Scalable magnet geometries enhance tumour targeting of magnetic nano-carriers

Targeted drug delivery systems aim to increase therapeutic effect within the target tissue or organ, while reducing off-target toxicity associated with systemic delivery. Magnetic drug targeting has been shown to be an effective strategy by manipulating therapeutics inside the body using a magnetic field and an iron oxide carrier. However, the effective targeting range of current magnets limits this method to small animal experiments or superficial parts of the human body. Here we produce clinically translatable magnet designs capable of increasing exposure of tissue to magnetic fields and field gradients, leading to increased carrier accumulation. The iron oxide nanoparticle capturing efficiency was first assessed in vitro using a simple vascular flow system. Secondly, accumulation of these particles, following magnetic targeting, was evaluated in vivo using a range of different magnet designs. We observed that our bespoke magnet produced a 4-fold increase in effective targeting depth when compared to a conventional 1 T disk magnet. Finally, we show that this magnet is readily scalable to human size proportions and has the potential to target 100 nm particles up to a depth of 7 cm at specific locations of human body

OriDB, the DNA replication origin database updated and extended

OriDB (http://www.oridb.org/) is a database containing collated genome-wide mapping studies of confirmed and predicted replication origin sites. The original database collated and curated Saccharomyces cerevisiae origin mapping studies. Here, we report that the OriDB database and web site have been revamped to improve user accessibility to curated data sets, to greatly increase the number of curated origin mapping studies, and to include the collation of replication origin sites in the fission yeast Schizosaccharomyces pombe. The revised database structure underlies these improvements and will facilitate further expansion in the future. The updated OriDB for S. cerevisiae is available at http://cerevisiae.oridb.org/ and for S. pombe at http://pombe.oridb.org/

Eating dysfunction associated with oromandibular dystonia: clinical characteristics and treatment considerations

BACKGROUND: In oromandibular dystonia (OMD) abnormal repetitive contractions of masticatory, facial, and lingual muscles as well as the presence of orobuccolingual (OBL) dyskinesias may interfere with the appropriate performance of tasks such as chewing and swallowing leading to significant dysphagia and weight loss. We present here the clinical characteristics and treatment variables of a series of patients that developed an OMD-associated eating dysfunction. METHODS: We present a series of patients diagnosed and followed-up at the Movement Disorders Clinic of the Department of Neurology of University of Miami, Miller School of Medicine over a 10-year period. Patients were treated with botulinum toxin injections according to standard methods. RESULTS: Five out of 32 (15.6%) OMD patients experienced symptoms of eating dysfunction associated with OMD. Significant weight loss was reported in 3/5 patients (ranged for 13–15 lbs). Two patients regained the lost weight after treatment and one was lost to follow-up. Tetrabenazine in combination with other antidystonic medication and/or botulinum toxin injections provided substantial benefit to the patients with dysphagia caused by OMD. CONCLUSION: Dystonic eating dysfunction may occasionally complicate OMD leading to weight loss. Its adequate characterization at the time of history taking and clinical examination should be part of outcome measurements of the anti-dystonic treatment in clinical practice

Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

Introduction: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. Methods: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. Results: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). Conclusion: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases. © 2019 The Author

Effect of H-NS on the elongation and compaction of single DNA molecules in a nanospace

10.1039/c3sm51214bSoft Matter9409593-960

Association of Methylentetraydrofolate Reductase (MTHFR) 677 C > T gene polymorphism and homocysteine levels in psoriasis vulgaris patients from Malaysia: a case-control study

<p>Abstract</p> <p>Background</p> <p>The methylenetetrahydrofolate reductase (MTHFR) enzyme catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and methyl donors. The methyl donors are required for the conversion of homocysteine to methionine. Mutation of MTHFR 677 C > T disrupts its thermostability therefore leads to defective enzyme activities and dysregulation of homocysteine levels.</p> <p>Methods</p> <p>This case-control study (n = 367) was conducted to investigate the correlation of the MTHFR gene polymorphism [NM_005957] and psoriasis vulgaris amongst the Malaysian population. Overnight fasting blood samples were collected from a subgroup of consented psoriasis vulgaris patients and matched controls (n = 84) for the quantification of homocysteine, vitamin B₁₂and folic acid levels.</p> <p>Results</p> <p>There was no significant increase of the MTHFR 677 C > T mutation in patients with psoriasis vulgaris compared with controls (<it>χ</it>²= 0.733, p = 0.392). No significant association between homocysteine levels and MTHFR gene polymorphism in cases and controls were observed (F = 0.91, df = 3, 80, p = 0.44). However, homocysteine levels in cases were negatively correlated with vitamin B₁₂(r = -0.173) and folic acid (r = -0.345) levels. Vitamin B₁₂and folic acid levels in cases were also negatively correlated (r = -0.164).</p> <p>Conclusions</p> <p>Our results indicate that there was no significant association between the MTHFR gene polymorphism and psoriasis vulgaris in the Malaysian population. There was no significant increase of the plasma homocysteine level in the psoriasis patients compared to the controls.</p

Effects of sulfate starvation on agar polysaccharides of Gracilaria species (Gracilariaceae, Rhodophyta) from Morib, Malaysia

The effects of sulfate starvation on the agar characteristics of Gracilaria species was investigated by culturing two red algae from Morib, Malaysia, Gracilaria changii and Gracilaria salicornia in sulfate-free artificial seawater for 5 days. The seaweed samples were collected in October 2012 and March 2013, periods which have significant variation in the amount of rainfall. The agar yields were shown to be independent of sulfate availability, with only 0.60–1.20 % increment in treated G. changii and 0.31–1.40 % increment in treated G. salicornia while their gel strengths did not increase significantly (approximately 5–7 %) after sulfate starvation for both species. The gelling and melting temperatures did not vary between control and treated samples from both species, except for the treated G. changii collected in March 2013. The gel syneresis index of G. salicornia collected in March 2013 increased significantly after sulfate deprivation. Sulfate starvation introduced some variations in the content of 3, 6-anhydrogalactose and total sulfate esters, but the changes did not have a pronounced effect on the physical properties of agar