16 research outputs found

    Neurodevelopmental disorders in children aged 2-9 years: Population-based burden estimates across five regions in India.

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    BACKGROUND: Neurodevelopmental disorders (NDDs) compromise the development and attainment of full social and economic potential at individual, family, community, and country levels. Paucity of data on NDDs slows down policy and programmatic action in most developing countries despite perceived high burden. METHODS AND FINDINGS: We assessed 3,964 children (with almost equal number of boys and girls distributed in 2-<6 and 6-9 year age categories) identified from five geographically diverse populations in India using cluster sampling technique (probability proportionate to population size). These were from the North-Central, i.e., Palwal (N = 998; all rural, 16.4% non-Hindu, 25.3% from scheduled caste/tribe [SC-ST] [these are considered underserved communities who are eligible for affirmative action]); North, i.e., Kangra (N = 997; 91.6% rural, 3.7% non-Hindu, 25.3% SC-ST); East, i.e., Dhenkanal (N = 981; 89.8% rural, 1.2% non-Hindu, 38.0% SC-ST); South, i.e., Hyderabad (N = 495; all urban, 25.7% non-Hindu, 27.3% SC-ST) and West, i.e., North Goa (N = 493; 68.0% rural, 11.4% non-Hindu, 18.5% SC-ST). All children were assessed for vision impairment (VI), epilepsy (Epi), neuromotor impairments including cerebral palsy (NMI-CP), hearing impairment (HI), speech and language disorders, autism spectrum disorders (ASDs), and intellectual disability (ID). Furthermore, 6-9-year-old children were also assessed for attention deficit hyperactivity disorder (ADHD) and learning disorders (LDs). We standardized sample characteristics as per Census of India 2011 to arrive at district level and all-sites-pooled estimates. Site-specific prevalence of any of seven NDDs in 2-<6 year olds ranged from 2.9% (95% CI 1.6-5.5) to 18.7% (95% CI 14.7-23.6), and for any of nine NDDs in the 6-9-year-old children, from 6.5% (95% CI 4.6-9.1) to 18.5% (95% CI 15.3-22.3). Two or more NDDs were present in 0.4% (95% CI 0.1-1.7) to 4.3% (95% CI 2.2-8.2) in the younger age category and 0.7% (95% CI 0.2-2.0) to 5.3% (95% CI 3.3-8.2) in the older age category. All-site-pooled estimates for NDDs were 9.2% (95% CI 7.5-11.2) and 13.6% (95% CI 11.3-16.2) in children of 2-<6 and 6-9 year age categories, respectively, without significant difference according to gender, rural/urban residence, or religion; almost one-fifth of these children had more than one NDD. The pooled estimates for prevalence increased by up to three percentage points when these were adjusted for national rates of stunting or low birth weight (LBW). HI, ID, speech and language disorders, Epi, and LDs were the common NDDs across sites. Upon risk modelling, noninstitutional delivery, history of perinatal asphyxia, neonatal illness, postnatal neurological/brain infections, stunting, LBW/prematurity, and older age category (6-9 year) were significantly associated with NDDs. The study sample was underrepresentative of stunting and LBW and had a 15.6% refusal. These factors could be contributing to underestimation of the true NDD burden in our population. CONCLUSIONS: The study identifies NDDs in children aged 2-9 years as a significant public health burden for India. HI was higher than and ASD prevalence comparable to the published global literature. Most risk factors of NDDs were modifiable and amenable to public health interventions

    Theoretische Untersuchung von Liganden und polymeren Linkern zur Erstellung multivalenter Liganden

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    The indirect drug design approach outlined in the first section provides an alternative way to model drugs efficiently in case structural knowledge about the target protein is absent. The procedure employs a specialized energy function to be used with molecular dynamics (MD) simulations of ligand pairs binding to same target, allowing the ligands to exchange the information they have about the target. This yields ligand conformers that are most similar to bound ligand conformers. The proposition in the second section is about successful application of an optimized ether force field for polyethylene glycol (PEG), which is used to connect ligands serving as drugs to form dimeric or even multimeric ligands and thus enhancing drug activity by the multivalent binding effect. The proposed ether force field, specifically optimized for implicit solvent (IS) simulation allows to perform molecular dynamics of ligands connected by PEG that are as realistic as explicit solvent (ES) simulation but at much reduced cost. Structure based drug design involves structural knowledge on the target protein and its binding pocket. However, in absence of that and if the structural information of a set of ligands binding to the same target is available, one can still use indirect drug-design approach proposed in the present study. However, this requires a set of ligands with chemically different architecture binding to the same target protein. There exist several indirect drug design methods. The present approach yields coordinates of the ligand that is the bound ligand conformer in binding pocket (BLC), which can then be taken further ahead where different strategies of drug design can be pursued. The assumption that a set of ligands with chemically different architecture binding to the same target protein carry hidden information of their corresponding true BLCs has been exploited in the indirect drug-design approach. Pairwise flexible structure alignment (FSA) using molecular dynamics simulations with specialized energy function employed for this procedure extract the hidden information derived from the molecular similarity of the ligands that allows the ligands to adopt the same space. The conformations of different ligand pairs obtained from FSA once combined yield consensus ligand conformers (CLCs) that should be similar to BLCs. This proposed procedure has been validated on 44 HIV-1 protease (HIV-P) bound ligands of sufficiently diverse chemical composition, the crystal structures of which are available in PDB. The described four different cluster of HIV-P BLCs based on similarity measures are consistent with the H-bond patterns of the ligands bound to HIV-P in the crystal structures exhibiting four different binding modes. MD simulations of biomolecules with realistic representations of cellular environments remain challenging. Explicitly considering water molecules during molecular modeling studies is the most realistic theoretical approach but is computationally expensive. Implicit solvent (IS) approaches, which include the effect of water in a potential of mean force have a clear advantage over explicit solvent (ES) in efficiency. For the attractive features of the IS methodology one has to pay a price in making certain approximations, which may not be sufficient to provide agreement between ES and IS approaches. In our study, an accurate polyether force field for IS MD simulations was developed that matches local and global conformations of 1,2-dimethoxy-ethane (DME) and polyethylene glycol (PEG), respectively. In the IS model, since solvent molecules are missing, the competition of attractive van der Waals (vdW) interactions between solute- solute and solute-solvent atom pairs is absent. As a consequence the remaining attractive vdW interactions between solute atom pairs yield too compact structures. To regain balance of attractive interactions in the IS model, surface energy terms are turned off and attractive vdW interactions are reduced to 90% or as an alternative even slightly negative surface energies with no change in the vdW attractive interactions are employed. However, to obtain quantitatively the same local and global distributions of PEG conformers as in ES, additional force field adjustments involving torsion potentials and 1-4 and 1-5 atom pair Coulomb interactions are also suggested. The proposed ether force field, specifically optimized for IS simulation conditions is equally valid for monomeric and polymeric ethylene glycol.Der im ersten Absatz beschriebene indirekte Ansatz erlaubt eine effiziente Alternative für das drug design im Falle nicht vorhandener Strukturinformation. Die Methode nutzt eine spezialisierte Energiefunktion für Molekulardynamik (MD) Simulationen von Ligandenpaaren die das selbe Zielprotein binden, die es den Liganden erlaubt ihre Informationen über das Zielprotein auszutauschen. Dies führt zu Ligandenkonformationen die extreme Ähnlichkeit mit denen gebundener Liganden aufweisen. Der Vorschlag im zweiten Absatz beschreibt die erfolgreiche Anwendung optimierter Etherkraftfelder für polyethylenglykol (PEG ). PEG findet im drug design als Linker zwischen Liganden Anwendung, um sie zu Dimeren oder Multimeren zusammenzufassen und dadurch die Wirkung über multivalente Bindungen zu erhöhen. Das vorgestellte Etherkraftfeld, erlaubt MD Simulationen mit implizitem Lösemittel (implicit solvent: IS) für Liganden die über PEG verknüpft sind mit der selben Güte wie mit explizitem Lösemitteln (explicit solvent: ES) aber mit deutlich verringerter benötigter Rechnerleistung. Für strukturbasiertes design von Medikamenten (drugs) benötigt man Strukturinformationen über das Zielprotein und dessen Bindungstasche. Falls diese Informationen nicht verfügbar sind, kann man immer noch eine indirekte Methode des drug designs einsetzen. Dazu benötigt man allerdings ein Ensemble von Liganden unterschiedlicher chemischer Architektur, die alle an dasselbe Zielprotein binden. Es gibt zahlreiche Methoden des indirekten drug design. Neu an dieser Arbeit ist, dass mit der hier verwendeten Methode des drug design explizit die Koordinaten der Liganden konstruiert werden, die dessen Struktur in der Bindungstasche wiedergeben [BLC (bound ligand conformer)]. Diese Strukturinformation ermöglicht es, neue Wege beim dem design von Medikamenten zu beschreiten. Die Arbeit beruht auf der Annahme, dass ein Ensemble von Liganden, deren chemischer Aufbau sich unterscheidet, die aber an dasselbe Protein binden, versteckte Informationen ihres entsprechenden BLC in sich tragen. Die hier eingesetzte Methode des paarweisen flexiblen Strukturalignment (FSA) nutzt Molekulardynamik (MD) Simulationen von Ligandenpaaren mit für diese Aufgaben maßgeschneiderten Energiefunktionen, um die versteckten Strukturähnlichkeiten der Liganden zu extrahieren. Diese Energiefunktionen sind so konstruiert, dass die Liganden beim Strukturalignment das gleiche Volumen einnehmen können. Die Konformationen verschiedener Ligandenpaare, die über FSA erhalten werden ergeben in Kombination eine Konsensuskonformation für die Liganden (consensus ligand conformers: CLCs), die dann Ähnlichkeit mit dem BLC aufweisen. Der vorgeschlagene Ansatz ist anhand von 44 der PDB entnommenen HIV-1 Proteaseliganden (HIV-P) von ausreichend unterschiedlichem chemischem Aufbau überprüft worden. Die auf Grundlage der Strukturähnlichkeiten gefundenen vier unterschiedlichen Cluster von HIV-P BLCs sind konsistent mit den vier in den Kristallstrukturen vorgefundenen Mustern an Wasserstoffbrücken zwischen den gebundenen Formen der Liganden und der HIV-P. MD Simulation von Biomolekülen mit einer realistischen Repräsentation der zellulären Umgebung ist eine Herausforderung für computergestützte theoretische Methoden. Die Verwendung von explizit modelliertem Wasser (explicit solvent: ES) ist der realistischste Ansatz, erfordern aber enorme Rechenzeiten. MD Simulationsverfahren mit implizit modelliertem Wasser (implicit solvent: IS), bei denen den Effekt des Wassers durch ein angepaßtes Kraftfeld ersetzt wird, haben gegenüber ES- Verfahren einen großen Vorteil, da sie deutlich weniger Rechenzeit benötigen. Der Preis den man für diesen Vorteil zahlt, sind aber Abweichungen in den Simulationsdaten, die durch die Näherungen im IS Kraftfeld bedingt sind. Im Rahmen dieser Arbeit wurde ein Polyether-Kraftfeld für IS MD Simulationen entwickelt, das lokale Konformationen von 1,2-dimethoxy-ethane (DME) und globale Konformationen von Polyethylenglykol (PEG) akkurat beschreibt. Im IS Model fehlen die Wassermoleküle. Dies hat zur Folge, dass die anziehenden van der Waals (vdW) Wechselwirkungen der Atompaare in PEG einerseits und der Atompaare zwischen Wassermolekülen und PEG andererseits nicht ausbalanciert ist. Die im IS Model verbleibenden anziehenden vdW Wechselwirkungen zwischen den Atompaaren in PEG führen, verglichen mit einem ES Model, zu kompakteren Strukturen. Um die Balance der anziehenden vdW Kräfte im IS Model wieder herzustellen, werden entweder die Oberflächenenergieterme abgeschaltet und die vdW Wechselwirkungen auf 90% reduziert oder alternativ die Oberflächenenergieterme leicht negativ gesetzt, während die vdW Wechselwirkungen unverändert bleiben. Jedoch werden, um quantitativ die gleichen PEG Konformationen wie im ES-Model zu erreichen, zusätzliche Kraftfeldänderungen für die Torsionspotentiale und die Coulomb Wechselwirkungen der 1-4 und 1-5 Atompaare vorgeschlagen. Das vorgestellte IS Etherkraftfeld für MD Simulationen ist für Monomere wie für Polyether gleichermaßen gültig

    Implicit Solvent Models and Stabilizing Effects of Mutations and Ligands on the Unfolding of the Amyloid β‑Peptide Central Helix

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    We have systematically evaluated the ability of molecular dynamics simulation with implicit solvation models (EEF1.1, SASA, ASPENR, SCPISM, RUSH, ACE2, GBORN, GBSW, GBMV II, FACTS) to characterize the unfolding of the amyloid beta (Aβ) peptide and the stabilizing effects of mutations and ligands. The 13–26 region of Aβ (Aβ<sub>13–26</sub>) unfolds and leads to the formation of amyloid fibrils, the causative agent of Alzheimer’s disease. Stabilization of Aβ<sub>13–26</sub> decreases Aβ polymerization as well as the formation of intermediate structures, which may also be toxic. The unfolding behavior of wild-type Aβ<sub>13–26</sub> with an increase in temperature led us to select GBORN, GBMV II, and SCPISM for further investigation considering their ability to reproduce the stabilizing effect on the Aβ<sub>13–26</sub> helical conformation due to mutations (V18A/F19A/F20A and V18L/F19L/F20L) and ligands (Dec-DETA and Pep1b) designed to stabilize Aβ<sub>13–26</sub>. Structural parameters (RMSD, helicity) of the peptide were used to assess the performance of the implicit solvent models with reference to previous explicit solvent simulations

    Elucidating the Relation between Internal Motions and Dihedral Angles in an RNA Hairpin Using Molecular Dynamics

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    Molecular dynamics simulations were performed to characterize the internal motions of the ribonucleic acid apical stem loop of human hepatitis B virus. The NMR relaxation rates calculated directly from the trajectory are in good agreement with the experiment. Calculated order parameters follow the experimental pattern. Order parameters lower than 0.8 are observed for nucleotides that are weakly hydrogen bonded to their base pair partner, unpaired, or part of the loop. These residues show slow decay of the internal correlation functions of their base and sugar C–H vectors. Concerted motions around backbone dihedral angles influence the amplitude of motion of the sugar and base C–H vectors. The order parameters for base C–H vectors are also affected by the fluctuation of the glycosidic dihedral angle

    Influence of Spacer–Receptor Interactions on the Stability of Bivalent Ligand–Receptor Complexes

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    Experiments show that a ligand–receptor complex formed by binding a bivalent ligand (D) in which the two ligating units are joined covalently by a flexible polymeric spacer (S) can be orders of magnitude more stable than the corresponding complex formed with monomeric ligands. Although molecular models rationalizing this “enhancement effect” have been proffered, they ignore spacer–receptor (S–R) interactions, which can substantially influence the relative stability of complexes. Here, the results of a computational study designed to assess the impact of S–R interactions in the prototypic bivalent complex are presented and compared to results of experiments. The S–R interactions mimicking general features of biological systems are modeled by contoured R surfaces with hills (or depressions) at the binding sites. In the fictitious limit of vanishing S–R interactions, the enhancement is pronounced, as observed in experiments. For strictly repulsive S–R interactions (hard R surface), the enhancement vanishes, or even reverses. This is particularly the case if the R surface is convex (i.e., rising between the binding sites), while the enhancement is only moderately reduced if the R surface is concave. Alternatively, a weak S–R attraction close to the R surface can increase the enhancement. It is concluded that large enhancement should be observed only if both features are present: a concave R surface plus a weak S–R attraction. The latter occurs for spacer material such as polyethylene glycol (PEG), which is weakly hydrophobic and thus attracted by protein surfaces. It is shown that the enhancement of bivalent binding can be characterized by a single key parameter, which may also provide guidelines for the design of multivalent complexes with large enhancement effect

    Neurodevelopmental disorders in children aged 2–9 years: Population-based burden estimates across five regions in India

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