Effective connectivity among the working memory regions during preparation for and during performance of the n-back task

Recent neuroimaging studies have shown that working memory (WM) task difficulty can be decoded from patterns of brain activation in the WM network during preparation to perform those tasks. The inter-regional connectivity among the WM regions during task preparation has not yet been investigated. We examined this question using the graph modeling methods IMaGES and LOFS, applied to the previously published fMRI data of Manelis and Reder (2013). In that study, subjects performed 1-, 2-, and 3-back tasks. Each block of n-back was preceded by a preparation period and followed by a rest period. The analyses of task-related brain activity identified a network of 18 regions that increased in activation from 1to 3-back (Increase network) and a network of 17 regions that decreased in activation from 1to 3-back (Decrease network). The graph analyses revealed two types of connectivity sub-networks within the Increase and Decrease networks: "default" and "preparation-related." The "default" connectivity was present not only during task performance, but also during task preparation and during rest. We propose that this sub-network may serve as a core system that allows one to quickly activate cognitive, perceptual and motor systems in response to the relevant stimuli. The "preparation-related" connectivity was present during task preparation and task performance, but not at rest, and depended on the n-back condition. The role of this sub-network may be to pre-activate a connectivity "road map" in order to establish a top-down and bottom-up regulation of attention prior to performance on WM tasks. © 2014 Manelis and Reder

A History of the Florida Supreme Court

To a certain extent, the development of Florida\u27s modern judicial processes and institutions can be understood by looking closely at the history of the individuals who have served on the state\u27s foremost judicial body, the Florida Supreme Court. Unfortunately, many of the historical insights and anecdotes concerning the justices have been lost or are scattered over many different sources. This article pulls together many of these scattered materials and presents an insider\u27s look into the lives and aspirations of the men who have served and shaped Florida\u27s Supreme Court

Конформація пропоксазепаму та його орієнтація у центрі зв’язування ГАМКА-рецептора

Introduction. One of 1.4-benzodiazepine 3-alcoxy derivatives – propoxazepam, possessing high analgetic action, also effectively suppressed different experimental seizures types. Unexpected combination of pharmacological spectrum components suggests its different binding sites of GABAA receptor.The aim of the work was to determine the geometry of the ligand-receptor complexes of GABA-RC using experimental data of the propoxazepam conformation and calculated data for the three-dimensional structure of the ligandbinding site and subsequent docking to characterize its binding to this receptor.Materials and methods. X-ray diffraction studies of the compound were performed using Xcalibur 3 single crystal X-ray diffractometer. Calculation of the molecular docking parameters was performed using the iGEMDOCK v2.1 program for the GABA receptor (GABA (A) R-beta3 homopentamer, 4COF), the molecular structures of propoxazepam conformers were prepared using ChemAxon (MarvinSketch 17.11.0).Results and discussion. Based on the X-ray diffraction analysis, the coordinates of the atoms, bond lengths and valence angles in the propoxazepam molecule were calculated, it is found that it form crystallographic twins as racemate. The molecular docking method showed that propoxazepam several binding sites with the energy of complex formation from -78.64 to -85.29 kcal/mol exist on the isolated site of the GABA-receptor.Conclusions. The highest contribution to the formation of the bond of the complex is carried out by residues of polar amino acids (serine, asparagine, methionine and arginine in polar binding sub-center). However, also for individual conformers, aromatic amino acids, predominantly phenylalanine (Phe-31, Ala-135 – hydrophobic binding sub-center) make a significant contribution.Актуальность. Одно из 3-алкоксипроизводных 1,4-бенздиазепина – пропоксазепам – продемонстрировал высокую анальгетическую активность, а также эффективно блокировал разные типы экспериментальных судорог. Нестандартная комбинация компонентов фармакологического спектра предусматривает разные места его связывания на ГАМКА-рецепторе.Цель исследования состояла в определении геометрии лигандрецепторных комплексов ГАМК-РК на основе использования экспериментальных данных о конформации пропоксазепама и расчетных данных о трехмерном строении лигандсвязывающего центра и последующее проведение докинга для характеристики его связывания с данным рецептором.Материалы и методы. Рентгеноструктурное исследование соединения выполнено на монокристальном рентгеновском дифрактометре Xcalibur 3, Расчет параметров молекулярного докинга был осуществлен с использованием программы iGEMDOCK v2.1, для ГАМК-рецептора (GABA(A) R-beta3 гомопентамер, 4COF), молекулярные структуры конформеров пропоксазепама были подготовлены в программе ChemAxon (MarvinSketch 17.11.0).                                                                                              Результаты и их обсуждение. На основании данных рентгеноструктурного анализа рассчитаны координаты атомов, длины связей и валентные углы в молекуле пропоксазепама, установлено, что он существует в виде кристаллографического двойника в виде рацемата.                                      Выводы. Методом молекулярного докинга показано, что на выделенном участке ГАМКА-рецептора существует несколько мест связывания пропоксазепама с энергией образования комплекса от -78,64 до -85,29 ккал/моль. Наибольший вклад в формирование связи комплекса осуществляют остатки полярных аминокислот (серин, аспарагин, метионин и аргинин – полярный подцентр связывания). Однако также для отдельных конформеров значительный вклад имеют ароматические аминокислоты, преимущественно фенилаланин (Phe-31, Ala-135 – гидрофобный подцентр связывания).Актуальність. Одне з 3-алкоксипохідних 1,4-бенздіазепіну – пропоксазепам, який продемонстрував високу аналгетичну активність, а також ефективно блокував різні типи експериментальних судом. Нестандартна комбінація компонентів фармакологічного спектра передбачає різні місця його зв’язування на ГАМКА-рецепторі.Мета дослідження полягала у визначенні геометрії ліганд-рецепторних комплексів ГАМК-РК на підставі використання експериментальних даних про конформацію пропоксазепаму та розрахункових даних тривимірної будови лігандзв’язуючого центра та подальше проведення докінгу для характеристики його зв’язування з даним рецептором.Матеріали та методи. Рентгеноструктурне дослідження сполуки було виконано на монокристальному рентгенівському дифрактометрі Xcalibur 3, розрахунок параметрів молекулярного докінгу буз здійснений у програмі GEMDOCK v2.1, для ГАМК-рецептора (GABA(A) R-beta3 пентамер); молекулярні структури конформерів пропоксазепаму були підготовлені у програмі ChemAxon (MarvinSketch 17.11.0).Результати та їх обговорення. На підставі даних рентгеноструктурного аналізу розраховані координати атомів, довжини зв’язків та валентні кути у молекулі пропоксазепаму, встановлено, що він існує у вигляді кристалографічного двійника як рацемат.Висновки. Методом молекулярного докінгу показано, що на виділеній частині ГАМКА-рецептора існує декілька місць зв’язування пропоксазепаму з енергією утворення комплексів від -78,64 до -85,29 ккал/моль. Найбільший внесок у формування зв’язку комплексу здійснюють залишки полярних амінокислот (серин, аспарагін, метіонін та аргінін – полярний підцентр зв’язування). Однак також для окремих конформерів значний внесок мають ароматичні амінокислоти, переважно фенілаланін (Phe-31, Ala-135 – гідрофобний підцентр зв’язування)

The TeleTAnDem intervention - Study protocol for a psychotherapeutic intervention for family caregivers of people with dementia

Soellner R, Reder M, Machmer A, Holle R, Wilz G. The TeleTAnDem intervention - Study protocol for a psychotherapeutic intervention for family caregivers of people with dementia. BMC Nursing. 2015;14(11): 11

Assessing variations of extreme indices inducing weather-hazards on critical infrastructures over Europe?the INTACT framework

Extreme weather events are projected to be more frequent and severe across the globe because of global warming. This poses challenging problems for critical infrastructures, which could be dramatically affected (or disrupted), and may require adaptation plans to the changing climate conditions. The INTACT FP7-European project evaluated the resilience and vulnerability of critical infrastructures to extreme weather events in a climate change scenario. To identify changes in the hazard induced by climate change, appropriate extreme weather indicators (EWIs), as proxies of the main atmospheric features triggering events with high impact on the infrastructures, were defined for a number of case studies and different approaches were analyzed to obtain local climate projections. We considered the influence of weighting and bias correction schemes on the delta approach followed to obtain the resulting projections, considering data from the Euro-CORDEX ensemble of regional future climate scenarios over Europe. The aim is to provide practitioners, decision-makers, and administrators with appropriate methods to obtain actionable and plausible results on local/regional future climate scenarios. Our results show a small sensitivity to the weighting approach and a large sensitivity to bias correcting the future projections.This work has been carried out within the activities of INTACT project, receiving funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° FP7-SEC-2013-1-606799. The information and views set out in this paper are those of the authors and do not necessarily reflect the opinion of the European Union. We acknowledge the World Climate Research Programme's Working Group on Regional Climate, and the Working Group on Coupled Modelling, former coordinating body of CORDEX and responsible panel for CMIP5

Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial

BACKGROUND: Evidence for efficacy of disease-modifying drugs in multiple sclerosis (MS) comes from trials of short duration. We report results from a 16 y, retrospective follow-up of the pivotal interferon beta-1b (IFNB-1b) study. METHODS: The 372 trial patients were randomly assigned to placebo (n=123), IFNB-1b 50 microg (n=125) or IFNB-1b 250 microg (n=124) subcutaneously every other day for at least 2 y. Some remained randomised for up to 5 y but, subsequently, patients received treatment according to physicians' discretion. Patients were re-contacted and asked to participate. Efficacy related measures included MRI parameters, relapse rate, the Expanded Disability Status Scale, the Multiple Sclerosis Functional Composite Measure and conversion to secondary progressive MS. RESULTS: Of the 88.2% (328/372) of patients who were identified, 69.9% (260/372) had available case report forms. No differences in outcome between original randomisation groups could be discerned using standard disability and MRI measures. However, mortality rates among patients originally treated with IFNB-1b were lower than in the original placebo group (18.3% (20/109) for placebo versus 8.3% (9/108) for IFNB-1b 50 microg and 5.4% (6/111) for IFNB-1b 250 microg). CONCLUSIONS: The original treatment assignment could not be shown to influence standard assessments of long-term efficacy. On-study behaviour of patients was influenced by factors that could not be controlled with the sacrifice of randomisation and blinding. Mortality was higher in patients originally assigned to placebo than those who had received IFNB-1b 50 microg or 250 microg. The dataset provides important resources to explore early predictors of long-term outcome