital CT scan is an essential diagnostic aid. Therapy is based on orbitaldecompression, via different surgical approaches, with the intention of reducing the pressure on the nerve and vascular structures inside the orbit. Emergent management is of utmost importance as any delay between the onset of symptoms and treatment can have a significant effect onrecovery

Towards Understanding and Harnessing the Potential of Clause Learning

Efficient implementations of DPLL with the addition of clause learning are the fastest complete Boolean satisfiability solvers and can handle many significant real-world problems, such as verification, planning and design. Despite its importance, little is known of the ultimate strengths and limitations of the technique. This paper presents the first precise characterization of clause learning as a proof system (CL), and begins the task of understanding its power by relating it to the well-studied resolution proof system. In particular, we show that with a new learning scheme, CL can provide exponentially shorter proofs than many proper refinements of general resolution (RES) satisfying a natural property. These include regular and Davis-Putnam resolution, which are already known to be much stronger than ordinary DPLL. We also show that a slight variant of CL with unlimited restarts is as powerful as RES itself. Translating these analytical results to practice, however, presents a challenge because of the nondeterministic nature of clause learning algorithms. We propose a novel way of exploiting the underlying problem structure, in the form of a high level problem description such as a graph or PDDL specification, to guide clause learning algorithms toward faster solutions. We show that this leads to exponential speed-ups on grid and randomized pebbling problems, as well as substantial improvements on certain ordering formulas

Critical analysis of vendor lock-in and its impact on cloud computing migration: a business perspective

Vendor lock-in is a major barrier to the adoption of cloud computing, due to the lack of standardization. Current solutions and efforts tackling the vendor lock-in problem are predominantly technology-oriented. Limited studies exist to analyse and highlight the complexity of vendor lock-in problem in the cloud environment. Consequently, most customers are unaware of proprietary standards which inhibit interoperability and portability of applications when taking services from vendors. This paper provides a critical analysis of the vendor lock-in problem, from a business perspective. A survey based on qualitative and quantitative approaches conducted in this study has identified the main risk factors that give rise to lock-in situations. The analysis of our survey of 114 participants shows that, as computing resources migrate from on-premise to the cloud, the vendor lock-in problem is exacerbated. Furthermore, the findings exemplify the importance of interoperability, portability and standards in cloud computing. A number of strategies are proposed on how to avoid and mitigate lock-in risks when migrating to cloud computing. The strategies relate to contracts, selection of vendors that support standardised formats and protocols regarding standard data structures and APIs, developing awareness of commonalities and dependencies among cloud-based solutions. We strongly believe that the implementation of these strategies has a great potential to reduce the risks of vendor lock-in