Twisted intersection colorings, invariants and double coverings of twisted links

Twisted links are a generalization of classical links and correspond to stably equivalence classes of links in thickened surfaces. In this paper we introduce twisted intersection colorings of a diagram and construct two invariants of a twisted link using such colorings. As an application, we show that there exist infinitely many pairs of twisted links such that for each pair the two twisted links are not equivalent but their double coverings are equivalent. We also introduce a method of constructing a pair of twisted links whose double coverings are equivalent

Characterization of Tunable Magnetic Sensor Using Bias Magnetic Field of a Hard Magnetic Film Magnetized by Pulsed-Magnetic Field

A tunable magnetoresistance (MR) sensor with variable sensitivity and measuring range is fabricated and characterized. The sensor has been fabricated using a combination of Ni-Fe soft magnetic film, Fe-Co-Sm hard magnetic film. The sensor is placed in a magnetizing coil for the process of magnetizing the hard magnetic film. The sensitivity and the measuring range of the sensor are tuned by bias magnetic field produced by the magnetic poles of the hard magnetic film. The sensitivity change was about 60%, and the measuring range change was about 30% in the tunable MR sensor from the experimental results. The bias magnetic field is controlled by changing amplitude of the pulsed magnetic field in the magnetizing for the hard magnetic film. The control power for one time tuning is about 18 mu Wh.ArticleIEEE TRANSACTIONS ON MAGNETICS. 49(7):3854-3857 (2013)journal articl

Generation of antagonistic biparatopic anti-CD30 antibody from an agonistic antibody by precise epitope determination and utilization of structural characteristics of CD30 molecule

BACKGROUND: CD30 is a member of the tumor necrosis factor receptor superfamily. Recently, blocking CD30-dependent intracellular signaling has emerged as potential strategy for immunological regulation. Development of antibody-based CD30 antagonists is therefore of significant interest. However, a key challenge is that the bivalent form of natural antibody can crosslink CD30 molecules, leading to signal transduction even in the absence of specific ligand, CD153. Biparatopic antibodies (BpAbs) offer a solution, using two different variable fragments (Fvs) to bind distinct epitopes on a single antigen molecule. BpAbs format is an attractive alternative of natural antibody by potentially avoiding unwanted crosslinking and signaling induction. METHODS: We systematically characterized 36 BpAbs, each designed with pairs of Fvs binding to nine distinct epitopes across the CD30 extracellular domain. We first identified the precise epitope sites of the nine antibodies by assessing the binding to multiple orthologous CD30 proteins and mutants. We then produced the 36 BpAbs and analyzed their biological activities and binding modes. RESULTS: Among 36 BpAbs, we identified both potent ligand-independent agonists and ligand-blocking antagonists, with many displayed reduced signal activation, including 1:1-binding antagonists derived from AC10, a strong agonist developed for lymphoma therapy. Epitope dependency in reduced signaling activity was observed and associated with the flexible nature of CD30 protein. CONCLUSIONS: We successfully developed antagonistic BpAbs against CD30 by controlling the stoichiometry of antibody-antigen binding mode. This study elucidated the mechanism of signaling induction, informing the design strategies of the development of biparatopic antibodies

Fecal microbiota transplantation prevents Candida albicans from colonizing the gastrointestinal tract

Gut microbes symbiotically colonize the gastrointestinal (GI) tract, interacting with each other and their host to maintain GI tract homeostasis. Recent reports have shown that gut microbes help protect the gut from colonization by pathogenic microbes. Here, we report that commensal microbes prevent colonization of the GI tract by the pathogenic fungus, Candida albicans. Wild‐type specific pathogen‐free (SPF) mice are resistant to C. albicans colonization of the GI tract. However, administering certain antibiotics to SPF mice enables C. albicans colonization. Quantitative kinetics of commensal bacteria are inversely correlated with the number of C. albicans in the gut. Here, we provide further evidence that transplantation of fecal microbiota is effective in preventing Candida colonization of the GI tract. These data demonstrate the importance of commensal bacteria as a barrier for the GI tract surface and highlight the potential clinical applications of commensal bacteria in preventing pathogenic fungal infections.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149500/1/mim12680_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149500/2/mim12680.pd

Markov models for the evolution of duplicate genes, and microsatellites

Duplicate genes and microsatellites are two key sequences in the study of evolutionary genomics. Gene duplication has been identified as a central process driving functional change in genomes, since it creates functional redundancy in the genome and allows for subsequent mutation to occur in the absence of selective pressure. Microsatellites are rapidly evolving sequences which can be studied over much smaller timescales than most other sequences, and are thus key to the study of population demographics and forensic science. In this thesis we construct mathematical models for the evolution of duplicate genes, and microsatellites, respectively. We analyse the models in order to make scientific predictions, and derive the following novel results. We introduce and analyse a modified hazard function, which we use to investigate the preservation of gene duplicates. Further, we construct individual-level models, and present a framework for the extension to population-level models. Also, we construct mappings from mechanistically-motivated intuitive models for gene duplicate evolution, to less intuitive models, which have smaller state spaces and hence are more computationally tractable. Throughout this analysis, we make scientific predictions based on the properties of the models. We find that the pattern of gene duplicate preservation is more consistent with subfunctionalization than with neofunctionalization. This result is of particular scientific interest, since it is the opposite conclusion of earlier work in the gene duplication literature. ${Duplicate}$ ${genes}$ Several biological models exist for the evolution of a pair of duplicate genes after a duplication event, and it is believed that gene duplicates can evolve in different ways, according to one process, or a mix of processes. Subfunctionalization is a process under which the two duplicates can be preserved by dividing up the functions of the original gene between them. Here, we find that subfunctionalization is highly consistent with the pattern of gene duplicate preservation, in contrast to previous analysis in the literature. Another process important to gene duplicate evolution is neofunctionalization, under which both duplicates can be preserved when one copy mutates so as to produce some new beneficial function. Our analysis of neofunctionalization suggests that this process is not a significant contributor to the preservation of duplicates over the timescales during which regulatory subfunctionalization is resolved. Instead, it is likely that neofunctionalization occurs subsequent to previous subfunctionalization, which acts to preserve copies over the longer time frames required for rare beneficial mutations to have any significant probability of occurring. Analysis of genomic data using sub- and neofunctionalization models has thus far been relatively coarse-grained, with mathematical treatments usually focusing on the phenomenological features of gene duplicate evolution. In contrast, we develop mechanistically motivated Markov models, and fit directly to duplicate preservation data. We introduce a modified-cause-specific hazard function to analyse the preservation of gene duplicates. In the context of gene duplication, we refer to this as the pseudogenization rate, owing to the biological interpretation. We analyse the properties of the modified-cause-specific hazard rate in detail, including limit analysis of the general case, and discuss the shape properties of the specific case of the pseudogenization rate. Further, we extend our model for the evolution of a pair of gene duplicates to model a population of duplicate pairs, by modelling the birth of such pairs as a homogeneous Poisson process. We show that the age distribution of preserved duplicates follows an inhomogenous Poisson distribution, with its rate function depending on the individuallevel model. We then fit this distribution to count-data of surviving duplicates in the genomes of four animal species. Additionally, we extend the individual-level model to a model that includes the process of neofunctionalization, and next, to a model of subfunctionalization for families of gene duplicates. Finally, we map these intuitive models, to less intuitive but more computationally tractable models, and discuss a number of related computational considerations. ${Microsatellites}$ Microsatellites are repetitive regions of DNA where a short motif is repeated many times. Mutations in the number of repeat units occur frequently compared to point mutations and thus provide a useful source of genetic variation for studying recent events. Empirical studies have suggested that the rate of length-changing mutations due to slipped-strand mispairing may depend on the purity of the repeat units, i.e. how well they each match the motif. However, most studies that use microsatellite data are based on models that only track the number of repeat units. In order to address this gap, we introduce a series of models on a two-dimensional state-space (which are level-dependent quasi-birth-and-death processes) that track the length of the sequence as the level variable, and the number of interruptions (purity) as the phase variable. Our models account for the biological process of point mutation, and its observed effect on the rate of slipped-strand mispairing. We find that modelling microsatellite purity leads to some complications due to the nature of available data. In terms of the initial model, we discover what constitutes a state-dependent bias in the reporting of repeat sequences by Tandem Repeats Finder (or any similar software used to search whole-genomes for microsatellite sequences). Consequently, we construct a modified model such that all states fall into one of two categories - 'observable states', against which the reporting algorithm is unbiased, and 'unobservable states', which are never reported. We consider two approaches for treating the unobservable states, first to condition on the process being in the observable states, second to treat unobservable states as absorbing. Our initial analysis and underlying biological intuition suggest that transitions from the unobservable to observable states are very rare, and thus we ultimately treat the unobservable states as absorbing. Additionally, we extend the individual-level model to a population-level model by modelling the birth of microsatellites as a homogeneous Poisson process. We then derive the transient distribution of such model in terms of the individual-level process. This distribution has appropriate relative clock via the inclusion of point mutation. We fit this transient distribution to whole-genome derived sequence data, however we encounter some dificulties in the optimisation owing to the presence of many local optima. The standard approach for microsatellite models is to make the assumption that the empirical distribution is at equilibrium, and then to fit the stationary distribution to data. The key exception to this is the step-wise mutation model, which predicts infinite growth of the repeat number. Here we fit the above-mentioned transient distribution, and thus do not assume that the empirical distribution is at equilibrium. In contrast to the step-wise mutation model, our model does not predict infinite sequence lengths in the long run

Case Report: Anomalous drainage vein sampling for diagnosing aldosterone-producing lesions undetectable by segmental adrenal venous sampling in a two-case series

Adrenal vein sampling (AVS) is the gold standard for subtyping primary aldosteronism (PA). However, through conventional AVS, unilateral PA may be misdiagnosed as bilateral PA. Compared with conventional AVS, segmental AVS with additional sampling in adrenal tributaries can detect aldosterone-producing adenomas (APAs) with higher sensitivity. Herein, we describe two cases wherein high aldosterone levels were not detected through initial segmental AVS but were identified in anomalous drainage veins during the second AVS session. In Case 1, computed tomography (CT) during left adrenal arteriovenography revealed a fine renal capsular vein connecting an adrenal nodule to the third lumbar vein. Sampling in this vein during the second AVS revealed high aldosterone levels. The surgical specimen showed the presence of an 11 mm APA. Furthermore, Case 2 presented with bilateral small adrenal nodules; bilateral renal capsular vein sampling was performed during the second AVS session. The samples from the renal capsular vein connected to the renal vein revealed considerably high aldosterone levels. Left adrenalectomy revealed the presence of a 6 mm aldosterone-producing nodule. These cases highlight the importance of anomalous drainage vein sampling, the limitation of conventional and segmental AVS in diagnosing PA, and the utility of CT during adrenal arteriovenography for estimating the drainage route

Androgen’s effects in female

The metabolic effects of androgens and their underlying mechanisms in females have been revealed by recent studies. An excess of androgens can have adverse effects on feeding behavior and metabolic functions and induce metabolic disorders / diseases, such as obesity, insulin resistance, and diabetes, in women and experimental animals of reproductive age. Interestingly, these effects of androgens are not observed in ovariectomized animals, indicating that their effects might be dependent on the estrogen milieu. Central and peripheral mechanisms, such as alterations in the activity of hypothalamic factors, reductions in energy expenditure, skeletal muscle insulin resistance, and β-cell dysfunction, might be related to these androgens’ effects

Biotin levels in blood and follicular fluid

It has been shown that biotin, a water-soluble vitamin (B7), plays roles in reproductive functions, such as oocyte maturation and embryo development, in experimental animals. On the other hand, little is known about the clinical effects of biotin on human reproduction. In this study, serum and follicular fluid biotin levels were measured in patients who underwent in vitro fertilization / intracytoplasmic sperm injection (IVF / ICSI), and their associations with reproductive outcomes were evaluated. As a result, biotin was detected in follicular fluid, as well as serum, and the biotin levels of follicular fluid were found to be positively correlated with those of serum. The biotin levels of serum were higher than those of follicular fluid, suggesting that biotin may be taken up into the follicular fluid from the blood. Although serum and follicular fluid biotin levels tended to be higher in pregnant patients than in non-pregnant patients, these data did not show the significant statistical difference. These findings indicate that biotin does not contribute to the maintenance of oocyte quality, and hence, it does not increase fertilization and pregnancy rates