16 research outputs found
Neurodevelopmental disorders in children aged 2-9 years: Population-based burden estimates across five regions in India.
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
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 fĂĽr das drug design im Falle nicht vorhandener
Strukturinformation. Die Methode nutzt eine spezialisierte Energiefunktion fĂĽr
Molekulardynamik (MD) Simulationen von Ligandenpaaren die das selbe
Zielprotein binden, die es den Liganden erlaubt ihre Informationen ĂĽber das
Zielprotein auszutauschen. Dies fĂĽhrt zu Ligandenkonformationen die extreme
Ă„hnlichkeit mit denen gebundener Liganden aufweisen. Der Vorschlag im zweiten
Absatz beschreibt die erfolgreiche Anwendung optimierter Etherkraftfelder fĂĽr
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) fĂĽr Liganden die ĂĽber PEG verknĂĽpft sind mit der selben GĂĽte 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 verfĂĽgbar 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 fĂĽr diese Aufgaben maĂźgeschneiderten
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 ĂĽber FSA erhalten werden
ergeben in Kombination eine Konsensuskonformation fĂĽr die Liganden (consensus
ligand conformers: CLCs), die dann Ă„hnlichkeit 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 WasserstoffbrĂĽcken zwischen den
gebundenen Formen der Liganden und der HIV-P. MD Simulation von BiomolekĂĽlen
mit einer realistischen Repräsentation der zellulären Umgebung ist eine
Herausforderung fĂĽr computergestĂĽtzte 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 angepaĂźtes Kraftfeld ersetzt wird, haben gegenĂĽber ES-
Verfahren einen großen Vorteil, da sie deutlich weniger Rechenzeit benötigen.
Der Preis den man fĂĽr 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 fĂĽr 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 WassermolekĂĽle. Dies hat zur Folge, dass die anziehenden van
der Waals (vdW) Wechselwirkungen der Atompaare in PEG einerseits und der
Atompaare zwischen WassermolekĂĽlen und PEG andererseits nicht ausbalanciert
ist. Die im IS Model verbleibenden anziehenden vdW Wechselwirkungen zwischen
den Atompaaren in PEG fĂĽhren, 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 fĂĽr MD Simulationen ist fĂĽr Monomere wie fĂĽr Polyether
gleichermaĂźen gĂĽltig
Implicit Solvent Models and Stabilizing Effects of Mutations and Ligands on the Unfolding of the Amyloid β‑Peptide Central Helix
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
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
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