Targeting the OB-Folds of Replication Protein A with Small Molecules

Replication protein A (RPA) is the main eukaryotic single-strand (ss) DNA-binding protein involved in DNA replication and repair. We have identified and developed two classes of small molecule inhibitors (SMIs) that show in vitro inhibition of the RPA-DNA interaction. We present further characterization of these SMIs with respect to their target binding, mechanism of action, and specificity. Both reversible and irreversible modes of inhibition are observed for the different classes of SMIs with one class found to specifically interact with DNA-binding domains A and B (DBD-A/B) of RPA. In comparison with other oligonucleotide/oligosaccharide binding-fold (OB-fold) containing ssDNA-binding proteins, one class of SMIs displayed specificity for the RPA protein. Together these data demonstrate that the specific targeting of a protein-DNA interaction can be exploited towards interrogating the cellular activity of RPA as well as increasing the efficacy of DNA-damaging chemotherapeutics used in cancer treatment

Proteomic analysis of the cerebrospinal fluid of patients with restless legs syndrome/Willis-Ekbom disease

BACKGROUND: Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a sensorimotor disorder that causes patients to experience overwhelming and distressing sensations in the legs compelling the patient to move their legs to provide relief. The purpose of this study was to determine if biomarkers in the cerebrospinal fluid can distinguish RLS/WED patients from neurological controls. METHODS: We obtained CSF samples by lumbar puncture from 5 early-onset RLS/WED patients and 5 controls. We performed 2-dimensional difference in-gel electrophoresis (2D-DIGE). Proteins that were significantly altered were identified by Student’s t-test. Protein spots that were differentially expressed (p ≤ 0.05, Av. Ratio ≥ 2.0) between RLS/WED and control CSF samples were identified using MALDI-TOF-MS. Statistical analyses of the validation immunoblot assays were performed using Student’s t-test. RESULTS: In this discovery study we identified 6 candidate CSF protein markers for early-onset RLS/WED. Four proteins (Cystatin C, Lipocalin-type Prostaglandin D2 Synthase, Vitamin D binding Protein, and β-Hemoglobin) were increased and 2 proteins (Apolipoprotein A1 and α-1-acid Glycoprotein) were decreased in RLS/WED patients. CONCLUSIONS: Our results reveal a protein profile in the RLS/WED CSF that is consistent with clinical findings of disruptive sleep, cardiovascular dysfunction and painful symptoms. Moreover, protein profiles are consistent with neuropathological findings of activation of hypoxia inducible factor (HIF) pathways and alterations in dopaminergic systems. These data indicate the CSF of RLS/WED patients may provide information relevant to biological basis for RLS/WED, treatment strategies and potential new treatment targets

G_2 Perfect-Fluid Cosmologies with a proper conformal Killing vector

We study the Einstein field equations for spacetimes admitting a maximal two-dimensional abelian group of isometries acting orthogonally transitively on spacelike surfaces and, in addition, with at least one conformal Killing vector. The three-dimensional conformal group is restricted to the case when the two-dimensional abelian isometry subalgebra is an ideal and it is also assumed to act on non-null hypersurfaces (both, spacelike and timelike cases are studied). We consider both, diagonal and non-diagonal metrics and find all the perfect-fluid solutions under these assumptions (except those already known). We find four families of solutions, each one containing arbitrary parameters for which no differential equations remain to be integrated. We write the line-elements in a simplified form and perform a detailed study for each of these solutions, giving the kinematical quantities of the fluid velocity vector, the energy-density and pressure, values of the parameters for which the energy conditions are fulfilled everywhere, the Petrov type, the singularities in the spacetimes and the Friedmann-Lemaitre-Robertson-Walker metrics contained in each family.Comment: Latex, no figure

Supraclavicular decompression for neurogenic thoracic outlet syndrome in adolescent and adult populations

ObjectiveThis study was conducted to better define clinical results and understand factors determining responsiveness to surgical treatment for neurogenic thoracic outlet syndrome (NTOS) in adolescent and adult populations.MethodsA retrospective review was conducted for 189 patients with disabling NTOS who underwent primary supraclavicular decompression (scalenectomy, brachial plexus neurolysis and first rib resection, with or without pectoralis minor tenotomy) from April 2008 to December 2010. Clinical characteristics were compared between 35 adolescent patients (aged <21 years) and 154 adults (aged >21 years). Functional outcome measures were assessed before surgery and at 3- and 6-month follow-up using a composite NTOS Index combining the Disabilities of the Arm, Shoulder and Hand (DASH) survey, the Cervical-Brachial Symptom Questionnaire (CBSQ), and a 10-point visual analog scale (VAS) for pain.ResultsAdolescent and adult patients were not significantly different with respect to sex (overall 72.5% female), side affected (58.7% right, 60.3% dominant limb), bony anomalies (23.3%), previous injury (55.6%), coexisting pain disorders (11.1%), and positive responses to scalene muscle anesthetic blocks (95.6%). Compared with adults, adolescent patients had a significantly (P < .05) lower incidence of depression (11.4% vs 41.6%), motor vehicle injury (5.7% vs 20.1%), previous operations (11.4% vs 29.9%), preoperative use of opiate medications (17.1% vs 44.8%), and symptom duration >2 years (24.2% vs 50.0%). Mean preoperative NTOS Index (scale 0-100) was significantly lower in adolescent vs adult patients (46.5 ± 3.6 vs 58.5 ± 1.7; P = .009), and hospital length of stay was 4.4 ± 0.2 vs 4.9 ± 0.1 days (P = .03), but the rate of postoperative complications was no different (overall, 4.2%). Although both groups exhibited significant improvement in functional outcome measures at 3 and 6 months, adolescent patients had significantly lower NTOS Index (10.4 ± 3.1 vs 39.3 ± 3.3; P < .001) and use of opiate medications (11.4% vs 47.4%; P < .001) compared with adults.ConclusionsAdolescents undergoing supraclavicular decompression for NTOS had more favorable preoperative characteristics and enhanced 3-month and 6-month functional outcomes than adults. Further study is needed to delineate the age-dependent and independent factors that promote optimal surgical outcomes for NTOS

Individual leader to interdependent leadership: A case study in leadership development and tripartite evaluation

This article is available open access through the publisher’s website at the link below. Copyright @ 2013 Sage Publications.The Problem - In this case study we see a move away from orthodox views of school leadership as “headship” to a more contemporary model of educational leadership wherein we note a departure from functional, curricula-based school leadership toward more human resource development (HRD) approaches. The aim of this study was to consider the effectiveness of an educational development program for middle leaders within an educational establishment. The Solution - We examined the impact of a bespoke higher education leadership development intervention in Leadership (and Change) on the formation and cohesiveness of a newly formed innovative leadership structure. The Stakeholders - The leadership development intervention was designed through a tripartite collaboration including a university, senior school leaders, and staff. The intervention was designed to shift leadership from individual leader agency to interdependent human leadership agency. Through tripartite evaluation we uncover leadership development praxis that transcends the boundaries of conventional educational leadership and reemphasizes the benefits of bridging the academic/practitioner divide and the application of theory to praxis

The long-term treatment of restless legs syndrome/Willis–Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group

AbstractA Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) to develop evidence-based and consensus-based recommendations for the long-term pharmacologic treatment of restless legs syndrome/Willis–Ekbom disease (RLS/WED). The Task Force reviewed the results of all studies of RLS/WED treatments with durations of 6months or longer presented at meetings over the past 2years, posted on Web sites of pharmaceutical companies, or published in peer-reviewed journals, asking the questions, “What is the efficacy of this treatment in patients with RLS/WED?” and “What is the safety of this treatment in patients with RLS/WED?”The Task Force developed guidelines based on their review of 61 papers meeting inclusion criteria, and using a modified evidence-grading scheme. Pregabalin has been established as effective for up to 1year in treating RLS/WED (Level A evidence). Pramipexole, ropinirole, and rotigotine have been established as effective for up to 6months in treating RLS/WED (Level A). The following drugs have been established as probably effective (Level B) in treating RLS/WED for durations ranging from 1 to 5years: gabapentin enacarbil, pramipexole, and ropinirole (1year); levodopa (2years); and rotigotine (5years). Because of associated safety concerns, pergolide and cabergoline should not be used in the treatment of RLS/WED unless the benefits clearly outweigh the risks. Other pharmacologic therapies have insufficient evidence to support their long-term use in treating RLS/WED.The IRLSSG Task Force also developed consensus-based strategies for the prevention and treatment of complications (such as augmentation, loss of efficacy, excessive daytime sleepiness, and impulse control disorders) that may develop with the long-term pharmacologic treatment of RLS/WED. The use of either a dopamine-receptor agonist or α2δ calcium-channel ligand is recommended as the first-line treatment of RLS/WED for most patients, with the choice of agent dependent on the patient’s severity of RLS/WED symptoms, cognitive status, history, and comorbid conditions

Integration of a Spanish-to-LSE machine translation system into an e-learning platform

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-642-21657-2_61This paper presents the first results of the integration of a Spanish-to-LSE Machine Translation (MT) system into an e-learning platform. Most e-learning platforms provide speech-based contents, which makes them inaccessible to the Deaf. To solve this issue, we have developed a MT system that translates Spanish speech-based contents into LSE. To test our MT system, we have integrated it into an e-learning tool. The e-learning tool sends the audio to our platform. The platform sends back the subtitles and a video stream with the signed translation to the e-learning tool. Preliminary results, evaluating the sign language synthesis module, show an isolated sign recognition accuracy of 97%. The sentence recognition accuracy was of 93%.Authors would like to acknowledge the FPU-UAM grant program for its financial support. Authors are grateful to the FCNSE linguistic department for sharing their knowledge in LSE and performing the evaluations. Many thanks go to María Chulvi and Benjamín Nogal for providing help during the imple-mentation of this system. This work was partially supported by the Telefónica Móviles España S.A. project number 10-047158-TE-Ed-01-1

Atrial fibrillation cryoablation is an effective day case treatment: the UK PolarX vs. Arctic Front Advance experience

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. AIMS: Pulmonary vein isolation (PVI) is the cornerstone of catheter ablation for atrial fibrillation (AF). There are limited data on the PolarX Cryoballoon. The study aimed to establish the safety, efficacy, and feasibility of same day discharge for Cryoballoon PVI. METHODS AND RESULTS: Multi-centre study across 12 centres. Procedural metrics, safety profile, and procedural efficacy of the PolarX Cryoballoon with the Arctic Front Advance (AFA) Cryoballoon were compared in a cohort large enough to provide definitive comparative data. A total of 1688 patients underwent PVI with cryoablation (50% PolarX and 50% AFA). Successful PVI was achieved with 1677 (99.3%) patients with 97.2% (n = 1641) performed as day case procedures with a complication rate of &lt;1%. Safety, procedural metrics, and efficacy of the PolarX Cryoballoon were comparable with the AFA cohort. The PolarX Cryoballoon demonstrated a nadir temperature of -54.6 \ub1 7.6\ub0C, temperature at 30 s of -38.6 \ub1 7.2\ub0C, time to -40\ub0C of 34.1 \ub1 13.7 s, and time to isolation of 49.8 \ub1 33.2 s. Independent predictors for achieving PVI included time to reach -40\ub0C [odds ratio (OR) 1.34; P &lt; 0.001] and nadir temperature (OR 1.24; P &lt; 0.001) with an optimal cut-off of ≤34 s [area under the curve (AUC) 0.73; P &lt; 0.001] and nadir temperature of ≤-54.0\ub0C (AUC 0.71; P &lt; 0.001), respectively. CONCLUSIONS: This large-scale UK multi-centre study has shown that Cryoballoon PVI is a safe, effective day case procedure. PVI using the PolarX Cryoballoon was similarly safe and effective as the AFA Cryoballoon. The cryoablation metrics achieved with the PolarX Cryoballoon were different to that reported with the AFA Cryoballoon. Modified cryoablation targets are required when utilizing the PolarX Cryoballoon

Atrial fibrillation cryoablation is an effective day case treatment: the UK PolarX vs. Arctic Front Advance experience.

AIMS: Pulmonary vein isolation (PVI) is the cornerstone of catheter ablation for atrial fibrillation (AF). There are limited data on the PolarX Cryoballoon. The study aimed to establish the safety, efficacy, and feasibility of same day discharge for Cryoballoon PVI. METHODS AND RESULTS: Multi-centre study across 12 centres. Procedural metrics, safety profile, and procedural efficacy of the PolarX Cryoballoon with the Arctic Front Advance (AFA) Cryoballoon were compared in a cohort large enough to provide definitive comparative data. A total of 1688 patients underwent PVI with cryoablation (50% PolarX and 50% AFA). Successful PVI was achieved with 1677 (99.3%) patients with 97.2% (n = 1641) performed as day case procedures with a complication rate of <1%. Safety, procedural metrics, and efficacy of the PolarX Cryoballoon were comparable with the AFA cohort. The PolarX Cryoballoon demonstrated a nadir temperature of -54.6 ± 7.6°C, temperature at 30 s of -38.6 ± 7.2°C, time to -40°C of 34.1 ± 13.7 s, and time to isolation of 49.8 ± 33.2 s. Independent predictors for achieving PVI included time to reach -40°C [odds ratio (OR) 1.34; P < 0.001] and nadir temperature (OR 1.24; P < 0.001) with an optimal cut-off of ≤34 s [area under the curve (AUC) 0.73; P < 0.001] and nadir temperature of ≤-54.0°C (AUC 0.71; P < 0.001), respectively. CONCLUSIONS: This large-scale UK multi-centre study has shown that Cryoballoon PVI is a safe, effective day case procedure. PVI using the PolarX Cryoballoon was similarly safe and effective as the AFA Cryoballoon. The cryoablation metrics achieved with the PolarX Cryoballoon were different to that reported with the AFA Cryoballoon. Modified cryoablation targets are required when utilizing the PolarX Cryoballoon