1,060 research outputs found
Development of gene therapy for the treatment of retinal dystrophies caused by mutations in AIPL1
Genetic defects in AIPL1 cause a heterogeneous set of clinical conditions
depending on the severity of the mutant alleles. Diseases can range from
Leber Congenital Amaurosis (LCA), the severest form of early-onset retinal
degeneration, to milder forms such as retinitis pigmentosa (RP) and cone-rod
dystrophy. There is currently no effective treatment for LCA and inherited
retinal dystrophies, which are the commonest cause of childhood blindness.
AIPL1 is expressed primarily in retinal photoreceptors and is required for the
biosynthesis of photoreceptor phosphodiesterase (PDE).
This thesis describes a programme of work that examines the potential and
efficacy of gene replacement therapy in the treatment of AIPL1- associated
retinal diseases. It centres on the use of recombinant adeno-associated virus
for the transfer of murine and human AIPL1 cDNA into photoreceptor cells.
AAV-mediated gene replacement was assessed in two genetically
engineered mouse models carrying null and hypomorphic alleles, Aipl1 -/-
and Aipl1 h/h mice, which simulate retinal degenerations similar to human
LCA and RP respectively. Three different rates of photoreceptor
degeneration were simulated using the mouse models. To treat the different
rates of degeneration, two pseudotypes of AAV (serotype 2 and 8) exhibiting
different transduction kinetics were used for gene transfer. Substantial and
long term rescue of the disease phenotype was seen as a result of Aipl1
transgene expression mediated by AAV2/2 vector in Aipl1 h/h mice and by
AAV2/8 in rapid degenerations in light accelerated Aipl1 h/h mice and in
Aipl1 -/- mice. Thus, the results presented in this thesis validates the efficacy
of AIPL1 gene replacement using AAV vectors in varying rates of
degeneration that reflected the clinical spectrum of disease. This is the first
study to report long-term rescue of a photoreceptor-specific defect and to
demonstrate effective rescue of rapid photoreceptor degeneration.
The development of an efficient therapy depends on the identification of
patients and characterisation of disease phenotype. A panel of DNA samples
from patients with LCA and early onset severe retinal dystrophy was screened for mutations in the AIPL1 gene. Patients identified with AIPL1-
associated disease demonstrated varying severity of disease from LCA to
milder form of rod cone dystrophy. Clinical characterisation and imaging of
the patients highlighted distinctive features which will direct future
identification and molecular screening of patients. Residual retinal integrity
and function in young patients and patients with milder phenotype suggests
that AIPL1 defects may be amenable to treatment
Characterization of Pneumatic Artificial Muscle System in an Opposing Pair Configuration
Pneumatic artificial muscle (PAM) is a pneumatic actuator that commonly used in the biomimetic robotic devices in rehabilitation applications due to its advantageous in high powerto-weight ratio and high degree of safety in use characteristics. Several techniques exist in the literature for the PAM system modeling, and these include theoretical modeling, phenomenological modeling and empirical modeling. This paper focuses on explaining the experimental setup of an opposing pair configuration of PAM system, and gives an analysis of the pneumatic muscle system dynamic in the theoretical modeling. The simulated dynamic model is compared with the actual PAM system for the validation in the open-loop step and sinusoidal positioning responses and pressures. It is concluded that the simulation result is verified and agreed with the actual system
Rank one preservers between spaces of boolean matrices
In this paper. we characterize (i) linear transformations from one space of Boolean matrices to another that send pairs of distinct rank one elements to pairs of distinct rank one elements and (ii) subjective mappings from one space of Boolean matrices to another that send rank one matrices to rank one matrices and preserve order relation in both directions. Both results are proved in a more general setting of tensor products of two Boolean vector spaces of arbitrary dimension
Tracking Control of Vertical Pneumatic Artificial Muscle System Using PID
The advantages of pneumatic system such as compactness, high power to weight ratio, ease of maintenance, cleanliness and inherent safety led to the development of McKibben muscle and pneumatic artificial muscle (PAM). However, the air compressibility and the lack of damping ability of PAM bring dynamic delay to the pressure response and causes oscillatory motion to occur. It is not easy to realize the motion with high accuracy and high speed due to all the non-linear characteristics of pneumatic system. In this paper, we present a vertical PAM system with a simple PID controller to control the motion of the PAM. The experiment setup is explained and Ziegler Nichols tuning method is used in getting the approximation PID parameters. The effectiveness of the proposed control algorithm is demonstrated through experiments
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Effects of perceived social isolation, fear of social isolation and gratitude during COVID-19 pandemic on anxiety in Malaysia
YesMany governments including Malaysia imposed movement restrictions as public health measure to minimize COVID-19 (coronavirus) risks. Due to prolonged isolation, poorer physical and mental health is expected in the general population. Our aims were to examine (1) the mediating role of perceived social isolation (SI) and fear of social isolation (FSI) on the relationship between gratitude and anxiety, and (2) to explore the moderating role of age, education and socioeconomic status (SES) on the mediation model. A total of 427 participants currently living in Malaysia (Mage = 37.90, SD = 16.51, 313 females) completed a survey on isolation, gratitude and anxiety during a period of national lockdown. Results showed that that those with higher gratitude reported having less SI and FSI and less anxiety (Model 1). In Model 2 with age as moderator, young adults (YA) and middle-aged adults (MA) who had higher gratitude experienced lower SI and in turn had lowered anxiety, but such mediating role of SI was not observed among older adults (OA). As for FSI, MA who had higher gratitude had lower FSI and also lower anxiety but this relationship was not observed in YA or OA. We also examined the role of education and SES as moderators in the parallel mediation analysis. Results showed that the indirect association of gratitude with anxiety via FI and FSI was moderated by both education and SES. Specifically, among those with low education levels (regardless of SES), those with higher gratitude had lower SI and FSI which in turn reduced anxiety. This relationship is similar for those with medium level of education and from low and middle level of SES as well. Our findings highlight the importance of having some coping mechanism e.g., gratitude and social connection during the pandemic to have higher wellbeing and quality of life, especially for MA sample and people from low education and SES background.This work was supported by Newton Fund Institutional Links grant ID: 331745333, under Newton-Ungku Omar Fund partnership to MHY. The grant is funded by the UK Department for Business, Energy and Industrial Strategy and Malaysian Industry-Government Group for High Technology (MIGHT) and delivered by the British Council. For further information, please visit www.newtonfund.ac.uk . The Newton Fund played no role in the planning and conceptualization of the manuscript, did not participate in the writing of the manuscript, and played no role in the decision to submit the manuscript
Health-related quality of life in pediatric patients with leukemia in Singapore: a cross-sectional pilot study
There has been a paradigm shift in health service delivery to a more holistic approach, which
considers Quality of Life (QoL) and overall functioning. Health-Related Quality of Life (HRQoL)
is a multidimensional construct that encompasses physical functioning as well as psychosocial
aspects of emotional and social functioning. This study explored factors related to HRQoL in Asian
pediatric patients with leukemia in Singapore. The available variables included: age, treatment
duration, household income, gender, ethnicity, religion, diagnosis, and phase of treatment. It is
hypothesized that the relationships will be significant. In the current study, there were 60 patients
(60% males) with leukemia; their ages ranged from 1 to 21 years (Mean = 8.03, Standard Deviation
= 4.55). The hypothesis was partially supported. Age had a significant positive relationship with
physical functioning, r(60) = 0.28, p < 0.05, physical health, r(60) = 0.28, p < 0.05, and the total HRQoL
score, r(60) = 0.29, p < 0.05. Treatment duration had a positive relationship with school functioning,
r(60) = 0.28, p < 0.05. All other correlations were statistically non-significant. The effects of the
available psychosocial variables of gender, ethnicity, and religion were examined on scores from the
Pediatric Quality of Life Inventory (PedsQL). Ethnicity had a significant effect on social functioning,
U = 292.00, p < 0.05, r = 0.3 (medium effect size). Specifically, Chinese (Median = 85.00, n = 33) had
significantly higher scores on social functioning than others (Median = 70.00, n = 27). The remaining
comparisons were statistically non-significant. The current findings added to QoL research, and
provided an impetus for more research in the area of HRQoL for children with leukemia in Singapore
Electronic and thermal sequential transport in metallic and superconducting two-junction arrays
The description of transport phenomena in devices consisting of arrays of
tunnel junctions, and the experimental confirmation of these predictions is one
of the great successes of mesoscopic physics. The aim of this paper is to give
a self-consistent review of sequential transport processes in such devices,
based on the so-called "orthodox" model. We calculate numerically the
current-voltage (I-V) curves, the conductance versus bias voltage (G-V) curves,
and the associated thermal transport in symmetric and asymmetric two-junction
arrays such as Coulomb-blockade thermometers (CBTs),
superconducting-insulator-normal-insulator-superconducting (SINIS) structures,
and superconducting single-electron transistors (SETs). We investigate the
behavior of these systems at the singularity-matching bias points, the
dependence of microrefrigeration effects on the charging energy of the island,
and the effect of a finite superconducting gap on Coulomb-blockade thermometry.Comment: 23 pages, 12 figures; Berlin (ISBN: 978-3-642-12069-5
Analysis of acoustic emission during the melting of embedded indium particles in an aluminum matrix: a study of plastic strain accommodation during phase transformation
Acoustic emission is used here to study melting and solidification of
embedded indium particles in the size range of 0.2 to 3 um in diameter and to
show that dislocation generation occurs in the aluminum matrix to accommodate a
2.5% volume change. The volume averaged acoustic energy produced by indium
particle melting is similar to that reported for bainite formation upon
continuous cooling. A mechanism of prismatic loop generation is proposed to
accommodate the volume change and an upper limit to the geometrically necessary
increase in dislocation density is calculated as 4.1 x 10^9 cm^-2 for the
Al-17In alloy. Thermomechanical processing is also used to change the size and
distribution of the indium particles within the aluminum matrix. Dislocation
generation with accompanied acoustic emission occurs when the melting indium
particles are associated with grain boundaries or upon solidification where the
solid-liquid interfaces act as free surfaces to facilitate dislocation
generation. Acoustic emission is not observed for indium particles that require
super heating and exhibit elevated melting temperatures. The acoustic emission
work corroborates previously proposed relaxation mechanisms from prior internal
friction studies and that the superheat observed for melting of these
micron-sized particles is a result of matrix constraint.Comment: Presented at "Atomistic Effects in Migrating Interphase Interfaces -
Recent Progress and Future Study" TMS 201
ND5 gene marker reveals recent population expansion of wild Pearse’s mudskipper (Periophthalmus novemradiatus Hamilton) inhabits Setiu Wetlands in East Peninsular Malaysia
Genetic variation and differences in wild Pearse’s mudskipper Periophthalmus novemradiatus populations from Setiu Wetlands
in East Peninsular Malaysia were analysed using the partial mitochondrial DNA ND5 gene sequences. Among the 91 individuals
sampled from six different localities, 35 novel putative haplotypes of P. novemradiatus were detected. 77% (27) of the
haplotypes were unique sequences, with high level of haplotype diversity (H = 0.875) and low nucleotide diversity (π =
0.0037), contributing to the overall highly diversified gene pool of the P. novemradiatus. This reflects a large effective
population size with current population expansion, which allows the retention of new alleles in populations. However, due to
insufficient time, the accumulation of deeper divergent groups among haplotypes was not possible. Hap05 is the most dominant
(33%) and widespread haplotype, followed by Hap11 and 31. Low genetic differentiation with high gene flow was detected
between sampling sites, and no pattern for isolation by distance was observed despite being territorial creatures. All sites are
at the top priority for conservation because they possess unique haplotypes that are only present at the respective location.
Further samples collection from other native regions are required to provide full understanding of its genetic distribution and
phylogeographical study over larger scale of geographic regions. Heuristic approach to study other species in this area prior
to gazetting the Setiu Wetlands as state park is required in order to conserve the biodiversity in-situ
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