Ultra-small cobalt particles embedded in titania by ion beam synthesis: Additional datasets including electron microscopy, neutron reflectometry, modelling outputs and particle size analysis.

This Data-in-brief article includes datasets of electron microscopy, polarised neutron reflectometry and magnetometry for ultra-small cobalt particles formed in titania thin films via ion beam synthesis. Raw data for polarised neutron reflectometry, magnetometry and the particle size distribution are included and made available on a public repository. Additional elemental maps from scanning electron microscopy (SEM) with energy dispersive spectroscopy (EDS) are also presented. Data were obtained using the following types of equipment: the NREX and PLATYPUS polarised neutron reflectometers; a Quantum Design Physical Property Measurement System (14 T); a JEOL JSM-6490LV SEM, and a JEOL ARM-200F scanning transmission electron microscope (STEM). The data is provided as supporting evidence for the article in Applied Surface Science (A. Bake et al., Appl. Surf. Sci., vol. 570, p. 151068, 2021, DOI 10.1016/j.apsusc.2021.151068), where a full discussion is given. The additional supplementary reflectometry and modelling datasets are intended to assist future scientific software development of advanced fitting algorithms for magnetization gradients in thin films.

Simulating the Self-Assembly and Hysteresis Loops of Ferromagnetic Nanoparticles with Sticking of Ligands.

The agglomeration of ferromagnetic nanoparticles in a fluid is studied using nanoparticle-level Langevin dynamics simulations. The simulations have interdigitation and bridging between ligand coatings included using a computationally-cheap, phenomenological sticking parameter c. The interactions between ligand coatings are shown in this preliminary study to be important in determining the shapes of agglomerates that form. A critical size for the sticking parameter is estimated analytically and via the simulations and indicates where particle agglomerates transition from well-ordered (c is small) to disordered (c is large) shapes. Results are also presented for the hysteresis loops (magnetization versus applied field) for these particle systems in an oscillating magnetic field appropriate for hyperthermia applications. The results show that the clumping of particles has a significant effect on their macroscopic properties, with important consequences on applications. In particular, the work done by an oscillating field on the system has a nonmonotonic dependence on c.

Exploiting Unique Alignment of Cobalt Ferrite Nanoparticles, Mild Hyperthermia, and Controlled Intrinsic Cobalt Toxicity for Cancer Therapy.

Nanoparticle-based magnetic hyperthermia is a well-known thermal therapy platform studied to treat solid tumors, but its use for monotherapy is limited due to incomplete tumor eradication at hyperthermia temperature (45 °C). It is often combined with chemotherapy for obtaining a more effective therapeutic outcome. Cubic-shaped cobalt ferrite nanoparticles (Co-Fe NCs) serve as magnetic hyperthermia agents and as a cytotoxic agent due to the known cobalt ion toxicity, allowing the achievement of both heat and cytotoxic effects from a single platform. In addition to this advantage, Co-Fe NCs have the unique ability to form growing chains under an alternating magnetic field (AMF). This unique chain formation, along with the mild hyperthermia and intrinsic cobalt toxicity, leads to complete tumor regression and improved overall survival in an in vivo murine xenograft model, all under clinically approved AMF conditions. Numerical calculations identify magnetic anisotropy as the main Co-Fe NCs' feature to generate such chain formations. This novel combination therapy can improve the effects of magnetic hyperthermia, inaugurating investigation of mechanical behaviors of nanoparticles under AMF, as a new avenue for cancer therapy.

The formation of linear aggregates in magnetic hyperthermia: implications on specific absorption rate and magnetic anisotropy.

The design and application of magnetic nanoparticles for use as magnetic hyperthermia agents has garnered increasing interest over the past several years. When designing these systems, the fundamentals of particle design play a key role in the observed specific absorption rate (SAR). This includes the particle's core size, polymer brush length, and colloidal arrangement. While the role of particle core size on the observed SAR has been significantly reported, the role of the polymer brush length has not attracted as much attention. It has recently been reported that for some suspensions linear aggregates form in the presence of an applied external magnetic field, i.e. chains of magnetic particles. The formation of these chains may have the potential for a dramatic impact on the biomedical application of these materials, specifically the efficiency of the particles to transfer magnetic energy to the surrounding cells. In this study we demonstrate the dependence of SAR on magnetite nanoparticle core size and brush length as well as observe the formation of magnetically induced colloidal arrangements. Colloidally stable magnetic nanoparticles were demonstrated to form linear aggregates in an alternating magnetic field. The length and distribution of the aggregates were dependent upon the stabilizing polymer molecular weight. As the molecular weight of the stabilizing layer increased, the magnetic interparticle interactions decreased therefore limiting chain formation. In addition, theoretical calculations demonstrated that interparticle spacing has a significant impact on the magnetic behavior of these materials. This work has several implications for the design of nanoparticle and magnetic hyperthermia systems, while improving understanding of how colloidal arrangement affects SAR.

Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency.

RATIONALE: Most sarcomere gene mutations that cause hypertrophic cardiomyopathy are missense alleles that encode dominant negative proteins. The potential exceptions are mutations in the MYBPC3 gene (encoding cardiac myosin-binding protein-C [MyBP-C]), which frequently encode truncated proteins. OBJECTIVE: We sought to determine whether there was evidence of haploinsufficiency in hypertrophic cardiomyopathy caused by MYBPC3 mutations by comparing left ventricular muscle from patients undergoing surgical myectomy with samples from donor hearts. METHODS AND RESULTS: MyBP-C protein and mRNA levels were quantitated using immunoblotting and RT-PCR. Nine of 37 myectomy samples had mutations in MYBPC3: 2 missense alleles (Glu258Lys, Arg502Trp) and 7 premature terminations. No specific truncated MyBP-C peptides were detected in whole muscle homogenates of hypertrophic cardiomyopathy tissue. However, the overall level of MyBP-C in myofibrils was significantly reduced (P<0.0005) in tissue containing either a truncation or missense MYBPC3 mutation: 0.76+/-0.03 compared with 1.00+/-0.05 in donor and 1.01+/-0.06 in non-MYBPC3 mutant myectomies. CONCLUSIONS: The absence of any detectable truncated MyBP-C argues against its incorporation in the myofiber and any dominant negative effect. In contrast, the lowered relative level of full length protein in both truncation and missense MYBPC3 mutations argues strongly that haploinsufficiency is sufficient to cause the disease.

Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis.

Haemochromatosis (HH) is a clinically and genetically heterogeneous disease caused by inappropriate iron absorption. Most HH patients are homozygous for the C282Y mutation in the HFE gene. However, penetrance of the C282Y mutation is incomplete, and other genetic factors may well affect the HH phenotype. Ferroportin and TFR2 mutations also cause HH, and two HAMP mutations have recently been reported that causes juvenile haemochromatosis (JH) in the homozygous state. Here, we report evidence for digenic inheritance of HH. We have detected two new HAMP mutations in two different families, in which there is concordance between severity of iron overload and heterozygosity for HAMP mutations when present with the HFE C282Y mutation. In family A, the proband has a JH phenotype and is heterozygous for C282Y and a novel HAMP mutation Met50del IVS2+1(-G). This is a four nucleotide ATGG deletion which causes a frameshift. The proband's unaffected mother is also heterozygous for Met50del IVS2+1(-G), but lacks the C282Y mutation and is heterozygous for the HFE H63D mutation. Met50del IVS2+1(-G) was absent from 642 control chromosomes. In family B, a second novel, less severe HAMP mutation, G71D, was identified. This was detected in the general population at an allele frequency of 0.3%. We propose that the phenotype of C282Y heterozygotes and homozygotes may be modified by heterozygosity for mutations which disrupt the function of hepcidin in iron homeostasis, with the severity of iron overload corresponding to the severity of the HAMP mutation.

Hemochromatosis gene (HFE) mutations in South East Asia: a potential for iron overload.

Hereditary hemochromatosis (HH) is an autosomal recessive disease caused by mutations in the HFE gene that mainly affects populations of European descent. Recently a novel mutation (IVS5+1 G-->A) has been described in a Vietnamese patient with HH that was not detected in a European control population. We have developed a novel method to screen for this mutation based on restriction enzyme digestion of a PCR product using a modified forward primer. We have screened 314 Vietnamese people from several ethnic groups and 154 people from Thailand for this mutation and have detected two heterozygotes in the Vietnamese subjects (allele frequency 0.003). Analysis of these heterozygotes indicates that the mutation is on the same haplotype as that found in the original proband. Screening for the widely distributed HFE mutation, H63D, gave an allele frequency of 0.049 in the Vietnamese subjects and 0.032 in the subjects from Thailand. This is the first report of H63D allele frequencies in these populations. We suggest that the presence of the IVS5+1 G-->A and H63D mutations should be considered when investigating iron overload in Vietnamese patients and those of mixed origin as co-inheritance of both mutations is likely to be a risk factor for iron overload.

Pilot study of early diagnosis of hereditary haemochromatosis through systematic case finding in primary care.

OBJECTIVES: To test the feasibility of adopting and evaluating a systematic case-finding approach to the early diagnosis of hereditary haemochromatosis (HHC) in primary care, and to estimate the prevalence of presenting conditions for which HHC testing could be offered. METHODS: Systematic identification of, and genotyping for, C282Y and H63D mutations in patients presenting in primary care with possible symptoms of HHC during a 4-week period to 1 of 14 doctors in Oxfordshire. RESULTS: From a total of 4,022 consultations, 169 (4.2%; 95% CI: 3.6-4.8) adult patients had possible symptoms of HHC. Of these, 88 (2.2%; 95% CI: 1.7-2.6) were aged 25-70 and were offered genotyping for HHC, of whom 60 agreed to be tested. There were no C282Y homozygotes (0%; 95% CI: 0-6.0), no C282Y/H63D compound heterozygotes (0%; 95% CI: 0-6.0), 2 H63D homozygotes with normal iron indices (3.3%%; 95% CI: 0.4-11.5) and 3 C282Y heterozygotes (5.0%; 95% CI: 1.0-13.9). CONCLUSIONS: This study raises doubts about a case-finding approach to early diagnosis of HHC in primary care. The non-specific nature and high prevalence of possible symptoms of HHC in primary care mean that many patients would require testing to identify a single case. Whether this offers a more cost-effective alternative to population screening requires further study.