1,075 research outputs found
AChR deficiency due to ε-subunit mutations: two common mutations in the Netherlands
Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular transmission. We have identified mutations within the acetylcholine receptor (AChR) ε-subunit gene underlying congenital myasthenic syndromes in nine patients (seven kinships) of Dutch origin. Previously reported mutations ε1369delG and εR311Q were found to be common; ε1369delG was present on at least one allele in seven of the nine patients, and εR311Q in six. Phenotypes ranged from relatively mild ptosis and external ophthalmoplegia to generalized myasthenia. The common occurrence of εR311Q and ε1369delG suggests a possible founder for each of these mutations originating in North Western Europe, possibly in Holland. Knowledge of the ethnic or geographic origin within Europe of AChR deficiency patients can help in targeting genetic screening and it may be possible to provide a rapid genetic diagnosis for patients of Dutch origin by screening first for εR311Q and ε1369delG
A Human Recombinant Autoantibody-Based Immunotoxin Specific for the Fetal Acetylcholine Receptor Inhibits Rhabdomyosarcoma Growth In Vitro and in a Murine Transplantation Model
Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumor in children and
is highly resistant to all forms of treatment currently available once metastasis or relapse has commenced. As it has recently been determined that the acetylcholine receptor (AChR) γ-subunit, which defines the fetal AChR (fAChR) isoform, is almost exclusively expressed in RMS post partum, we recombinantly fused a single chain variable fragment (scFv) derived from a fully human anti-fAChR Fab-fragment to Pseudomonas exotoxin A to generate an anti-fAChR immunotoxin (scFv35-ETA). While scFv35-ETA had no damaging effect on fAChR-negative control cell lines, it killed human embryonic and alveolar RMS cell lines in vitro and delayed RMS development in a murine transplantation model. These results indicate that scFv35-ETA may be a valuable new therapeutic tool as well as a relevant step towards the development of a fully human immunotoxin directed against RMS. Moreover, as approximately 20% of metastatic malignant melanomas (MMs) display rhabdoid features
including the expression of fAChR, the immunotoxin we developed may also prove to be of significant use in the treatment of these more common and most often fatal neoplasms
Impact of Community-Based Larviciding on the Prevalence of Malaria Infection in Dar es Salaam, Tanzania.
The use of larval source management is not prioritized by contemporary malaria control programs in sub-Saharan Africa despite historical success. Larviciding, in particular, could be effective in urban areas where transmission is focal and accessibility to Anopheles breeding habitats is generally easier than in rural settings. The objective of this study is to assess the effectiveness of a community-based microbial larviciding intervention to reduce the prevalence of malaria infection in Dar es Salaam, United Republic of Tanzania. Larviciding was implemented in 3 out of 15 targeted wards of Dar es Salaam in 2006 after two years of baseline data collection. This intervention was subsequently scaled up to 9 wards a year later, and to all 15 targeted wards in 2008. Continuous randomized cluster sampling of malaria prevalence and socio-demographic characteristics was carried out during 6 survey rounds (2004-2008), which included both cross-sectional and longitudinal data (N = 64,537). Bayesian random effects logistic regression models were used to quantify the effect of the intervention on malaria prevalence at the individual level. Effect size estimates suggest a significant protective effect of the larviciding intervention. After adjustment for confounders, the odds of individuals living in areas treated with larviciding being infected with malaria were 21% lower (Odds Ratio = 0.79; 95% Credible Intervals: 0.66-0.93) than those who lived in areas not treated. The larviciding intervention was most effective during dry seasons and had synergistic effects with other protective measures such as use of insecticide-treated bed nets and house proofing (i.e., complete ceiling or window screens). A large-scale community-based larviciding intervention significantly reduced the prevalence of malaria infection in urban Dar es Salaam
Genetic defects are common in myopathies with tubular aggregates
Objective: A group of genes have been reported to be associated with myopathies with tubular aggregates (TAs). Many cases with TAs still lack of genetic
clarification. This study aims to explore the genetic background of cases with
TAs in order to improve our knowledge of the pathogenesis of these rare
pathological structures. Methods: Thirty-three patients including two family
members with biopsy confirmed TAs were collected. Whole-exome sequencing
was performed on 31 unrelated index patients and a candidate gene search
strategy was conducted. The identified variants were confirmed by Sanger
sequencing. The wild-type and the mutant p.Ala11Thr of ALG14 were transfected into human embryonic kidney 293 cells (HEK293), and western blot
analysis was performed to quantify protein expression levels. Results: Eleven
index cases (33%) were found to have pathogenic variant or likely pathogenic
variants in STIM1, ORAI1, PGAM2, SCN4A, CASQ1 and ALG14. Among them,
the c.764A>T (p.Glu255Val) in STIM1 and the c.1333G>C (p.Val445Leu) in
SCN4A were novel. Western blot analysis showed that the expression of ALG14
protein was severely reduced in the mutant ALG14 HEK293 cells (p.Ala11Thr)
compared with wild type. The ALG14 variants might be associated with TAs in
patients with complex multisystem disorders. Interpretation: This study
expands the phenotypic and genotypic spectrums of myopathies with TAs. Our
findings further confirm previous hypothesis that genes related with calcium
signalling pathway and N-linked glycosylation pathway are the main genetic
causes of myopathies with TAs
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Photon recycling in lead iodide perovskite solar cells.
Lead-halide perovskites have emerged as high-performance photovoltaic materials. We mapped the propagation of photogenerated luminescence and charges from a local photoexcitation spot in thin films of lead tri-iodide perovskites. We observed light emission at distances of ≥50 micrometers and found that the peak of the internal photon spectrum red-shifts from 765 to ≥800 nanometers. We used a lateral-contact solar cell with selective electron- and hole-collecting contacts and observed that charge extraction for photoexcitation >50 micrometers away from the contacts arose from repeated recycling between photons and electron-hole pairs. Thus, energy transport is not limited by diffusive charge transport but can occur over long distances through multiple absorption-diffusion-emission events. This process creates high excitation densities within the perovskite layer and allows high open-circuit voltages.The authors acknowledge financial support from the Engineering and Physical Sciences Research Council of the UK (EPSRC) and King Abdulaziz City for Science and Technology (KACST). L.M.P.O. and H.J.B. also thank the Nano doctoral training center (NanoDTC) for financial support. M.S., M.V. and J.M.R. thank the Winton programme for the physics of sustainability. M.C.Q would like to thank the Marie Curie Actions (FP7-PEOPLE-IEF2013) for funding. M.A.J. thanks Nyak Technology Ltd for PhD scholarship and B.E. acknowledges the Foundation for Fundamental Research on Matter (FOM), which is part of the Netherlands Organization for Scientific Research (NWO). F.D. acknowledges funding through a Herchel Smith Research Fellowship. We acknowledge Prof. Henning Sirringhaus, Prof. Neil Greenham, Prof. Ullrich Steiner, Dr. Erwin Reisner and Prof. Richard Phillips for providing support and access to their facilities.This is the author accepted manuscript. The final version is available from the American Association for the Advancement of Science via http://dx.doi.org/10.1126/science.aaf116
Comparing uni-modal and multi-modal therapies for improving writing in acquired dysgraphia after stroke.
Writing therapy studies have been predominantly uni-modal in nature; i.e., their central therapy task has typically been either writing to dictation or copying and recalling words. There has not yet been a study that has compared the effects of a uni-modal to a multi-modal writing therapy in terms of improvements to spelling accuracy. A multiple-case study with eight participants aimed to compare the effects of a uni-modal and a multi-modal therapy on the spelling accuracy of treated and untreated target words at immediate and follow-up assessment points. A cross-over design was used and within each therapy a matched set of words was targeted. These words and a matched control set were assessed before as well as immediately after each therapy and six weeks following therapy. The two approaches did not differ in their effects on spelling accuracy of treated or untreated items or degree of maintenance. All participants made significant improvements on treated and control items; however, not all improvements were maintained at follow-up. The findings suggested that multi-modal therapy did not have an advantage over uni-modal therapy for the participants in this study. Performance differences were instead driven by participant variables
Ligand-Receptor Interactions
The formation and dissociation of specific noncovalent interactions between a
variety of macromolecules play a crucial role in the function of biological
systems. During the last few years, three main lines of research led to a
dramatic improvement of our understanding of these important phenomena. First,
combination of genetic engineering and X ray cristallography made available a
simultaneous knowledg of the precise structure and affinity of series or
related ligand-receptor systems differing by a few well-defined atoms. Second,
improvement of computer power and simulation techniques allowed extended
exploration of the interaction of realistic macromolecules. Third, simultaneous
development of a variety of techniques based on atomic force microscopy,
hydrodynamic flow, biomembrane probes, optical tweezers, magnetic fields or
flexible transducers yielded direct experimental information of the behavior of
single ligand receptor bonds. At the same time, investigation of well defined
cellular models raised the interest of biologists to the kinetic and mechanical
properties of cell membrane receptors. The aim of this review is to give a
description of these advances that benefitted from a largely multidisciplinar
approach
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A "novel" reading therapy programme for reading difficulties after a subarachnoid haemorrhage
Background: Although several treatments for acquired reading difficulties exist, few studies have explored the effectiveness of treatment for mild reading difficulties and treatment for reading difficulties associated with cognitive impairment.
Aims: This study explored the effectiveness of an individual strategy-based reading treatment of 11 sessions given to a female participant (IW) who had mild reading difficulties following a subarachnoid haemorrhage (SAH). The impact of treatment on reading ability, confidence and emotions associated with reading were investigated.
Methods & Procedures: Treatment focussed on the use of strategies to support IW’s memory when reading books, the use of a checklist to select appropriate reading materials, and increasing IW’s confidence in discussing the book she was reading with others. A person-centred approach and personally relevant materials were used throughout the treatment. Reading ability was assessed using the Gray Oral Reading Tests (GORT-4; Lee Wiederholt & Bryant, 2001), and IW’s perspective was obtained using the Reading Confidence and Emotions Questionnaire (RCEQ; see Cocks et al., 2010. Pre-treatment, post-treatment and maintenance (7 weeks post) assessments were undertaken, with an additional exit interview at the final time point.
Outcomes & Results: Gains were noted in reading rate, accuracy, comprehension, and confidence, with parallel increased pleasure gained from reading and reduced negative emotions and frustration. Self-reported gains included conversing with others about material read, verbal communication, and re-engagement with the identity of being a reader.
Conclusions: Strategy-based treatment resulted in positive gains in reading for pleasure, conversation, and identity, for an individual with mild chronic reading difficulties. Participant self-report and interview reveal the true value of this treatment for the individual. The positive results suggest that further research is warranted that investigates the effectiveness of strategy-based reading therapy approaches for others with acquired reading difficulties
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