89 research outputs found
Vertical distribution of buoyant Microcystis blooms in a Lagrangian particle tracking model for shortâterm forecasts in Lake Erie
Cyanobacterial harmful algal blooms (CHABs) are a problem in western Lake Erie, and in eutrophic fresh waters worldwide. Western Lake Erie is a large (3000 km2), shallow (8 m mean depth), freshwater system. CHABs occur from July to October, when stratification is intermittent in response to wind and surface heating or cooling (polymictic). Existing forecast models give the present location and extent of CHABs from satellite imagery, then predict twoâdimensional (surface) CHAB movement in response to meteorology. In this study, we simulated vertical distribution of buoyant Microcystis colonies, and 3âD advection, using a Lagrangian particle model forced by currents and turbulent diffusivity from the Finite Volume Community Ocean Model (FVCOM). We estimated the frequency distribution of Microcystis colony buoyant velocity from measured size distributions and buoyant velocities. We evaluated several randomâwalk numerical schemes to efficiently minimize particle accumulation artifacts. We selected the Milstein scheme, with linear interpolation of the diffusivity profile in place of cubic splines, and varied the time step at each particle and step based on the curvature of the local diffusivity profile to ensure that the Visser time step criterion was satisfied. Inclusion of vertical mixing with buoyancy significantly improved model skill statistics compared to an advectionâonly model, and showed greater skill than a persistence forecast through simulation day 6, in a series of 26 hindcast simulations from 2011. The simulations and in situ observations show the importance of subtle thermal structure, typical of a polymictic lake, along with buoyancy in determining vertical and horizontal distribution of Microcystis.Key Points:Microcystis vertical distribution is a dynamic balance between turbulence and buoyancyAppropriate time step and numerical scheme avoid artifacts in random walk modelsVertical mixing with buoyancy improved simulation of bloom spatial distributionPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134116/1/jgrc21832_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134116/2/jgrc21832.pd
Noncommutative Particles in Curved Spaces
We present a formulation in a curved background of noncommutative mechanics,
where the object of noncommutativity is considered as an
independent quantity having a canonical conjugate momentum. We introduced a
noncommutative first-order action in D=10 curved spacetime and the covariant
equations of motions were computed. This model, invariant under diffeomorphism,
generalizes recent relativistic results.Comment: 1+15 pages. Latex. New comments and results adde
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ĐŸĐČŃŃŃĐž ŃĐœĐŽĐ”ĐșŃ ŃĐœŃĐ»ŃŃŃŃ. ĐŃŃĐ°ĐœĐŸĐČĐ»Đ”ĐœĐŸ, ŃĐŸ ŃпаЎ ŃĐ”ĐŒĐżŃĐČ Đ·ŃĐŸŃŃĐ°ĐœĐœŃ ĐŽĐžĐœĐ°ĐŒŃĐșĐž ŃДалŃĐ·ĐŸĐČĐ°ĐœĐŸŃ ĐżŃĐŸĐŽŃĐșŃŃŃ ĐżŃОзĐČĐŸĐŽĐžŃŃ ĐŽĐŸ Đ·ĐŒĐ”ĐœŃĐ”ĐœĐœŃ ĐČĐžŃŃĐ°Ń ĐœĐ° ŃĐœĐœĐŸĐČĐ°ŃŃĐčĐœŃ ĐŽŃŃĐ»ŃĐœŃŃŃŃ.ĐĐ°Đœ Đ°ĐœĐ°Đ»ĐžĐ· ĐœĐ°ŃĐžĐŸĐœĐ°Đ»ŃĐœĐŸĐč ĐžĐœĐœĐŸĐČĐ°ŃĐžĐŸĐœĐœĐŸĐč ŃĐžŃŃĐ”ĐŒŃ ĐŁĐșŃĐ°ĐžĐœŃ. Đ Đ°ŃŃĐŒĐŸŃŃĐ”ĐœŃ ĐŸŃŃĐ°ŃлО ĐżŃĐŸĐŒŃŃĐ»Đ”ĐœĐœĐŸŃŃĐž ĐŁĐșŃĐ°ĐžĐœŃ ĐżĐŸ ĐżŃĐžĐ·ĐœĐ°ĐșĐ°ĐŒ ĐžĐœĐœĐŸĐČĐ°ŃĐžĐŸĐœĐœĐŸĐč Đ°ĐșŃĐžĐČĐœĐŸŃŃĐž Đž ĐžŃŃĐ»Đ”ĐŽĐŸĐČĐ°ĐœŃ ŃĐ”ĐŒĐżŃ ŃĐŸŃŃĐ° ĐżĐŸĐșĐ°Đ·Đ°ŃДлДĐč, ŃŃĐžŃŃĐČĐ°Ń ĐžĐœĐŽĐ”ĐșŃ ĐžĐœŃĐ»ŃŃОО. ĐŁŃŃĐ°ĐœĐŸĐČĐ»Đ”ĐœĐŸ, ŃŃĐŸ ŃпаЎ ŃĐ”ĐŒĐżĐŸĐČ ŃĐŸŃŃĐ° ĐŽĐžĐœĐ°ĐŒĐžĐșĐž ŃĐ”Đ°Đ»ĐžĐ·ĐŸĐČĐ°ĐœĐœĐŸĐč ĐżŃĐŸĐŽŃĐșŃОО ĐżŃĐžĐČĐŸĐŽĐžŃ Đș ŃĐŒĐ”ĐœŃŃĐ”ĐœĐžŃ Đ·Đ°ŃŃĐ°Ń ĐœĐ° ĐžĐœĐœĐŸĐČĐ°ŃĐžĐŸĐœĐœŃŃ ĐŽĐ”ŃŃДлŃĐœĐŸŃŃŃ.This article analyses national innovation system of Ukraine. Examined the industry of Ukraine based on innovative activity and investigated the growth indicators, taking into account inflation-index. It is established that the slowdown in the dynamics realized production leads to a decrease in the cost of innovation
Nanobody-targeted photodynamic therapy induces significant tumor regression of trastuzumab-resistant HER2-positive breast cancer, after a single treatment session
Rationale: A substantial number of breast cancer patients with an overexpression of the human epidermal growth factor receptor 2 (HER2) have residual disease after neoadjuvant therapy or become resistant to trastuzumab. Photodynamic therapy (PDT) using nanobodies targeted to HER2 is a promising treatment option for these patients. Here we investigate the in vitro and in vivo antitumor efficacy of HER2-targeted nanobody-photosensitizer (PS) conjugate PDT. Methods: Nanobodies targeting HER2 were obtained from phage display selections. Monovalent nanobodies were engineered into a biparatopic construct. The specificity of selected nanobodies was tested in immunofluorescence assays and their affinity was evaluated in binding studies, both performed in a panel of breast cancer cells varying in HER2 expression levels. The selected HER2-targeted nanobodies 1D5 and 1D5-18A12 were conjugated to the photosensitizer IRDye700DX and tested in in vitro PDT assays. Mice bearing orthotopic HCC1954 trastuzumab-resistant tumors with high HER2 expression or MCF-7 tumors with low HER2 expression were intravenously injected with nanobody-PS conjugates. Quantitative fluorescence spectroscopy was performed for the determination of the local pharmacokinetics of the fluorescence conjugates. After nanobody-PS administration, tumors were illuminated to a fluence of 100 Jâcm-2, with a fluence rate of 50 mWâcm-2, and thereafter tumor growth was measured with a follow-up until 30 days. Results: The selected nanobodies remained functional after conjugation to the PS, binding specifically and with high affinity to HER2-positive cells. Both nanobody-PS conjugates potently and selectively induced cell death of HER2 overexpressing cells, either sensitive or resistant to trastuzumab, with low nanomolar LD50 values. In vivo, quantitative fluorescence spectroscopy showed specific accumulation of nanobody-PS conjugates in HCC1954 tumors and indicated 2 h post injection as the most suitable time point to apply light. Nanobody-targeted PDT with 1D5-PS and 1D5-18A12-PS induced significant tumor regression of trastuzumab-resistant high HER2 expressing tumors, whereas in low HER2 expressing tumors only a slight growth delay was observed. Conclusion: Nanobody-PS conjugates accumulated selectively in vivo and their fluorescence could be detected through optical imaging. Upon illumination, they selectively induced significant tumor regression of HER2 overexpressing tumors with a single treatment session. Nanobody-targeted PDT is therefore suggested as a new additional treatment for HER2-positive breast cancer, particularly of interest for trastuzumab-resistant HER2-positive breast cancer. Further studies are now needed to assess the value of this approach in c
Methyl-binding domain protein-based DNA isolation from human blood serum combines DNA analyses and serum-autoantibody testing
<p>Abstract</p> <p>Background</p> <p>Circulating cell free DNA in serum as well as serum-autoantibodies and the serum proteome have great potential to contribute to early cancer diagnostics via non invasive blood tests. However, most DNA preparation protocols destroy the protein fraction and therefore do not allow subsequent protein analyses. In this study a novel approach based on methyl binding domain protein (MBD) is described to overcome the technical difficulties of combining DNA and protein analysis out of one single serum sample.</p> <p>Methods</p> <p>Serum or plasma samples from 98 control individuals and 54 breast cancer patients were evaluated upon silica membrane- or MBD affinity-based DNA isolation via qPCR targeting potential DNA methylation markers as well as by protein-microarrays for tumor-autoantibody testing.</p> <p>Results</p> <p>In control individuals, an average DNA level of 22.8 ± 25.7 ng/ml was detected applying the silica membrane based protocol and 8.5 ± 7.5 ng/ml using the MBD-approach, both values strongly dependent on the serum sample preparation methods used. In contrast to malignant and benign tumor serum samples, cell free DNA concentrations were significantly elevated in sera of metastasizing breast cancer patients. Technical evaluation revealed that serum upon MBD-based DNA isolation is suitable for protein-array analyses when data are consistent to untreated serum samples.</p> <p>Conclusion</p> <p>MBD affinity purification allows DNA isolations under native conditions retaining the protein function, thus for example enabling combined analyses of DNA methylation and autoantigene-profiles from the same serum sample and thereby improving minimal invasive diagnostics.</p
Discovery of High-Affinity Protein Binding Ligands â Backwards
BACKGROUND: There is a pressing need for high-affinity protein binding ligands for all proteins in the human and other proteomes. Numerous groups are working to develop protein binding ligands but most approaches develop ligands using the same strategy in which a large library of structured ligands is screened against a protein target to identify a high-affinity ligand for the target. While this methodology generates high-affinity ligands for the target, it is generally an iterative process that can be difficult to adapt for the generation of ligands for large numbers of proteins. METHODOLOGY/PRINCIPAL FINDINGS: We have developed a class of peptide-based protein ligands, called synbodies, which allow this process to be run backwards--i.e. make a synbody and then screen it against a library of proteins to discover the target. By screening a synbody against an array of 8,000 human proteins, we can identify which protein in the library binds the synbody with high affinity. We used this method to develop a high-affinity synbody that specifically binds AKT1 with a K(d)<5 nM. It was found that the peptides that compose the synbody bind AKT1 with low micromolar affinity, implying that the affinity and specificity is a product of the bivalent interaction of the synbody with AKT1. We developed a synbody for another protein, ABL1 using the same method. CONCLUSIONS/SIGNIFICANCE: This method delivered a high-affinity ligand for a target protein in a single discovery step. This is in contrast to other techniques that require subsequent rounds of mutational improvement to yield nanomolar ligands. As this technique is easily scalable, we believe that it could be possible to develop ligands to all the proteins in any proteome using this approach
Large expert-curated database for benchmarking document similarity detection in biomedical literature search
Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term FrequencyâInverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research
Large expert-curated database for benchmarking document similarity detection in biomedical literature search
Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe
Site-Specifically Labeled Immunoconjugates for Molecular ImagingâPart 1: Cysteine Residues and Glycans
Due to their remarkable selectivity and specificity for cancer biomarkers, immunoconjugates have emerged as extremely promising vectors for the delivery of diagnostic radioisotopes and fluorophores to malignant tissues. Paradoxically, however, these tools for precision medicine are synthesized in a remarkably imprecise way. Indeed, the vast majority of immunoconjugates are created via the random conjugation of bifunctional probes (e.g., DOTA-NCS) to amino acids within the antibody (e.g., lysines). Yet antibodies have multiple copies of these residues throughout their macromolecular structure, making control over the location of the conjugation reaction impossible. This lack of site specificity can lead to the formation of poorly defined, heterogeneous immunoconjugates with suboptimal in vivo behavior. Over the past decade, interest in the synthesis and development of site-specifically labeled immunoconjugatesâboth antibody-drug conjugates as well as constructs for in vivo imagingâhas increased dramatically, and a number of reports have suggested that these better defined, more homogeneous constructs exhibit improved performance in vivo compared to their randomly modified cousins. In this two-part review, we seek to provide an overview of the various methods that have been developed to create site-specifically modified immunoconjugates for positron emission tomography, single photon emission computed tomography, and fluorescence imaging. We will begin with an introduction to the structure of antibodies and antibody fragments. This is followed by the core of the work: sections detailing the four different approaches to site-specific modification strategies based on cysteine residues, glycans, peptide tags, and unnatural amino acids. These discussions will be divided into two installments: cysteine residues and glycans will be detailed in Part 1 of the review, while peptide tags and unnatural amino acids will be addressed in Part 2. Ultimately, we sincerely hope that this review fosters interest and enthusiasm for site-specific immunoconjugates within the nuclear medicine and molecular imaging communities
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