MULTI-SCALE NUMERICAL APPROACH TO THE POLYMER FILLING PROCESS IN THE WELD LINE REGION

In this paper, a multi-scale coupling mathematical model is suggested for simulating the polymer filling process in the weld line region on a micro scale. The model considers two aspects: one is the coupling model based on stresses in the whole cavity region; the other is the multi-scale coupling model of continuum mechanics (CM) and the molecular dynamics (MD) in a weldline region. A weak variational formulation is constructed for the finite element method (FEM), which is coupled with the Verlet algorithm based on the domain decomposition technique. Meanwhile, an overlap region is designed so that the FEM and the MD simulations are consistent with each other. The molecular backbone orientation of the whole cavity is illustrated and the position of the weld line is determined by the characteristics of the molecular backbone orientation. Finally, the properties of the polymer chain in the weld line region are studied conformationally and dynamically. The conformational changes and movement process elucidate that the polymer chains undertake stretching, entangling and orientating. Moreover, the effect of the number of chains and melt temperature on the spatial properties of chain conformation are investigated

Achieving unidirectional propagation of twisted magnons in a magnetic nanodisk array

Twisted magnons (TMs) have great potential applications in communication and computing owing to the orbital angular momentum (OAM) degree of freedom. Realizing the unidirectional propagation of TMs is the key to design functional magnonics devices. Here we theoretically study the propagation of TMs in one-dimensional magnetic nanodisk arrays. By performing micromagnetic simulations, we find that the one-dimensional nanodisk array exhibits a few bands due to the collective excitations of TMs. A simple model by considering the exchange interaction is proposed to explain the emerging multiband structure and theoretical results agree well with micromagnetic simulations. Interestingly, for a zigzag structure, the dispersion curves and propagation images of TMs show obvious nonreciprocity for specific azimuthal quantum number ($l$), which originates from a geometric effect depending on the phase difference of TMs and the relative angle between two adjacent nanodisks. Utilizing this feature, one can conveniently realize the unidirectional propagation of TMs with arbitrary nonzero $l$. Our work provides important theoretical references for controlling the propagation of TMs.Comment: 7 pages, 6 figure

The correlation of the intestinal with pharyngeal microbiota in early neonates

IntroductionThe gut-lung axis has long been recognized as an important mechanism affecting intestinal and lung immunity. Still, few studies have examined the correlation between the intestinal and pharyngeal microbiota in early neonates, especially when feeding patterns are one of the main drivers of microbiota development.MethodsTo explore the composition and function of intestinal and pharyngeal microbiota and to analyze the effect of limited formula feeding on the initial microbiota colonization in early full-term neonates, we characterized the stool and oropharyngeal microbiota of 20 healthy full-term newborns sampled on days 0 and 5–7 after birth using 16S rRNA gene sequencing. Based on the sequencing results, a comparison was made of the compositions and functions of the intestinal and oropharyngeal microbiota for analysis.Results and discussionAt the phylum level, Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes were the most abundant in both niches. At the genus level, the species of pioneer bacteria were rich in the intestine and oropharynx but low in abundance on day 0. On days 5–7, Bifidobacterium (25.40%) and Escherichia-Shigella (22.16%) were dominant in the intestine, while Streptococcus (38.40%) and Staphylococcus (23.13%) were dominant in the oropharynx. There were eight core bacteria genera in the intestine and oropharynx on days 5–7, which were Bifidobacterium, Escherichia-Shigella, Staphylococcus, Streptococcus, Bacteroides, Parabacteroides, Rothia, and Acinetobacter. As indicated by PICRUSt analysis, on days 5–7, the intestinal microbiota was more predictive than the oropharyngeal microbiota in transcription, metabolism, cell motility, cellular processes and signaling, and organismal system function in the KEGG pathway. Compared to exclusive breastfeeding, limited formula feeding (40–60%) had no significant effect on the neonatal intestinal and oropharyngeal microbiota composition during the initial colonization period. Our results suggest that the initial colonization of microbiota is closely related to the ecological niche environment in the intestine and oropharynx, with their core microbiota being closely correlated. We found that early limited formula feeding could not significantly affect the initial colonization of microbiota in the intestine and oropharynx

Comprehensive evaluation of a somatostatin-based radiolabelled antagonist for diagnostic imaging and radionuclide therapy

Purpose: Targeting of tumours positive for somatostatin receptors (sst) with radiolabelled peptides is of interest for tumour localization, staging, therapy follow-up and targeted radionuclide therapy. The peptides used clinically are exclusively agonists, but recently we have shown that the radiolabelled somatostatin-based antagonist 111In-DOTA-sst2-ANT may be preferable to agonists. However, a comprehensive study of this radiolabelled antagonist to determine its significance was lacking. The present report describes the evaluation of this novel antagonist labelled with 111In and 177Lu in three different tumour models. Methods: Radiopeptide binding, internalization and dissociation studies were performed using cells expressing HEK293-rsst2. Biodistribution studies were performed in HEK293-rsst2, HEK293-hsst2 and HEK293-rsst3 xenografted mice. Results: Saturation binding analysis confirmed earlier IC50 data for 111/natIn-DOTA-sst2-ANT and showed similar affinity of 177/natLu-DOTA-sst2-ANT for the sst2. Only low internalization was found in cell culture (6.68 ± 0.06% at 4h), which was not unexpected for an antagonist, and this could be further reduced by the addition of sucrose. No internalization was observed in HEK293 cells not expressing sst. Both results indicate that the internalization was specific. 111In-DOTA-sst2-ANT and 177Lu-DOTA-sst2-ANT were shown to target tumour xenografts expressing the rat and the human sst2 receptor with no differences in their uptake or pharmacokinetics. The uptake in rsst2 and hsst2 was high (about 30 %IA/g 4h after injection) and surprisingly long-lasting (about 20-23 %IA/g 24h after injection). Kidney uptake was blocked by approximately 50% by lysine or Gelofusine. Conclusion: These results indicate that radiolabelled somatostatin-based antagonists may be superior to corresponding agonists. The long tumour retention time of 177Lu-DOTA-sst2-ANT indicates that this new class of compounds is of relevance not only in diagnostic imaging but also in targeted radionuclide therapy of sst-positive tumour

Development of new folate-based PET radiotracers: preclinical evaluation of 68Ga-DOTA-folate conjugates

Purpose: A number of 111In- and 99mTc-folate-based tracers have been evaluated as diagnostic agents for imaging folate receptor (FR)-positive tumours. A 68Ga-folate-based radiopharmaceutical would be of great interest, combining the advantages of PET technology and the availability of 68Ga from a generator. The aim of the study was to develop a new 68Ga-folate-based PET radiotracer. Methods: Two new DOTA-folate conjugates, named P3026 and P1254, were synthesized using the 1,2-diaminoethane and 3-{2-[2-(3-amino-propoxy)-ethoxy]-ethoxy}-propylamine as a spacer, respectively. Both conjugates were labelled with 67/68Ga. Binding affinity, internalization and externalization studies were performed using the FR-positive KB cell line. Biodistribution and PET/CT imaging studies were performed in nude mice, on a folate-deficient diet, bearing KB and HT1080 (FR-negative) tumours, concurrently. The new radiotracers were evaluated comparatively to the reference molecule 111In-DTPA-folate (111In-P3139). Results: The Kd values of 67/68Ga-P3026 (4.65 ± 0.82 nM) and 67/68Ga-P1254 (4.27 ± 0.42 nM) showed high affinity for the FR. The internalization rate followed the order 67/68Ga-P3026 > 67/68Ga-P1254 > 111In-P3139, while almost double cellular retention was found for 67/68Ga-P3026 and 67/68Ga-P1254, compared to 111In-P3139. The biodistribution data of 67/68Ga-DOTA-folates showed high and receptor-mediated uptake on the FR-positive tumours and kidneys, with no significant differences compared to 111In-P3139. PET/CT images, performed with 68Ga-P3026, showed high uptake in the kidneys and clear visualization of the FR-positive tumours. Conclusion: The DOTA-folate conjugates can be efficiently labelled with 68Ga in labelling yields and specific activities which allow clinical application. The characteristics of the 67/68Ga-DOTA-folates are comparable to 111In-DTPA-folate, which has already been used in clinical trials, showing that the new conjugates are promising candidates as PET radiotracers for FR-positive tumour

Immunogenicity and therapeutic effects of a Mycobacterium tuberculosis rv2190c DNA vaccine in mice

The Excel data file [FOLT] Figshare, [DOI: 10.6084/m9.figshare.4668148 and https://figshare.com/s/bd46c22986c673579bb6 ] includes all datasets supporting the conclusions of this article: IFN-Îł in spleen lymphocyte culture supernatants, IL-4 in spleen lymphocyte culture supernatants, CD4+ T cell subsets expressing intracellular IFN-Îł or IL-4, CFU in the lungs and spleens.. (XLS 143 kb

Development of a potent DOTA-conjugated bombesin antagonist for targeting GRPr-positive tumours

Purpose: Radiolabelled somatostatin-based antagonists show a higher uptake in tumour-bearing mouse models than agonists of similar or even distinctly higher receptor affinity. Very similar results were obtained with another family of G protein-coupled receptor ligands, the bombesin family. We describe a new conjugate, RM2, with the chelator DOTA coupled to D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 via the cationic spacer 4-amino-1-carboxymethyl-piperidine for labelling with radiometals such as 111In and 68Ga. Methods: RM2 was synthesized on a solid support and evaluated in vitro in PC-3 cells. IC50 and Kd values were determined. The antagonist potency was evaluated by immunofluorescence-based internalization and Ca2+ mobilization assays. Biodistribution studies were performed in PC-3 and LNCaP tumour-bearing mice with 111In-RM2 and 68Ga-RM2, respectively. PET/CT studies were performed on PC-3 and LNCaP tumour-bearing nude mice with 68Ga-RM2. Results: RM2 and 111In-RM2 are high-affinity and selective ligands for the GRP receptor (7.7±3.3nmol/l for RM2; 9.3±3.3nmol/l for natIn-RM2). The potent antagonistic properties were confirmed by an immunofluorescence-based internalization and Ca2+ mobilization assays. 68Ga- and 111In-RM2 showed high and specific uptake in both the tumour and the pancreas. Uptake in the tumour remained high (15.2±4.8%IA/g at 1h; 11.7±2.4%IA/g at 4h), whereas a relatively fast washout from the pancreas and the other abdominal organs was observed. Uptake in the pancreas decreased rapidly from 22.6±4.7%IA/g at 1h to 1.5±0.5%IA/g at 4h. Conclusion: RM2 was shown to be a potent GRPr antagonist. Pharmacokinetics and imaging studies indicate that 111In-RM2 and 68Ga-RM2 are ideal candidates for clinical SPECT and PET studie

Macrocyclic chelator-coupled gastrin-based radiopharmaceuticals for targeting of gastrin receptor-expressing tumours

Purpose: Diethylenetriamine-pentaacetic acid (DTPA)-coupled minigastrins are unsuitable for therapeutic application with the available β-emitting radiometals due to low complex stability. Low tumour-to-kidney ratio of the known radiopharmaceuticals is further limiting their potency. We used macrocyclic chelators for coupling to increase complex stability, modified the peptide sequence to enhance radiolytic stability and studied tumour-to-kidney ratio and metabolic stability using 111In-labelled derivatives. Methods: Gastrin derivatives with decreasing numbers of glutamic acids were synthesised using 111In as surrogate for therapeutic radiometals for in vitro and in vivo studies. Gastrin receptor affinities of the natIn-metallated compounds were determined by receptor autoradiography using 125I-CCK as radioligand. Internalisation was evaluated in AR4-2J cells. Enzymatic stability was determined by incubating the 111In-labelled peptides in human serum. Biodistribution was performed in AR4-2J-bearing Lewis rats. Results: IC50 values of the natIn-metallated gastrin derivatives vary between 1.2 and 4.8nmol/L for all methionine-containing derivatives. Replacement of methionine by norleucine, isoleucine, methionine-sulfoxide and methionine-sulfone resulted in significant decrease of receptor affinity (IC50 between 9.9 and 1,195nmol/L). All cholecystokinin receptor affinities were >100nmol/L. All 111In-labelled radiopeptides showed receptor-specific internalisation. Serum mean-life times varied between 2.0 and 72.6h, positively correlating with the number of Glu residues. All 111In-labelled macrocyclic chelator conjugates showed higher tumour-to-kidney ratios after 24h (0.37-0.99) compared to 111In-DTPA-minigastrin 0 (0.05). Tumour wash out between 4 and 24h was low. Imaging studies confirmed receptor-specific blocking of the tumour uptake. Conclusions: Reducing the number of glutamates increased tumour-to-kidney ratio but resulted in lower metabolic stability. The properties of the macrocyclic chelator-bearing derivatives make them potentially suitable for clinical purpose