The molecular basis for kinesin functional specificity during mitosis

Microtubule-based motor proteins play key roles dur-ing mitosis to assemble the bipolar spindle, define the cell division axis, and align and segregate the chromo-somes. The majority of mitotic motors are members of the kinesin superfamily. Despite sharing a conserved catalytic core, each kinesin has distinct functions and localization, and is uniquely regulated in time and space. These distinct behaviors and functional specific-ity are generated by variations in the enzymatic domain as well as the non-conserved regions outside of the kinesin motor domain and the stalk. These flanking regions can directly modulate the properties of the kinesin motor through dimerization or self-interactions, and can associate with extrinsic factors, such as microtubule or DNA binding proteins, to pro-vide additional functional properties. This review dis-cusses the recently identified molecular mechanisms that explain how the control and functional specifica-tion of mitotic kinesins is achieved. VC 2013 Wiley Periodicals, Inc. Key Words: mitosis; kinesin; microtubules; motors; regulatio

Network Modeling Sex Differences in Brain Integrity and Metabolic Health

Hypothesis-driven studies have demonstrated that sex moderates many of the relationships between brain health and cardiometabolic disease, which impacts risk for later-life cognitive decline. In the present study, we sought to further our understanding of the associations between multiple markers of brain integrity and cardiovascular risk in a midlife sample of 266 individuals by using network analysis, a technique specifically designed to examine complex associations among multiple systems at once. Separate network models were constructed for male and female participants to investigate sex differences in the biomarkers of interest, selected based on evidence linking them with risk for late-life cognitive decline: all components of metabolic syndrome (obesity, hypertension, dyslipidemia, and hyperglycemia); neuroimaging-derived brain-predicted age minus chronological age; ratio of white matter hyperintensities to whole brain volume; seed-based resting state functional connectivity in the Default Mode Network, and ratios of N-acetyl aspartate, glutamate and myo-inositol to creatine, measured through proton magnetic resonance spectroscopy. Males had a sparse network (87.2% edges = 0) relative to females (69.2% edges = 0), indicating fewer relationships between measures of cardiometabolic risk and brain integrity. The edges in the female network provide meaningful information about potential mechanisms between brain integrity and cardiometabolic health. Additionally, Apolipoprotein ϵ4 (ApoE ϵ4) status and waist circumference emerged as central nodes in the female model. Our study demonstrates that network analysis is a promising technique for examining relationships between risk factors for cognitive decline in a midlife population and that investigating sex differences may help optimize risk prediction and tailor individualized treatments in the future

Role of spin in the calculation of Hubbard U and Hund's J parameters from first principles

The density functional theory (DFT)+$U$ method is a pragmatic and effective approach for calculating the ground-state properties of strongly-correlated systems, and linear response calculations are widely used to determine the requisite Hubbard parameters from first principles. We provide a detailed treatment of spin within this linear response approach, demonstrating that the conventional Hubbard $U$ formula, unlike the conventional DFT+$U$ corrective functional, incorporates interactions that are off-diagonal in the spin indices and places greater weight on one spin channel over the other. We construct alternative definitions for Hubbard and Hund's parameters that are consistent with the contemporary DFT+$U$ functional, expanding upon the minimum-tracking linear response method. This approach allows Hund's $J$ and spin-dependent $U$ parameters to be calculated with the same ease as for the standard Hubbard $U$. Our methods accurately reproduce the experimental band gap, local magnetic moments, and the valence band edge character of manganese oxide, a canonical strongly-correlated system. We also apply our approach to a complete series of transition-metal complexes [M(H$_2$O)$_6$]$^{n+}$ (for M = Ti to Zn), showing that Hubbard corrections on oxygen atoms are necessary for preserving bond lengths, and demonstrating that our methods are numerically well-behaved even for near-filled subspaces such as in zinc. However, spectroscopic properties appear beyond the reach of the standard DFT+$U$ approach. Collectively, these results shed new light on the role of spin in the calculation of the corrective parameters $U$ and $J$, and point the way towards avenues for further development of DFT+$U$-type methods

Belga B-trees

We revisit self-adjusting external memory tree data structures, which combine the optimal (and practical) worst-case I/O performances of B-trees, while adapting to the online distribution of queries. Our approach is analogous to undergoing efforts in the BST model, where Tango Trees (Demaine et al. 2007) were shown to be $O(\log\log N)$-competitive with the runtime of the best offline binary search tree on every sequence of searches. Here we formalize the B-Tree model as a natural generalization of the BST model. We prove lower bounds for the B-Tree model, and introduce a B-Tree model data structure, the Belga B-tree, that executes any sequence of searches within a $O(\log \log N)$ factor of the best offline B-tree model algorithm, provided $B=\log^{O(1)}N$. We also show how to transform any static BST into a static B-tree which is faster by a $\Theta(\log B)$ factor; the transformation is randomized and we show that randomization is necessary to obtain any significant speedup

PainDroid: An android-based virtual reality application for pain assessment

Earlier studies in the field of pain research suggest that little efficient intervention currently exists in response to the exponential increase in the prevalence of pain. In this paper, we present an Android application (PainDroid) with multimodal functionality that could be enhanced with Virtual Reality (VR) technology, which has been designed for the purpose of improving the assessment of this notoriously difficult medical concern. Pain- Droid has been evaluated for its usability and acceptability with a pilot group of potential users and clinicians, with initial results suggesting that it can be an effective and usable tool for improving the assessment of pain. Participant experiences indicated that the application was easy to use and the potential of the application was similarly appreciated by the clinicians involved in the evaluation. Our findings may be of considerable interest to healthcare providers, policy makers, and other parties that might be actively involved in the area of pain and VR research

Grifonin-1: A Small HIV-1 Entry Inhibitor Derived from the Algal Lectin, Griffithsin

Background: Griffithsin, a 121-residue protein isolated from a red algal Griffithsia sp., binds high mannose N-linked glycans of virus surface glycoproteins with extremely high affinity, a property that allows it to prevent the entry of primary isolates and laboratory strains of T- and M-tropic HIV-1. We used the sequence of a portion of griffithsin's sequence as a design template to create smaller peptides with antiviral and carbohydrate-binding properties. Methodology/Results: The new peptides derived from a trio of homologous β-sheet repeats that comprise the motifs responsible for its biological activity. Our most active antiviral peptide, grifonin-1 (GRFN-1), had an EC50 of 190.8±11.0 nM in in vitro TZM-bl assays and an EC50 of 546.6±66.1 nM in p24gag antigen release assays. GRFN-1 showed considerable structural plasticity, assuming different conformations in solvents that differed in polarity and hydrophobicity. Higher concentrations of GRFN-1 formed oligomers, based on intermolecular β-sheet interactions. Like its parent protein, GRFN-1 bound viral glycoproteins gp41 and gp120 via the N-linked glycans on their surface. Conclusion: Its substantial antiviral activity and low toxicity in vitro suggest that GRFN-1 and/or its derivatives may have therapeutic potential as topical and/or systemic agents directed against HIV-1

Targeting the rheumatoid arthritis synovial fibroblast via cyclin dependent kinase inhibition: An early phase trial

Introduction: Targeted biologic therapies demonstrate similar efficacies in rheumatoid arthritis despite distinct mechanisms of action. They also exhibit a ceiling effect, with 10% to 20% of patients achieving remission in clinical trials. None of these therapies target synovial fibroblasts, which drive and maintain synovitis. Seliciclib (R-roscovitine) is an orally available cyclin-dependent kinase inhibitor that suppresses fibroblast proliferation, and is efficacious in preclinical arthritis models. We aim to determine the toxicity and preliminary efficacy of seliciclib in combination with biologic therapies, to inform its potential as an adjunctive therapy in rheumatoid arthritis. Methods and analysis: TRAFIC is a non-commercial, multi-center, rolling phase Ib/IIa trial investigating the safety, tolerability, and efficacy of seliciclib in patients with moderate to severe rheumatoid arthritis receiving biologic therapies. All participants receive seliciclib with no control arm. The primary objective of part 1 (phase Ib) is to determine the maximum tolerated dose and safety of seliciclib over 4 weeks of dosing. Part 1 uses a restricted 1-stage Bayesian continual reassessment method based on a target dose-limiting toxicity probability of 35%. Part 2 (phase IIa) assesses the potential efficacy of seliciclib, and is designed as a single arm, single stage early phase trial based on a Fleming-A’Hern design using the maximum tolerated dose recommended from part 1. The primary response outcome after 12 weeks of therapy is a composite of clinical, histological and magnetic resonance imaging scores. Secondary outcomes include adverse events, pharmacodynamic and pharmacokinetic parameters, autoantibodies, and fatigue. Ethics and dissemination: The study has been reviewed and approved by the North East - Tyne & Wear South Research Ethics Committee (reference 14/NE/1075) and the Medicines and Healthcare Products Regulatory Agency (MHRA), United Kingdom. Results will be disseminated through publication in relevant peer-reviewed journals and presentation at national and international conferences. Trials Registration: ISRCTN, ISRCTN36667085. Registered on September 26, 2014; http://www.isrctn.com/ISRCTN36667085 Current protocol version: Protocol version 11.0 (March 21, 2019

As ocupações neolíticas em lapiás: o caso de Negrais (Sintra)

Novas perspectivas de leitura em torno do Complexo de Negrais (Sintra, Portugal) onde se verificou a associação de vários sítios a uma paisagem muito peculiar proporcionada pelos campos de lapiás. Estas fortificações rochosas calcárias criam um ambiente fechado com abrigos e caminhos labirínticos que foram ocupados desde inícios do Neolítico até finais do Calcolítico. Apesar de apenas contarmos com dados descontextualizados a longevidade da ocupação nos lapiás de Negrais funciona como indicador dos vários momentos cronológico-culturais do Neolítico e Calcolítico da Estremadura Meridional.New perspectives upon the arcaheological sites of Negrais (Sintra, Portugal) where several sites are associated in a peculiar surrounding the fields of "lapiás". These limestone rock formations create a closed environment with shelters, labyrinth paths that had been chosen by peasants since the early Neolithic till the late Chalcolithic. A specific study was made about two of the most significant sites: Barruncheiros and Pedraceiras.info:eu-repo/semantics/publishedVersio

Body composition and body fat distribution are related to cardiac autonomic control in non-alcoholic fatty liver disease patients

BACKGROUND/OBJECTIVES: Heart rate recovery (HRR), a cardiac autonomic control marker, was shown to be related to body composition (BC), yet this was not tested in non-alcoholic fatty liver disease (NAFLD) patients. The aim of this study was to determine if, and to what extent, markers of BC and body fat (BF) distribution are related to cardiac autonomic control in NAFLD patients. SUBJECTS/METHODS: BC was assessed with dual-energy X-ray absorptiometry in 28 NAFLD patients (19 men, 51±13 years, and 9 women, 47±13 years). BF depots ratios were calculated to assess BF distribution. Subjects’ HRR was recorded 1 (HRR1) and 2 min (HRR2) immediately after a maximum graded exercise test. RESULTS: BC and BF distribution were related to HRR; particularly weight, trunk BF and trunk BF-to-appendicular BF ratio showed a negative relation with HRR1 (r 1⁄4 0.613, r 1⁄4 0.597 and r 1⁄4 0.547, respectively, Po0.01) and HRR2 (r 1⁄4 0.484, r 1⁄4 0.446, Po0.05, and r 1⁄4 0.590, Po0.01, respectively). Age seems to be related to both HRR1 and HRR2 except when controlled for BF distribution. The preferred model in multiple regression should include trunk BF-to-appendicular BF ratio and BF to predict HRR1 (r2 1⁄4 0.549; Po0.05), and trunk BF-to-appendicular BF ratio alone to predict HRR2 (r2 1⁄4 0.430; Po0.001). CONCLUSIONS: BC and BF distribution were related to HRR in NAFLD patients. Trunk BF-to-appendicular BF ratio was the best independent predictor of HRR and therefore may be best related to cardiovascular increased risk, and possibly act as a mediator in age-related cardiac autonomic control variation.info:eu-repo/semantics/publishedVersio

Defining and Detecting Crossover-Interference Mutants in Yeast

The analysis of crossover interference in many creatures is complicated by the presence of two kinds of crossovers, interfering and noninterfering. In such creatures, the values of the traditional indicators of interference are subject not only to the strength of interference but also to the relative frequencies of crossing over contributed by the two kinds. We formalize the relationship among these variables and illustrate the possibilities and limitations of classical interference analysis with meiotic tetrad data from wild-type Saccharomyces cerevisiae and from mlh1 and ndj1 mutants