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Monoclonal antibody humanness score and its applications
Sean H Gao1,
Kexin Huang1,
Hua Tu1 &
Adam S Adler1
Monoclonal antibody therapeutics are rapidly gaining in popularity for the treatment of a myriad of diseases, ranging from cancer to autoimmune diseases and neurological diseases. Multiple forms of antibody therapeutics are in use today that differ in the amount of human sequence present in both the constant and variable regions, where antibodies that are more human-like usually have reduced immunogenicity in clinical trials.
Here we present a method to quantify the humanness of the variable region of monoclonal antibodies and show that this method is able to clearly distinguish human and non-human antibodies with excellent specificity. After creating and analyzing a database of human antibody sequences, we conducted an in-depth analysis of the humanness of therapeutic antibodies, and found that increased humanness score is correlated with decreased immunogenicity of antibodies. We further discovered a surprisingly similarity in the immunogenicity of fully human antibodies and humanized antibodies that are more human-like based on their humanness score.
Our results reveal that in most cases humanizing an antibody and confirming the humanness of the final form may be sufficient to eliminate immunogenicity issues to the same extent as using fully human antibodies. We created a public website to calculate the humanness score of any input antibody sequence based on our human antibody database. This tool will be of great value during the preclinical drug development process for new monoclonal antibody therapeutics.
The first monoclonal antibody therapeutic was approved for use in the United States in 1986, the mouse anti-CD3 molecule muromonab that reduces organ transplant rejection [1]. Since then, nearly 30 full-length therapeutic antibodies and 10 fragment antigen-binding (Fab) antibodies have been approved in the United States or Europe, with hundreds more in preclinical and clinical development [2–7]. Therapeutic antibodies are used in a myriad of disease settings, including oncology, autoimmune, and neurological disorders. There are four major antibody types used as therapeutics: fully non-human (most commonly mouse), chimeric (non-human variable region, human constant) [8], humanized (human and non-human variable region sequence, human constant) [9, 10], and fully human [4]. Therapeutics have evolved to include more human sequences, since in general the more human sequence that is present in the antibody, the less immunogenic the antibody will be once introduced to humans [11]. Immunogenicity refers to the ability of a therapeutic antibody to induce the formation of anti-drug antibodies (ADAs) when administrated into a human. ADAs are immune system generated antibodies against the therapeutic that can reduce the efficacy of the drug, and more importantly they can also cause adverse effects ranging from a rash at the site of injection to a systemic inflammatory reaction that can be fatal [12, 13]. Therefore it would be extremely valuable to know whether an antibody may be immunogenic prior to clinical trials are initiated.
The complementarity determining regions (CDRs) of an antibody are the most variable segments of the variable domain that are essential for the antibody-antigen binding specificity and affinity [14]. The CDRs and the surrounding framework segments comprise the full variable sequence of an antibody. Several attempts have previously been made to calculate a humanness score of the variable region sequences of antibodies, since a vital use for such a tool is to aid in identifying antibody sequences that are likely to have reduced immunogenicity when introduced to humans. First, Abhinandan and Martin [15] developed the H-score, which calculates the average sequence identity of a given antibody sequence as compared to a small database of human variable region sequences. Using these data, however, the authors were unable to find a clear correlation between H-score and immunogenicity of a small set of therapeutic antibodies. Second, Pelat et al. [16] defined a germinality index that is the proportion of framework residues that are identical between a given antibody variable region sequence and the closest related human germline sequence. The score was used to analyze humanized forms of a macaque anthrax toxin antibody. Third, Thullier et al. [17] developed the G-score, which is similar to the H-score expect that the score attempts to classify which germline framework sequence the input antibody was originally derived from. The authors used this tool to study the humanness of multiple macaque antibody sequences.
The germinality index only compares sequences to a single germline sequence, and the databases for the H-score and G-score were composed of a small set of ~3,500 antibody sequences. Further, after assigning H-scores to a set of mouse antibody sequences, nearly all mouse heavy chain sequences scored in the same range as human heavy chain sequences, and more than half of the mouse light chains scored in the same range as human light chain sequences [15]. If an antibody humanness scoring method is unable to clearly distinguish a human and mouse sequence, it is not possible to definitely state how human a given sequence really is by these scoring methods. Here we have developed a new tool to determine the humanness of antibody variable region sequences, termed the T20 score analyzer. After refining the input antibody databases, we found that the T20 score can clearly separate human sequences from mouse sequences and many other species as well. The T20 score was used to conduct a thorough analysis of a large set of therapeutic antibodies, revealing surprising similarities between human-like humanized antibodies and fully human antibodies. The T20 score analyzer is available for free use online: http://abAnalyzer.lakepharma.com.
T20 score analyzer development
First, we curated a large database of ~38,700 human antibody variable region sequences in order to develop a new tool to analyze human antibody variable region sequences. The variable region sequence of antibody sequences were numbered using the Kabat numbering system [18] and the CDR and framework regions were annotated. Sequences for variable heavy chain (VH), variable kappa light chain (VK), and variable lambda light chain (VL) were stored as full-length sequences or as framework only sequences (where the CDR regions were removed from the sequences) to obtain the All Human Databases (Figure 1A). Starting with a single input variable region antibody sequence (either full-length or framework only VH, VK, or VL), protein BLAST [19] was performed against all sequences in the respective database. Following BLAST the matching sequences were sorted from high to low based on the percent identity with the input sequence. The percent identity of the Top 20 matched sequences were averaged to obtain the T20 Score (Figure 1B), where the T20 score is a measurement of how human-like the variable region of an antibody looks, with 100 being the highest possible score; most antibodies analyzed with this method scored at least 40. When the T20 score was obtained for each sequence from the curated All Human Databases and then the scores were sorted from high to low, a relatively normal distribution was observed for both full-length and framework only sequences (Figure 2A, Additional file 1: Figure S1A).
T20 analyzer development. (A) Antibody sequence curation. Variable region protein sequences had Kabat numbering applied and the CDR regions identified. Variable heavy chain (VH), variable light kappa chain (VK), and variable light lambda chain (VL) sequences were curated into databases as full-length sequences or framework-only sequences (where the CDR regions were removed). The number of unique antibody sequences in each database is shown. (B) Defining the T20 score. Protein BLAST is used to determine the sequence identity of an input sequence with each database sequence. The percent identities of the Top 20 matched sequences are averaged to obtain the T20 score for a given input sequence. (C) Left: Details of obtaining the T20 Cutoff Human Databases. Right: Histogram of the T20 scores of a sample set of antibody sequences, indicating the T20 score cutoff and the 15% of sequences below this cutoff that were removed to form the T20 Cutoff Human Database for each chain type. The number of unique antibody sequences in each database is shown.
T20 scores distinguish human and mouse antibody variable region sequences. (A) T20 scores using All Human Databases. Shown are histograms of the T20 scores for large sets of human or mouse antibody sequences of the indicated chain type. The T20 score cutoff for each antibody chain is indicated by the dashed line. (B) Comparing scores using T20 All Human and Cutoff Human Databases. Shown are histograms of the T20 scores for the same set of human or mouse antibody sequences scored with the indicated database. Note that the human sequences with scores below the T20 score were removed from these graphs. The percent of mouse antibodies sequences scored with the T20 Cutoff Human Database that are above the T20 cutoff is provided on the right.
An antibody humanness score should possess the ability to distinguish human antibody sequences from other species' antibody sequences, such as mouse, with high specificity. To determine the ability of the T20 score to differentiate human antibody sequences from mouse, we scored thousands of mouse antibody sequences with the T20 score analyzer using the All Human Databases (Figure 2A, Additional file 1: Figure S1A). Most of the scores for human and mouse sequences had clear separation; however some amount of overlap remained between human and mouse VH and VK sequences. One potential reason to explain why many of the mouse sequences are scoring higher T20 scores is due to their similarity with the human sequences that had the lowest T20 scores, i.e. the mouse sequences could be similar to the human sequences that looked the least human-like. If this was correct, we predicted that if the least human-like sequences were removed from the database and the mouse sequences were re-scored, this would create a clearer separation between mouse and human sequences. To test this, we removed the bottom 15% of human sequences from each database to obtain T20 Cutoff Human Databases (Figure 1C). This created a T20 score cutoff, which is the T20 score where sequences above this cutoff are considered human-like. We then re-scored the mouse sequences using the T20 Cutoff Human Databases and found a striking reduction in the T20 scores for the full-length and framework only mouse sequences, with minimal overlap between human and mouse sequences (Figure 2B, Additional file 1: Figure S1B). Importantly, despite removing many human sequences from the databases, re-scoring all human sequences with the refined databases lead to very little change in their T20 scores (Additional file 2: Figure S2). Therefore by developing a humanness analysis tool that focused on the top 85% of human antibody sequences, we were able to clearly separate human and mouse antibody sequences with excellent specificity, and defined human-like sequences as those scoring above the T20 score cutoff. From here on, the T20 score only refers to sequences scored with the T20 Cutoff Human Databases.
T20 score analysis of a collection of antibody sequences
To determine the reproducibility of the T20 score distinguishing most human and mouse sequences based on their variable region sequences, an independent set of human and mouse antibodies were evaluated. For both full-length sequences (Figure 3A-C) and framework only sequences (Figure 3D-F), the T20 score was able to accurately classify the vast majority of human sequences as human-like and most if not all mouse sequences as not human-like. This validated the T20 score as a reproducible method to classify the humanness of an antibody sequence with high specificity.
T20 scores of a collection of antibody sequences. T20 scores were obtained for each listed group of antibodies for the indicated chain type for full-length antibody sequences (A-C) or framework only antibody sequences (D-F). Individual antibody sequences are shown as small circles, and the average ± SD T20 score is shown for each group. The percent of antibody sequences with T20 scores above their respective T20 score cutoff (indicated by the dashed line) is provided below each graph. The antibody groups with 85% or more of the sequences above the cutoff (i.e. they are mostly human-like) are indicated by the blue text. Groups with dashes for the percent value did not have any sequences represented by the particular chain.
We next analyzed the variable regions of human and mouse germline sequences, and while there was some variability depending on the chain type being analyzed, in general the T20 score accurately classified the human germline sequences as having high T20 scores with the mouse germline sequences having scores mostly below the human-like T20 score cutoff; similar trends were seen for both full-length and framework only germline sequences (Figure 3). We further found that human antibodies produced in mice that were transgenic for human IgG genes [20–22] produced human antibodies with high T20 scores that were similar to germline sequences. By this metric these human antibodies from mice were indistinguishable from fully human antibodies. Overall, these data further validate the T20 score as a means to consistently and accurately classify antibody sequences as human-like or not.
To determine the humanness of antibody sequences from other species, T20 scores were calculated for full-length and framework only sequences for 12 additional species ranging from fish to non-human primates (Figure 3). Generally, the non-human primate antibody sequences had high T20 scores and thus many of them are difficult to distinguish from human sequences, with the Rhesus macaque and Chimpanzee having the highest scores. Fish sequences showed the lowest T20 scores, while mammals and amphibians were somewhere in between. No antibody sequences from non-primates besides mice and rats looked human-like (Figure 3).
The humanness of therapeutic antibodies
We curated a set of 98 mouse, chimeric (from mouse), humanized, and fully human antibody sequences that are either approved for clinical use or in various stages of clinical development. We only focused on antibodies with kappa light chain sequences since very few therapeutic antibodies had lambda light chains. We first determined how well the T20 score could detect changes in the variable region sequence of therapeutic antibodies that underwent humanization. Of 22 antibody pairs analyzed, only the light chain of one sequence showed no change in the T20 score while all others showed an increase in their T20 scores upon humanization (Figure 4A). Interestingly, for the full-length sequences after humanization, half of the antibody sequences looked human-like, despite the inclusion of non-human sequences in the CDRs and framework regions. For the framework only sequences, nearly all humanized antibodies had framework sequences that looked human-like. This was generally expected since human germline framework sequences are typically utilized as donor sequences for the humanization process [10], and most germline sequences have very high T20 scores (Figure 3D-E).
Humanness of therapeutic antibodies. (A) T20 scores are shown for the indicated chain type for 22 therapeutic mouse antibodies that underwent humanization. Each circle is one antibody, and the lines connect a mouse antibody with its respective humanized antibody. The T20 score cutoff is indicated by the dashed line. (B- E) Shown are the T20 score (top), H-score (middle), and G-score (bottom) of 98 heavy chain full-length (B) and kappa light chain full-length (C) sequences for mouse, chimeric, humanized, and fully human therapeutic antibodies. Note that the H-score and G-score are scaled based on Z-scores. The T20 score of heavy chain framework only (D) and kappa light chain framework only (E) sequences are presented. Each antibody is a circle, and the average ± SD T20 score is provided for each group. The T20 score cutoff is indicated by the dashed line. Select groups of antibodies were compared using Student's t-tests, and the P-values of significance are listed for each comparison.
We next calculated the average T20 score for each type of therapeutic antibody. As anticipated the humanness of mouse and chimeric antibodies were nearly identical for both full-length and framework only sequences (Figure 4B-E). For full-length sequences, the humanness of humanized heavy and light chain sequences increased strongly, and the T20 score analyzer was sensitive enough to detect a further significant increase in the humanness of fully human antibodies (Figure 4B-C). In contrast for framework only sequences, the humanness of both humanized and human sequences were very similar (Figure 4D-E).
To compare the effectiveness of the T20 score to classify the humanness of antibodies as compared to other antibody humanness scoring tools, we determined the H-score [15] and G-score [17] for the 98 therapeutic antibodies. When the T20 score and H-score or G-score were directly compared for the same antibody sequences, the scores were positively correlated for both heavy and light chain sequences (P<10-20 for each comparison; Additional file 3: Figure S3). Despite the positive correlation with the T20 score, the H-score and G-score were unable to separate the humanness of the therapeutic antibody groups as well as the T20 score (Figure 4B-C). In particular the differences between mouse/chimeric and humanized or human antibodies, and the differences between humanized and human sequences, were much less significant with the H-score or G-score as compared to the T20 score. And although the average H-score and G-score for human antibodies were trending higher than humanized antibodies, when individual sequences were analyzed separate from their group, these scoring methods were not able to clearly distinguish most of the humanized antibodies from fully human antibodies to the same extent as the T20 score (Figure 4B-C). These data reveal that the T20 score is more reliable at classifying antibodies as human-like with better specificity than alternative antibody humanness analysis tools.
Correlation of humanness and immunogenicity of therapeutic antibodies
Of the 98 therapeutic antibodies curated above, 65 of them had available data on the antibody immunogenicity from human clinical trials ([11, 23, 24] and references within). When the T20 scores of all therapeutic antibodies were directly compared to their immunogenicity, there was a clear negative correlation for both full-length and framework only sequences: the higher the T20 score, the lower the immunogenicity of the antibody (Figure 5A, Additional file 4: Figure S4A). When these antibodies were separated into the respective antibody class, specific patterns emerged that were similar for full-length and framework only, heavy and light chain sequences. Although mouse and chimeric antibodies had similar T20 scores, on average there was a strong decrease in the immunogenicity of chimeric antibodies compared to mouse (Figure 5B-C, Additional file 4: Figure S4B-C). A further increase in T20 score seen with humanized antibodies resulted in a further drop in the immunogenicity. And although fully human antibodies have an even further increase in T20 score for full-length antibody sequences compared to humanized antibodies, there was little subsequent decrease in their immunogenicity (Figure 5B-C). One exception was the humanized antibody daclizumab that had a strong immunogenic response in 24% of patients (antibody indicated by the arrow in Figure 5B); when this antibody was removed from the analysis, the minor difference in the immunogenicity of humanized and human antibodies disappeared (Additional file 5: Figure S5). These data suggest that because the immunogenicity of humanized and fully human antibodies are nearly identical, with minor exceptions, there may not be an extra benefit of obtaining fully human therapeutic antibodies as long as the humanized antibody has a higher T20 score than its mouse/chimeric parental sequence.
Associating immunogenicity and humanness score of therapeutic antibodies. (A) The immunogenicity (percent of patients that had antibodies against the therapeutic antibody itself) and T20 score of 65 therapeutic antibodies (full-length heavy chains on the left, kappa light chains on the right) were graphed together, and Pearson correlations were calculated (red-dashed line; R2). P-values are one-sided t-tests. (B) The same data from (A) is shown with the antibody type indicated by different colors. Trend lines for each group are shown in their respective color. The arrow points to the humanized antibody daclizumab that is referenced in the main text. (C) The black bars are the average ± SD immunogenicity of the indicated group of antibodies; the gray bars show the average ± SD T20 score.
The benefit of performing antibody humanization was further evidenced by following the humanness and immunogenicity of therapeutic antibodies prior to and after humanization. Within our curated therapeutic antibody database, there were three mouse antibodies that underwent humanization and were included in clinical trials as both mouse and humanized antibodies. All three mouse antibodies initially had high levels of immunogenicity with low T20 scores (Figure 6). The humanness of the antibody heavy and light chain sequences increased following humanization, and this increase correlated with a shift to no detectable immunogenicity in all three cases, underscoring the critical importance of performing antibody humanization prior to conducting clinical trials. The data suggest that the framework only T20 score of the humanized heavy and light chains should be equal to or above the T20 score cutoff (i.e. they are human-like). In contrast, the full-length sequence appears to only need to increase its humanness T20 score, as it does not have to look human-like in order to benefit from antibody humanization and have similar immunogenic properties as a fully human antibody. Therefore quantifying the humanness of therapeutic antibody sequences with the T20 score analyzer is a powerful tool that can be a valuable asset during the antibody drug development process.
Immunogenicity of therapeutic antibodies before and after humanization. The immunogenicity and T20 score of three mouse therapeutic antibodies before and after humanization are shown for the indicated chain type. The arrows show the change in immunogenicity and T20 score of the mouse antibody after humanization.
A critical issue with therapeutic antibodies in the clinic is reducing the potential immunogenicity of the final therapeutic form [23]. One of the more recent tactics to avoid possible immunogenicity issues is by using fully human antibodies, either produced in transgenic mice [22] or using phage display technology [25], which are often difficult processes compared to traditional monoclonal antibody development [4]. Data presented here revealed that despite a significant difference in the humanness of humanized and fully human antibody sequences, with minor exceptions the immunogenicity of the antibodies was nearly indistinguishable. This was shown in detail for three antibodies that started with high levels of immunogenicity as mouse antibodies, and after their humanization they became non-immunogenic antibodies; the decreased immunogenicity was correlated with an increase in the humanness score of both the heavy and light chains of each antibody. Therefore an additional mechanism to decrease the chance of a humanized antibody being immunogenic in humans is verifying that both the heavy and light chains of the humanized antibody have increased T20 scores over the parental sequence and are thus more human-like. While it is possible that humanized antibodies with lower T20 score will not be immunogenic in the clinic, in general non-human-like antibodies were associated with increased immunogenicity (Figure 5A).
The unique ability of the T20 score analyzer to specifically determine the humanness of the framework regions of an antibody sequence is especially useful when performing antibody humanization, where the CDR sequences are purposely left as parental sequences and only the framework region is transformed into a human-like sequence. For example, the humanness of an antibody framework sequence can be followed throughout the process of performing humanization, where each subsequent change to the framework region can be scored and tracked. Our own antibody humanization efforts revealed that despite the high T20 scores for most donor human germline framework sequences (Figure 3D), re-introducing specific parental framework sequences into a human germline sequence is sometimes sufficient to revert the T20 score of the humanized framework sequence to the same score as the initial parental framework sequence (Additional file 6: Figure S6). Since the T20 score analyzer would be simple to implement during the therapeutic antibody development process, it can be used to prevent antibody sequences with low humanness scores from progressing along the pipeline.
Other methods have been developed to predict antibody immunogenicity, such as experimentally screening molecules for antigen specific activation of T-cells or experimentally searching for T-cell epitopes followed by their removal through targeted substations [23, 26]. However these methods require a combination of in vitro experimentation in addition to in silico prediction tools. We propose that these complicated and time-consuming methods are not necessary since it appears that increasing the humanness of the variable region sequence is sufficient to remove most cases of immunogenicity, which can be directly monitored with the T20 score analyzer.
Researchers have utilized phage display technologies to express synthetic repertoires of antibodies that can be screened for binding to specific antigens [27–29]. During the screening process it would be useful to predict whether these synthetic antibodies would be immunogenic in humans or not, for example by utilizing the T20 score to analyze the sequences. We used the T20 score analyzer to determine the humanness score of a small set of synthetic antibodies and compared these to human antibodies. Surprisingly, the average and range of T20 scores observed for the variable regions of synthetic antibodies was very similar to human antibodies (Additional file 7: Figure S7). Due to the absence of immunogenicity data from synthetic antibodies, we were unable to directly correlate the T20 score of synthetic antibodies with immunogenicity. However since the T20 scores of synthetic and human antibodies are similar, we suggest that the T20 score may be able to predict the immunogenicity of synthetic antibodies to a similar extent as human antibodies.
Here we have developed the T20 score analyzer to calculate the humanness of variable region sequences of monoclonal antibodies with high specificity and reproducibility. In addition to providing a score for the full-length antibody sequence of heavy, kappa light, and lambda light chains, the tool can exclude the CDR regions to calculate a separate score focusing only on the framework regions. We used this tool to study therapeutic antibodies that have been approved for clinical use or are currently in clinical development. Of note we observed consistent decreases in the immunogenicity of antibodies that underwent humanization that resulted in increased T20 scores, suggesting that the T20 score may be used as a metric to determine whether an antibody has been truly humanized. We further found that the T20 score analyzer was better at assessing the differences in the humanness of therapeutic antibodies compared to previously published humanness scoring methods. This tool will be a valuable asset to accurately measure the humanness of the variable region of new therapeutic antibodies during their preclinical development.
Antibody variable region sequence curation
For the All Human Databases, antibody variable region protein sequences were obtained from NCBI IgBLAST (http://www.ncbi.nlm.nih.gov/igblast/retrieveig.html). Sequences were obtained and processed in high-throughput using scripts written in Python. Variable heavy chain (VH), kappa light chain (VK), and lambda light chain (VL) sequences were downloaded separately. Synthetic Ig molecules were excluded, and the minimum sequence length was set to 90 amino acids. Sequences were assigned Kabat numbering using the Abnum tool [30] and CDR residues were identified following the guidelines put forth by Kabat [18]. Sequences that Abnum was unable to assign the numbering scheme to were excluded from further analysis. Duplicate sequences were removed prior to forming the final databases, and sequences mislabeled as 'human' humanized antibodies or human antibodies obtained from transgenic mice were also excluded. In total 29,958 heavy chain sequences, 5,042 kappa light chain sequences, and 3,708 lambda light chain sequences were curated for the All Human Databases.
The mouse protein sequences used to validate the human databases were also obtained from NCBI IgBLAST and processed in the same way as the human sequences. In total 11,781 heavy chain sequences, 3,652 kappa light chain sequences, and 357 lambda light chain sequences were curated.
The human and mouse germline sequences were obtained from NCBI IgBLAST (http://www.ncbi.nlm.nih.gov/igblast/showGermline.cgi). Human antibodies from transgenic mice were selected from the human sequences downloaded from IgBLST described above based on the descriptions found in the NCBI protein database (http://www.ncbi.nlm.nih.gov/protein). The independent set of human and mouse antibody sequences were obtained from Abysis database (http://www.bioinf.org.uk/abysis); these were compared to the sequences in the All Human Databases to remove any overlapping sequences. The antibody sequences for the remaining species and synthetic antibodies were obtained from Abysis and/or NCBI protein database. Sequences for the therapeutic antibodies were obtained from United States patent applications (patft.uspto.gov) and the KEGG drug database (http://www.genome.jp/kegg/drug).
T20 score analyzer
An input VH, VK, or VL variable region protein sequence is first assigned Kabat numbering and CDR residues are identified. The full-length sequence or the framework only sequence (with CDR residues removed) is compared to every sequence in the respective antibody database using the blastp protein-protein BLAST algorithm [19]. The sequence identity between each pairwise comparison is isolated, and after every sequence in the database has been analyzed, the sequences are sorted from high to low based on the sequence identity to the input sequence. The percent identity of the Top 20 matched sequences is averaged to obtain the T20 score. The T20 score analyzer was coded entirely using Python.
Formation of T20 cutoff human databases
For each chain type (VH, VK, VL) and sequence length (full-length or framework only) in the All Human Databases, each antibody sequence was scored with its respective database using the T20 score analyzer. The T20 score was obtained for the top 20 matched sequences after the input sequence itself was excluded (the percent identity of sequences 2 through 21 were averaged since sequence 1 was always the input antibody itself). The T20 scores for each group were sorted from high to low. The decrease in score was roughly linear for most of the sequences; however the T20 scores for the bottom ~15% of antibodies started decreasing sharply. Therefore the bottom 15 percent of sequences were removed and the remaining sequences formed the T20 Cutoff Human Databases, where the T20 score cutoff indicates the lowest T20 score of a sequence in the new database. The exact number of antibody sequences in each database for full-length and framework only is provided in Figure 1C; note that the numbers are slightly different for full-length and framework only sequences since the T20 score cutoff was rounded to the nearest whole number closest to the bottom 15th percentile sequence. A web-based tool is provided to calculate the T20 score of antibody sequences using the T20 Cutoff Human Databases: http://abAnalyzer.lakepharma.com.
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Knappik A, Ge L, Honegger A, Pack P, Fischer M, Wellnhofer G, Hoess A, Wolle J, Pluckthun A, Virnekas B: Fully synthetic human combinatorial antibody libraries (HuCAL) based on modular consensus frameworks and CDRs randomized with trinucleotides. J Mol Biol. 2000, 296 (1): 57-86. 10.1006/jmbi.1999.3444.
Barbas CF, Bain JD, Hoekstra DM, Lerner RA: Semisynthetic combinatorial antibody libraries: a chemical solution to the diversity problem. Proc Natl Acad Sci USA. 1992, 89 (10): 4457-4461. 10.1073/pnas.89.10.4457.
Abhinandan KR, Martin AC: Analysis and improvements to Kabat and structurally correct numbering of antibody variable domains. Mol Immunol. 2008, 45 (14): 3832-3839. 10.1016/j.molimm.2008.05.022.
We thank Brian Zabel for comments on the manuscript. All authors were funded internally by LakePharma, Inc., which is a private corporation that receives no outside financing.
LakePharma, Inc., 530 Harbor Boulevard, Belmont, CA, 94002, USA
Sean H Gao, Kexin Huang, Hua Tu & Adam S Adler
Sean H Gao
Kexin Huang
Hua Tu
Adam S Adler
Correspondence to Adam S Adler.
All authors are employees of LakePharma, Inc.
SG curated the antibody databases, co-developed the T20 score analyzer, and calculated the T20 scores for all antibodies in the databases. KH assisted with the design of the T20 score analyzer. HT conceived of the study and provided guidance on the development of the T20 score analyzer. AA co-developed the T20 score analyzer, performed all analyses on the therapeutic antibodies, prepared the figures, and wrote the manuscript. All authors read and approved the manuscript.
Additional file 1: Figure S1: T20 scores distinguish human and mouse antibody framework sequences. T20 scores using All Human Databases. Shown are histograms of the T20 scores for large sets of human or mouse antibody sequences of the indicated chain type. The T20 score cutoff for each antibody chain is indicated by the dashed line. (B) Comparing scores using T20 All Human and Cutoff Human Databases. Shown are histograms of the T20 scores for the same set of human or mouse antibody sequences scored with the indicated database. Note that the human sequences with scores below the T20 score were removed from these graphs. The percent of mouse antibodies sequences scored with the T20 Cutoff Human Database that are above the T20 cutoff is provided on the right. (PDF 126 KB)
Additional file 2: Figure S2: Comparing human sequences with All Human and T20 Cutoff Human Databases. Shown are histograms of the T20 scores for all human antibody sequences of the indicated chain type comparing the scores obtained using the indicated scoring database. Human sequences were separated into two groups, either above (red) or below (green) the T20 score cutoff using the All Human Databases. Each of the two groups of sequences was then scored with the T20 Cutoff Human Database, and the change in the T20 scores is shown separately for the sequences above (purple) or below (blue) the T20 score cutoff. (PDF 106 KB)
Additional file 3: Figure S3: Comparison of T20 score with H-score and G-score. T20 scores, H-scores, and G-scores were obtained for 98 heavy chain full-length (top) and kappa light chain full-length (bottom) therapeutic antibody sequences. Note that the H-score and G-score are scaled based on Z-scores. T20 scores were directly compared to H-scores (left) or G-scores (right), and Pearson correlations were calculated (red-dashed line; R2). P-values are one-sided t-tests. (PDF 99 KB)
Additional file 4: Figure S4: Associating immunogenicity and humanness score of therapeutic antibodies. The immunogenicity and T20 score of 65 therapeutic antibodies (framework only heavy chains on the left, kappa light chains on the right) were graphed together, and Pearson correlations were calculated (red-dashed line; R2). P-values are one-sided t-tests. (B) The same data from (A) is shown, with the antibody type indicated by different colors. Trend lines for each group are shown in their respective color. (C) The black bars are the average ± SD immunogenicity of the indicated group of antibodies; the gray bars show the average ± SD T20 score. (PDF 101 KB)
Additional file 5: Figure S5: No difference in immunogenicity of humanized and human antibodies after removing daclizumab. The black bars are the average ± SD immunogenicity of all human and humanized antibodies; the gray bars show the average ± SD immunogenicity of all human antibodies and humanized antibodies without daclizumab. (PDF 69 KB)
Additional file 6: Figure S6: Humanization of germline frameworks can revert the humanness of sequences back to the level of the parental antibody. Shown are the T20 scores of a heavy chain antibody that was humanized utilizing donor human germline framework sequences. The parental antibody sequence and three humanized versions with increasing number of re-introduced parental framework amino acids are shown. Note that the humanized version 3 sequence that contains the most parental framework sequence has identical T20 score to the parental sequence, despite the fact that the majority of the humanized sequence is still the human framework sequence. (PDF 69 KB)
Additional file 7: Figure S7: No difference in T20 score of human antibodies and synthetic antibodies. T20 scores were obtained for each listed group of antibodies for the indicated chain type for full-length antibody sequences. Individual antibody sequences are shown as small circles, and the average ± SD T20 score is shown for each group. (PDF 120 KB)
Gao, S.H., Huang, K., Tu, H. et al. Monoclonal antibody humanness score and its applications. BMC Biotechnol 13, 55 (2013). https://doi.org/10.1186/1472-6750-13-55
Therapeutic antibody
Humanization
Immunogenicity
Proteomics and drug discovery


When it comes to making money online, several controversies have come up from the different online communities, forums, discussion groups, social media as well as in blog comments. While some people are making hundreds of thousands of dollars daily promoting affiliate companies, others are busy doing all kinds of slavery jobs which pay a few cents per day such as forum posting jobs, get paid to read emails, get paid to click Ads and all of that.
Are those slavery jobs really worth your time? Can you afford to continue serving others when you can actually serve yourself? For instance, when a platform offers a forum posting job at the pay rate of $0.05 per post and the maximum number of posts to be made per day for each user is 10-20, how much would that kind of a job not be referred to as a slavery job?
If we do some simple Mathematics here, we'll find that the highest earner in any day can only earn $0.05 X 20 which is $1 per day, that is, $30 a month and the lowest earner among the users can only make $0.05 X 10 which is $0.5 a day, that is, $15 a month. I hope my readers would reason along with me that such jobs are nothing but slavery jobs.
If all Jon Morrow was doing online is such a forum posting job alone, I'm sure he wouldn't be making the hundreds of dollars that he's currently making from his personal blog monthly. He might have done such a job long ago or when he was still a struggling veteran blogger looking for ways to earn extra revenue alongside building a blog. It's normal for a newber blogger who is just starting out with a brand-new blog.
What about Arianna Huffington; the top richest blogger in the online world who earns more than $10, 000, 000 revenue every month from the millions of traffic hits that he generates monthly with his blog?
Literally speaking, the online money making opportunities are meant for only those who really want to make money online. I'm talking about only those who are action takers; the categories of people who can work hours daily building an online empire.
The most important thing about building an online business is having the right mindset which is tailored towards doing it the right way. Then, being able to recognize your audiences is another vital area in which you can establish a successful online business. Once you can recognize your target audiences, you'll run a successful business as they'll always be on the lookout to learn and buy from you at one time or the other.
The only way you can frustrate your business is when you don't have good, reliable and highly-rated products to promote. These are things many people are so meticulous about.
In today's publication, I'll show you some key strategies for making money in the online world.
Aside from using an integrated niche and keyword research tool like Jaaxy, you can also conduct a research for your intended niche any time using an affiliate marketing network like Shareasale, Commission and all of that.
On Commission Junction, for example, there's a Network Settings option for you to search for the niche-related affiliate products that you want to promote on your blog. Through the Network Settings option, you'll also find that each of the affiliate merchants listed shows their specific earning potentials.
Having searched and selected which niche product to promote, you're almost about to start making money promoting laudable products. Henceforth, you're free to search for the right niche product to sell based on the earning potentials found.
Brainstorm and find out the trending products which other affiliate marketers have regarded as hot selling products.
Conduct a market research to see if it's a hot selling product. You can probably make your searches by using the search volume on Jaaxy.
Go ahead and sell only the products that you've verified to be hot selling and highly-demanding products.
When it comes to making money online, it's not about how brilliant or resourceful you are but how smart. If you're not smart enough, you can't make money online. Try to introduce something that no one usually offers elsewhere and make sure it's something everybody needs.
Stand Out From the Crowd: You need to stand out as an expert in the affiliate marketing industry and in your niche. Once you've become an expert, you'll discover that a lot of people will look for whatever product you're promoting, believing in your personality and authority.
Write some high-quality and useful content based on the niche product: The antidote for standing out from the crowd on time comes out with something that has not yet been done by others. No matter how hurriedly most readers are while visiting blogs, present to them what will naturally make them stay and spend some quality time at your site before clicking away.
Help other people passionately by responding to their inquiries and let them practice whatever they've leanred so far. If you can continue to be unique and consistent, there's no time you won't stand out from the crowd.
Your trust flow and trust metrics will continue to increase so far you can keep at what you've been doing to build authority in the online world.
Do you really want to make more money online? Would you desire to start pulling the crowd with lots of strategies? Then, pay particular attention to the winners among your potential readers.
Finding out which of the posts on your blog is/are ranking well.
Winners in blog posts: Google Analytics is the best online tool to leverage when it comes to finding out which of the posts on your blog is producing the best in conversions.
Winners in digital products: Since you have a list of affiliate products you promote on your blog, always find out to know which of these products is converting the most. This will simply show the winner(s) from the product list. Try to figure out the reason such a product is converting more than others.
Having figured out the winner(s) from the products listed on your blog, create a compelling article that will boost traffic.
Winners in direct, referral, organic and social traffic: Visit Google Analytics, click on the "overview" tab and browse every other page to check what percentage of the site visitors comes from direct, referral, organic, or social traffic. Use the tool to control your traffic and minimize the bounce rate to improve your Google PageRank.
Nice article . Enjoyed the content and learnt that is important to pay attention to Google analytics to see which readers are coming to your site. I have a site similar to yours on Affiliate Marketing and sometime is just surprises to see what articles are being read that I put on my site. It would be helpful if you could show one practical example with screen shots of google analytics of this process. Otherwise enjoyed the content and will be on the look out for future articles from your site.


50 Cent clearly isn't sweating the post-bankruptcy life. In fact, 50 was kind enough to show fans and haters alike how to live reasonably large on a budget in a hilarious MTV Cribs parody aptly dubbed In Da Hostel. In just under three minutes, the G-Unit leader takes curious minds on a jovial tour of his budget-friendly spread at a hostel in Barcelona. Okay, okay, so it's not technically his budget-friendly spread, as the clip serves as an ad for the online booking company Hostelworld, but it's still funny to see 50 going along with it.
50 gave MTV a tour of of his non-hostel living quarters in Connecticut back in 2007, a clip more than worth a revisit in light of recent events (and this top-shelf parody).
All jokes aside, 50 filing for bankruptcy in 2015 in no way means dude is actually broke. Though he admitted to flexing with fake cash on Instagram, 50 will ultimately be just fine. Robert Gregg, president of Mainline Partners in Brooklyn, broke down what exactly goes down in a Chapter 11 filing for us last summer. "Look at Donald Trump," Gregg told Complex. "I think Donald filed for bankruptcy on multiple occasions. It's not because the person has no money so to speak. A lot of times they may have entered into an agreement which at the present moment may not be favorable."
As long as In Da Hostel actually becomes a real TV series, no complaints here.


They're showing as my old computer with an XP Home Edition. System is extremely thinking of with my old celeron. I dont know I would recommend you search it will start.
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You can get re-formatted HDD, re- replacing my failing C: drive with two drives RAID'ed together. So I copied the dri board, it saves aiglx upgrading the cpu. Thanks for you help some problem with playing game CMOS sometimes.


CHEYENNE, Wyo. — A 76-year-old Colorado woman led Wyoming police on an interstate highway pursuit that exceeded 100 mph at times before her vehicle was disabled by tire spikes.
The Wyoming Highway Patrol says the incident started about 12:25 p.m. Thursday when a trooper clocked a vehicle traveling 96 mph in an 80 mph zone on Interstate 25 near Kaycee.
The vehicle did not stop and eventually merged onto eastbound I-90 where police deployed the spikes.
No one was hurt, and the elderly woman was taken into custody without incident. She was preliminarily charged with reckless driving and eluding a police officer.


TC Electronic Flashback x4 is a great delay/looper but its looper functionality could have been a bit better. For instance there is a one shot switch that does not retrigger the loop when you press, just makes it stop once it reaches the end. People are hoping that these issues can be taken care off in the next firmware update but doesnt look like it.
So, my question would be if it is technically possible to alter the firmware so as to make it work as someone would desire. If people hack iPhones why not this? Having no knowledge at all on this I decompiled the FW file but could not make much out of it.


text:
ADEA/ADEA Council of Students, Residents and Fellows/Colgate-Palmolive Co. Junior Faculty Award
ADEA/Colgate-Palmolive Co. Allied Dental Educators Fellowship
ADEA/Colgate-Palmolive Co. Excellence in Teaching Award
ADEA Enid A. Neidle Scholar-in-Residence Program
ADEA Faculty of Color Tuition Scholarships for Professional Development
ADEA Leadership Institute Alumni Association Award to Honor Jack Bresch
ADEA Leadership Institute Phase V Leadership Development Tuition Scholarship
Home | ADEA Scholarships, Awards and Fellowships | For Faculty
The American Dental Education Association (ADEA), the ADEA Council of Students, Residents and Fellows (ADEA COSRF) and Colgate-Palmolive Co. wish to recognize outstanding junior faculty who demonstrate excellence in teaching, research and service and a commitment to dental education.
Junior faculty represent a unique group of educators who symbolize the future of dental education. Often, the contributions made by these faculty go unnoticed, influencing faculty retention. It is anticipated that this award will acknowledge the accomplishments of junior faculty and promote awareness of the needs of this distinct group of educators.
The recipient will receive a $2,500 award to be used to enhance his or her teaching, research and service efforts. The stipend will also be used for travel to the 2020 ADEA Annual Session & Exhibition in National Harbor, MD, March 14-17, 2020.
Applicants are to be initially identified and recognized within individual institutions or programs of dental education. Ideally, identification and recognition of candidates will be coordinated by the local ADEA Chapter. If an ADEA Chapter does not exist, it is recommended that the institution either establish a Junior Faculty Award nomination review committee (comprised of ADEA COSRF representative(s), ADEA Council of Faculties or ADEA Council of Allied Dental Program Directors representatives, and the dean) or convene an existing committee that includes a student representative.
The final selection will be made by a national selection committee comprised of representatives from the ADEA Council of Students, Residents, and Fellows, the ADEA Council of Faculties, the ADEA Council of Deans and an officer of the ADEA Board of Directors and the ADEA President and CEO (ex officio).
An applicant must:
Demonstrate excellence in teaching, research or service.
Have held a full-time predoctoral or advanced dental education faculty appointment at an ADEA Member Institution for no more than five years.
Have no more than five years of experience in academia.
Be an ADEA Individual Member.
All applications must be postmarked by Dec. 9, 2019. Applications will be returned if they are either incomplete or postmarked after Dec. 9, 2019.
Application Process Checklist
Submit five copies of the following documents postmarked by Dec. 9, 2019:
The completed ADEA Awards, Scholarships and Fellowships Application form.
A letter of nomination from the institution's ADEA COSRF representative detailing the applicant's contribution to teaching, research or service.
A letter of nomination from the chair of the institution's Junior Faculty Award nomination committee (or existing committee that includes a student representative) or department chair.
A personal statement from the applicant describing his or her philosophy of teaching, research or service; his or her contributions to the tripartite mission of the dental school; and how the award will be used to improve methods.
A curriculum vitae.
The dental school dean's signature on the application.
Incomplete applications will not be reviewed.
Submit applications to:
ADEA Access, Diversity and Inclusion
Attn: Angelo Lee
655 K Street NW, Suite 800
Notification Date and Award Announcement
The award recipient will be notified by February 14, 2020.
An award and commemorative certificate will be presented to the award recipient at the 2020 ADEA Annual Session & Exhibition in National Harbor, MD, March 14-17, 2020.
Please contact Angelo Lee at 202-289-7201, ext. 112, with any questions.
Dr. Faizan Kabani, Texas A&M College of Dentistry, Caruth School of Dental Hygiene
Dr. Edmund Khoo, New York University College of Dentistry
Dr. Jennifer Perkins, University of California, San Francisco School of Dentistry
Dr. Georgios Maroulakos, Marquette University School of Dentistry
Dr. Amy C. Killeen, University of Nebraska Medical Center College of Dentistry
Dr. Anita Joy, Southern Illinois University
Dr. Jompobe Vuthiganon, Medical University of South Carolina
Dr. Sophia Saeed, University of California, San Francisco
Dr. Berna Saglik, University of Michigan
Dr. Natasha Flake, University of Washington
Dr. Lee Warren Boushell, University of North Carolina at Chapel Hill
Dr. Paul S. Tiwana, University of Louisville
Dr. Sharon Lanning, Virginia Commonwealth University
Dr. Susan Hyde, University of California, San Francisco
Dr. Swee-Chian Tan, University of Iowa
Dr. Andres Pinto, University of Pennsylvania
Critical Thinking and Assessment

redpajama_set_name: RedPajamaCommonCrawl


text:
The Fight for the First U.S. Olympics | The Home Stretch | 3
04 Aug The Fight for the First U.S. Olympics | The Home Stretch | 3
In the summer of 1904, the young women of the Fort Shaw Indian School basketball team took the St. Louis Olympics and the World's Fair by storm with their fast-paced, dynamic play. But could they keep their undefeated record and win the world championship against their toughest opponent yet — a team of white all-stars from the best high school team in Missouri?
As the Fort Shaw girls prepared for their championship game, another Olympics drama unfolded: the marathon. Covering 25 miles of steep hills and dusty dirt roads, it would be the ultimate test of athletic endurance. But for some runners, it would nearly end in disaster.
Better Help – Get 10% off your first month at betterhelp.com/tellers.


text:
Song: Working On Me
Artist: mmeadows
Press Play: Ghost Beach
/By David Prock
Ghost Beach is a unique electronic music duo comprised of Josh Ocean and Eric Mendelsohn. They incorporate soaring synths, guitars and harmonies which are heavily inspired by 80's music. In fact, Mendelsohn admits that the group greatly enjoys writing pop music even though the sound that is coming out may be different. Their first full length album called Blonde was just released in early March and it is an upbeat, exciting, and fun project from beginning to end.
Their name, Ghost Beach, is actually taken from the popular children's book series called Goosebumps. The Brooklyn, NY based duo just got done playing in the well-known South By Southwest Music Festival. They have also performed with artists like David Guetta, Vampire Weekend, Imagine Dragons, and even Robin Thicke. Be on the lookout for this duo to do big things in the music industry very soon.


Do you want your people to be trained in working at height? Height Specialists has the experienced trainers, facilities and resources to train your people practically. Our certified rope access trainers have been active in the field on a weekly basis for almost 25 years. They take practical examples with them during the training and this ensures greater safety awareness among our participants. Check out the possibilities!


Assemble at Changi International Airport. Have a pleasant flight to Rome - Italy.
Interlaken Walking Orientation - Tour Situated at the base of the Jungfrau Mountains between Lake Brienz and Lake Thun.
Enjoy scenic drive to Paris.
Fragonard Perfumery Museum – Private museum presents the secrets of their fragrances and history of perfume making in Grasse, Eze and Paris.


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The Ravens aren't interested in revisiting their playoff loss to Tennessee: 'It doesn't matter'
Jonas Shaffer, The Baltimore Sun
It's only Monday, and the Ravens have already tired of questions about that Tennessee Titans playoff game.
No, not this weekend's wild-card-round matchup in Nashville. The other one — the divisional-round game from last January, when the Titans crushed the top-seeded Ravens' Super Bowl dreams in Baltimore.
Minutes after clinching a third straight postseason appearance with a dominant win Sunday over the Cincinnati Bengals, Ravens players were asked for their feelings on a potential rematch with Tennessee, which was considered the front-runner for the AFC's No. 4 seed.
Said safety Chuck Clark: "It doesn't matter. We're trying to line up with whoever we got. We're trying to go get the job done."
And quarterback Lamar Jackson: "It really doesn't matter, but I'll be grateful for whoever we play. I'm just happy we made the playoffs."
And outside linebacker Matthew Judon: "If we have to go to Tennessee, [or] if we have to go to upstate New York, it doesn't matter. It doesn't matter. We just have to win."
A few hours later, Titans kicker Sam Sloman hit a 37-yard, game-winning field-goal attempt as time expired, clinching the AFC South title and setting up yet another rematch with the fifth-seeded Ravens. Sunday's showdown will be the third meeting in less than a year; in Week 11, Tennessee overcame an 11-point third-quarter deficit in Baltimore, and star running back Derrick Henry sealed a 30-24 overtime win with a 29-yard touchdown run.
Asked Monday whether there was a "revenge factor" for his players, coach John Harbaugh said the team is "just focused on the game."
"Previous games really have little bearing. We've played them many times over the years," Harbaugh said. He mentioned how, on the bus ride back from Sunday's win in Cincinnati, general manager and executive vice president Eric DeCosta had discussed the teams' postseason history. The Ravens won in Tennessee in the 2000 and 2006 playoffs, and lost to the Titans at home in 2003.
"There's just been a lot of games over the years," Harbaugh continued. "It's got some history, the rivalry does, sure. But what impact does any of that have on the next game? We just have to go play our best game of the year. That's what we're preparing to try to do."
Which means looking at film from last season's playoff game, and this season's regular-season game, and a lot of other Titans games. The Ravens are preparing for the Tennessee team they'll face in the playoffs Sunday, Harbaugh said. It's too late to change what happened between them a year ago.
"You try to put it together and try to form a plan to attack the team that they are right now," Harbaugh said. "That's the main thing, who they're playing with and what they're doing."
Wild-card round
RAVENS@TITANS
Sunday, 1 p.m.
TV: Chs. 2, 7, ESPN
Radio: 97.9 FM, 1090 AM
Uganda election: Bobi Wine 'fearful for life' after Museveni win
The main opposition candidate rejects the result that saw President Museveni win a sixth term.
Hancock to lead press conference at 5pm PM hails milestone as 5m more offered jab Exclusive: Mass testing of entire regions considered Almost a third of recovered patients return to hospital One Covid patient admitted to hospital 'every 30 seconds' Resistance over plans for 24/7 vaccine drive Travel latest: UK's tough new border rules come into force Subscribe to The Telegraph for a month-long free trial Teachers, police officers and retail staff who cannot work from home "should be prioritised" in the second phase of the vaccine rollout, the Vaccines Minister has suggested. Speaking to ITV this morning, Nadhim Zahawi said there is a justification for certain occupations to be prioritised as the vaccination programme develops. He added that the Government will work with the Joint Committee on Vaccination and Immunisation as they set up an allocation framework. "My instinct is that anyone who, through no fault of their own, has to come into contact with the virus in much greater volume and probability should be protected - teachers, policemen and women, shop workers, all those who need that additional protection," he said. "Now, some of them will be captured in the top nine categories anyway if they are clinically vulnerable, for example, or in that age group of the over-50s which are in category nine, effectively. "But phase two - of course we'll be guided by the JCVI - but my instinct is that if you work in a job, a shop worker, policemen or women, any other profession which brings you into contact with the virus unfairly, then I think you should be prioritised." This week jabs will be offered to millions of over 70s and the clinically extremely vulnerable as the vaccination rollout gathers pace. Plans are also in place to begin pilots for 24/7 vaccination centres before the end of the month, Mr Zahawi said. Follow the latest updates below.
Two private hospitals in Thailand have ordered millions of doses of coronavirus vaccines ahead of regulatory approval, adding to government orders of vaccines as the Southeast Asian country tackles a second wave of the virus. "We ordered one million doses of the Sinovac vaccine with an option to buy nine million more," Boon Vanasin, the chairman of Thonburi Healthcare Group Pcl, told Reuters.
A man who did prison time for aggravated stalking and has convictions for domestic violence and violating a restraining order has an 18-year-old girl he has kidnapped at gunpoint, Pembroke Pines police said.


text:
package com.geth1b.coding.skills.lc;

import java.util.ArrayList;
import java.util.List;

/**
 *  [Reference URL]:  https://leetcode.com/problems/restore-ip-addresses/
 *      [Algorithm]:  Backtracking
 * [Data Structure]:  Array / String
 *      [Time BigO]:  O(1) - fixed input
 *     [Space BigO]:  O(1) - fixed input
 *
 * @author geth1b
 */
public class _093_RestoreIpAddresses {

  // Backtracking - '0' is valid; '010' is *invalid*
  // O(1) time - 3^4; almost constant; length is bounded too
  // O(1) space - at most 4 recursive calls
  public List<String> restoreIpAddresses(String s) {
    List<String> result = new ArrayList<>();
    backtracking(result, new ArrayList<>(), s, 0); // start from index = 0
    return result;
  }

  private void backtracking(List<String> result, List<String> list, String s, int start) {
    if (list.size() == 4 && start == s.length()) {
      String strIP = join(list);
      result.add(strIP);
      return;
    } else if (list.size() == 4 || start == s.length()) {
      return; // no need to continue
    }
    for (int j = 1; j <= 3 && start + j <= s.length(); j++) {
      String str = s.substring(start, start + j); // j is exclusive
      if (str.length() == 1 || (str.charAt(0) != '0' && Integer.valueOf(str) <= 255)) {
        list.add(str);
        backtracking(result, list, s, start + j);
        list.remove(list.size() - 1);
      }
    }
  }

  private String join(List<String> list) {
    StringBuilder sb = new StringBuilder(list.get(0));
    for (int i = 1; i < list.size(); i++) { // size must be 4 here; start from 1
      sb.append(".").append(list.get(i));
    }
    return sb.toString();
  }
}

redpajama_set_name: RedPajamaGithub


text:
Report: USPS must step up audits
By Margret Johnston
The General Accounting Office has criticized the U.S. Postal Service's National Change of Address program for not sufficiently policing the software used by companies that are licensed to access the database of new addresses.
NCOA, based in Memphis, Tenn., is responsible for the database of new addresses collected by the program when people move. The information is protected by the Privacy Act, and NCOA is required to make sure the companies that license the data do not release it to business mailers unless the name on their list matches the name on the NCOA list.
A list of people who have recently moved would be worth a lot of money to business mailers because it could be sold to home improvement companies or other retailers that target new homeowners. But NCOA only releases the data under license, and it is required to audit the licensees' software to ensure that the companies have not violated the public's privacy when the licensee releases names and addresses to business mailers.
The GAO report, issued late last month, said NCOA from 1996 to 1998 did not always conduct the minimum number of audits. NCOA is required to conduct at least three audits annually of the licensed companies. But in 1998, for example, only 17 of 25 companies licensed at the time were audited three times. Two companies were audited only once that year.
"They are doing some audits but not all they are supposed to, and they didn't document some that they did," said Bernard Ungar, director of government business operations issues at GAO.
The GAO report also found that during the same three-year period, NCOA did not quickly reaudit licensees that failed initial audits and did not always suspend licensees that failed successive audits, as required under the license agreement. Ungar said, however, the findings were an improvement over the results of a similar review of the NCOA program in 1996.
An NCOA official did not dispute GAO's findings. The required number of audits were not conducted during the period because NCOA was short-staffed, the official said. "These audits are of a technical nature," the official said. "We've had some turnover of experienced people."
NCOA has increased its staff of auditors to five. During the period reviewed, NCOA had three auditors, the official said, adding that NCOA is taking steps to ensure that the required number of audits is performed every year.
The GAO report has been sent to Rep. John McHugh, (R-N.Y.), chairman of the House Government Reform Committee's Postal Service Subcommittee. A spokesman for the subcommittee said the GAO report would be on the agenda of a subcommittee hearing after the House returns from its current recess.


text:
RUISSEAU FARM CEMETERY
GPS Coordinates - Latitude: 50.91184, Longitude: 2.89913
Langemark is located north of the town of Ieper off the N313. From the Markt take the Statiestraat, in the direction of Bikschote, go over the disused railway and then take the first turning left, Melkerijstraat. Follow this road for approximately 800 metres, past the milk factory where there is a sharp right hand bend followed by a sharp left hand bend. At the left hand bend there is a track going straight on which leads to the cemetery.
Wheelchair access to this cemetery is possible via main entrance.
Ruisseau Farm was taken by the Guards Division, fighting alongside French troops, on 8 October 1917 and the cemetery was begun by the divisional burial officer when the fighting was over. Later burials were made by artillery units and the cemetery continued in use until the end of November 1917.
Ruisseau Farm Cemetery contains 82 First World War burials, six of them unidentified.
Identified Casualties: United Kingdom 76. Total 76.
The cemetery was designed by W H Cowlishaw.
John Ryder Clark
196th Siege Battery, Royal Garrison Artillery
20th October 1917, aged 19.
Row B. 9.
His headstone bears the inscription "Beloved Eldest Son Of F. Hammond And Rose Of Wanstead, Essex"
Son of Frederick Hammond Clark and Rose Fanny Clark, of Montpellier House, Wanstead, London.
27748 Guardsman
Fred William Jackson
2nd Bn. Grenadier Guards
Row D. 14.
His headstone bears the inscription "Neath The Cross Gently Sleeping Sadly Missing"
Son of Thomas H. and Anna Jackson, of Burnley; husband of Evelyn Jackson, of 27, Bread St., Burnley.
Arthur Charles Ralph
19th Bn. Northumberland Fusiliers
3rd November 1917.
Row A. 1.
Pilkem, Belgium. c. 1918. British Army medical personnel attending to wounded soldiers including a Guard's officer.
German trenches in a wood near Langemarck, after the British bombardment; 11 June 1917. © IWM Q 2824
Aerial Photo. Langemarck Area. © IWM Q 48385
British 60-pounder guns of the Royal Garrison Artillery firing near Langemarck, 12th October 1917. © IWM Q 3140
Guardsmen washing and shaving in a small stream near Langemarck (Langemark-Poelkapelle), 12th October 1917. © IWM Q 3010
Wreck of the British tank named "Eldorado" by the ruins of church at Langemarck. © IWM Q 17840
CEMENT HOUSE CEMETERY
LANGEMARK GERMAN MILITARY CEMETERY


J'ai reçu mes petites tasses à café que j'affectionne particulièrement. Couleurs, forme, j'aime beaucoup les disposer sur ma table après le déjeuner ou pour le goûter. J'ai hâte de pouvoir accueillir d'autres pièces de l'univers de Nicolas.
Love, love, love this piece. It is precious and makes me smile every time I look at it. I have nothing in my pottery collection remotely like it and that makes me love it all the more. Quickly shipped and well packaged. I also can not tell you how much I "LOVED" the little tiny bowl that came with it. A bonus that now sits with my small pottery collection. Thank you so much. It's my first piece from France and I think it will always be my favorite one.


Astha Technocrats is promoted and managed by Technocrats. One of the two promoters, Mr. Sandeep Gupta is and Electrical Engineers and the other one, a lady entrepreneur Mrs. Kalpana Gupta is Bachelor in Science (Biology).
Astha Technocrats mainly manufactures Soft Acid Slurry - Linear Alkyl Benzene Sulphonic Acid (LABSA) and Spent Acid.
Complete customer satisfaction is the motto of the company. In the stiff market competition and varying degree of demands of customers, our is meeting the challenge since 1992, by maintaining the stringent Quality norms and competitive prices.
The Quality norms of each batch of the product, customers relations and other additional services are provided by our Double M.Sc. Technical Manager, Mr. Rajesh Shrivastava with vast industrial exposure.
On the whole, the company is determined to march ahead with our objective to grow and contribute positively to the society.


What exactly is brand positioning?
When we talk about brand positioning, we're not talking about where a brand sits in terms of market share, revenue or size. Brand positioning refers to the unique space a brand carves out in the mind of the consumer.
In other words: What differentiates one luxury brand from its competitors? How does the brand story connect with and entice a target audience? And what does the brand do to not only reinforce their story, but to ensure it stays relevant with the changing times?
To get a better idea of how it's done, let's take a look at five luxury brands who are doing it right.
Mention the idea of luxury with a conscience and the name Stella McCartney is bound to come up. Indeed, McCartney's brand isn't just in that space — she practically invented it. Since launching her eponymous label in 2001, McCartney has eschewed the use of leather, fur and PVC in her collections and has sought out ways to make luxury fashion sustainable and environmentally-friendly. It's this commitment to her values that gives McCartney a unique position in the luxury market. Consumers who share her values are drawn to the brand for more than its aesthetic.
The success of the Stella McCartney brand reveals one way to boost your brand's positioning: establish and uphold core values that your target audience connects with and cares about.
Breitling is certainly not the only luxury watch brand to make heritage an underlying part of their brand positioning strategy. But what differentiates them is their clear and consistent brand message as a maker of precise, indestructible watches of such high quality that they're trusted by the marine and aviation industries. This heritage of taking to the seas and skies brings with it adventure, nostalgia, and a pioneering spirit that certain consumers long to be associated with.
Breitling understands that positioning a heritage brand in the modern day requires a balance of the past and present. Hence their social media presence is aimed at a modern audience, yet draws heavily on the nostalgic mood that gives them a unique place in the market. And while Breitling has traditionally centered itself in the realm of the gentleman, the brand has recently adapted its brand positioning strategy to be more inclusive to women — a smart move in the post #metoo era.
British multihyphenate @gretabellamacina worked on a collection of poems, inspired by the #ValentinoFW19 collection. The works, which appear in #ValentinoOnLove are a study in the search for love, and "the broken light behind each day." Watch the Women's FW19 show live from Paris today at 5PM CET.
In the minds of consumers, Valentino is synonymous with elegance, sophistication and romance. That brand story was carved out from the start, by founder Valentino Garavani in the 1960s, and has been carefully maintained ever since.
The fashion house positions itself as elite and exclusive, often appearing on red carpets and in celebrity wardrobes; but all luxury fashion brands need to distinguish themselves in some way, and Valentino does it with a unique sense of refinement. This is displayed in their collections, which often reference art, mythology, history, and different cultures.
Valentino's unique brand position is also cemented by the right collaborations.These are used to further the brand image as being cultured and refined — for example, for their most recent collection they commissioned poetry from several modern poets, which was then shared on social media.
Louis Vuitton is one of the most well-known and covetable luxury brands in the world. But what is it that gives it a unique position in the minds of consumers?
While Louis Vuitton's design aesthetic changes dramatically depending on who's helming each subset of the brand, one thing remains consistent: the LV monogram print. This is an anchor to the brand's heritage — let's not forget that Louis Vuitton started out life as a maker of exceptionally-crafted luggage pieces. This fact is ever-present at the heart of the brand's positioning strategy, with the themes of travel and adventure underlying everything they do.
In the case of Louis Vuitton, travel is presented in a philosophical light. It's about the journey rather than the destination; adventure and exploration are presented as exciting, exotic and deeply desirable. This message echoes through the brand's collections, events and marketing materials, and positions it firmly as the kind of luxury brand that anyone who dreams of adventure would want to buy into.
If you want to know how to do brand positioning in the luxury jewelry space, look no further than Tiffany & Co. Their position is deeply rooted in an emotional connection between consumer and brand; a connection strengthened by cultural references, cinema and celebrity. It's because of this that, even before it is opened, their signature blue gift box is immediately recognized as a symbol of elegance, affluence and love.
Today, Tiffany & Co's brand positioning strategy is evident in their social media content. The brand collaborates with top-level influencers as a way to heighten their luxury image and boost their relevance with next-generation consumers. For example, a post from Kendall Jenner wearing Tiffany & Co at the 2018 Met Gala garnered over 4.4 million likes and, more importantly, leveraged both her celebrity power and the glamour and exclusivity of the event to strengthen the brand's position.
Are you aware of who your audience is? The influencers they follow, the events they attend or participate in digitally, the media outlets they read, and which of your competitors they pay the most attention to.
Knowing which influencers are loyal to your brand and the audiences they're activating will help you make more strategic decisions when collaborating with opinion leaders, so as to guard brand authenticity and activate your target consumers.
Another crucial step to understanding brand positioning is identifying which brands your brand is associated with. Perhaps you're hoping to be associated with Chanel, yet your brand gets mentioned alongside up and coming luxury brands as opposed to heritage ones. Spotting these incongruencies will aid you in perfecting your positioning strategy.
If you'd like to learn more about how to obtain a brand positioning analysis, read all about it here.


text:
Island Ecology
Racing Pigeons
Columbophilia
Ibiza Ecology
Natural Park
Ecotax
Es Cubells
Ibiza is to stage the World Racing Pigeon Grand Prix next year.
It is a big honour and comes after some notable successes by breeders from the island.
"Columbophilia" also "Peristeraphilia" or "Colombofilia" in Spanish, is a word made up of "Columbas" (Latin for pigeon) and "Philos" (Greek for lover).
It is about the art, the science and the rules to develop and increase the natural capacity of orientation and the flying resistance of the pigeon.
This word is only used for the "fanciers" who nurse and train the messenger or racing pigeon. They are "Columbophilos", a special name that distinguishes them from those who just nurse and keep any pigeon in general.
Men throughout history have used different kinds of messenger pigeons. It was probably a pigeon that flew back to Noah's Ark with a green olive tree branch in its beak (though it is a white dove that is nowadays recognised as the peace symbol).
The Egyptian pharaohs used them five thousand years ago to communicate with their vast empire. The Greeks used pigeons to communicate the names of the Olympic Games champions to all their cities. The Romans legions took them through France, Great Britain, Spain, North Africa, the Middle East, etc., leaving a few in every setting and camp, so their information could reach Rome in a matter of hours, when it would take days or even weeks by any other way.
There are historical records of Marc Anthony using them in the battle of Módena in the year 43 BC. But it was as early as 1171 BC when Malik el Adel Nour-Eddyn Mahmoud, Sultan of Alepo and Egypt, was considered to be the creator of the first regular airmail post.
Since then, messenger pigeons have been involved in most wars and historical events in this part of the world and also used as a regular post service in the Middle East cities. In the year 1280, in Cairo, there were more then two thousand messenger pigeons maintaining regular communication with Alexandria, Damieta, and Gaza and from there to Damascus, Jerusalem and Baghdad. They were also used by the Arabs to battle with the Crusaders and against the Christians in Mainland Spain.
In the Flanders wars of the sixteen century, in the siege of Paris in 1594, in the French Revolution, etc. History is full of citations and anecdotes about the very important role that messenger pigeons have been involved with.
But not only for war: sailors and merchants of any epoch sent pigeons in advance to announce their arrival. In 1815, after Napoleon's defeat at Waterloo, a messenger pigeon brought this news to Mr. Rothschild in London, fifty hours before the British government knew it. This was enough time for him to buy a big amount of public options, very cheaply because of the war and to make one of the biggest fortunes of the first half of the nineteenth century.
When the telegraph was invented, it looked like it was the end for the services of the messenger pigeon. But again when Paris was besieged in 1870, pigeon power was the only way that the Parisians could communicate with the rest of the country and over 60,000 messages were sent by them. This was also the first time that microphotography was used to reduce the size of the messages.
In World War One, there were over 30,000 messenger pigeons in the French army. One of them was called "Cher ami" and passed into history. This "Dear Friend" (this is what its French name means) was a really good friend to an American battalion trapped in between two fires and being bombed by error with their own guns. There was no radio or telephone available, so, the battalion commander sent this pigeon with the message to cease fire and the right situation of the enemy. The poor bird was wounded by the enemy fire, it was bleeding, almost dead when it reached the allied lines, the message in a little tube hanging from its broken leg, but a lot of American lives were saved by its action.
In World War Two, there were so many services and actions done by this amazing bird, that we would need a thick book to mention only part of them. They were sent with parachutes from planes flying very high, in special cages that opened automatically with a little explosion when they were two hundred metres above ground. Some were released from the seabed by submarines in special capsules, driving in special lorries in all the battle fronts, flaying day and night, with strong winds, snow, rain or fog, like the "Pony Express" etc. Only from England more then 17,000 were sent to the enemy territory and to the French resistance, 1,700 of them came back. These birds were trained since 1941 in great secrecy somewhere in England by British "columbophilos". One of these birds called "William of Ornare" flew from Arnhem (Holland) 260 miles in four hours and twenty-five minutes in a special message mission.
There are about three hundred species of the "Columba" family in the world. In Europe, three of the wild species are the most important, "Columba palumbus" the biggest of them, "Columba oenas" a little bit smaller and "Columba livia" of the same size as the one before, also the one to adapt itself better to life in the cities.
The actual racing pigeon, the Belgian pigeon, because it was created in Belgium, is a relatively new species. The first news we have of them is around 1815. Five years later there are already records of pigeon racing. No-one is one hundred per cent sure of its origins; its creators never told their secrets, most probably quite a few mixtures had to be done to get where we are, but we know that all domestic pigeons come originally from the wild European "Columba livia".
Before then there were several species used as "messengers" being created in Belgium, the wild and very well built "Bizet" is the ancestor of a good number of the actual domestic pigeons, the "Culbutants" almost extinguished today, the "Gravates" smaller and very fast, the "Camus" completely disappeared at present time, the "Persian messenger" and the "English carrier". Most probably all these species were used to create the "Liege pigeon" of small size, rounded head, short beak, fast and persistent, and the "Antwerp pigeon" bigger, more resistant and stronger. From these two races, mixed together, the actual racing pigeon was created, the "Gantt pigeon" of about 500 grams for the male and 450 grams for the female.
When a good "columbophilo" breeds a real champion, he forms his own stock, and his new pigeons will be called after his name, so we have the Hansenne stock (he was considered the first "King of the Columbophilos"), the Janssens stock, the Vanschingem stock, the Speder stock, etc.
Therefore the actual racing pigeons and the modern competition, can be considered a Belgian creation, where this art-science-sport can be considered too as the National sport, with more then 160,000 licences for "columbophilos" in actual times.
In Spain, the first club or society of "Columbophilia" was founded in Barcelona, "Sociedad Colombofila de Catalunya" in the year 1890, with Diego de la Llave as president. The army, the commandant Pedro Vives y Vich, as president of it, a real pigeon expert, in 1894 founded the Spanish columbophilos federation "Federación Colombofila Española". "Sociedad Colombofila de Mallorca" in 1899 was the first in the Balearic Islands. In Ibiza in 1928, "Sociedad Colombofila Mensajera La Ibicenca" was the fifth of the Balearic clubs to be founded. Two new ones have been founded in this Island since then. In following weeks we shall be proud to present them to you.
Racing Pigeons have a very special relevance and a relative old tradition in the Balearic Islands. Joan Torres Roselló, (Tarba) Joan Prats Ferrer, both from the "Sociedad Colombofila Portmany" of Sant Antoni (Eivissa) have been Spanish champions in some of the categories, Prats Ferrer is the actual Spanish champion, Ramón Palau Serra from "Club Colombofilo Eivissa" was third in a World championship celebrated in Mexico, his pigeons have also contributed to win an International tittle for Spain, as well as several National titles and plenty of other important awards. Within the following editions we shall explain all about the different categories and championships.
This very well gained reputation brought the chance and the honour of celebrating the next Racing Pigeon World Grand Prix 2002 here, in the island of Eivissa (local name for Ibiza). I am sure that our enthusiastic and very much "columbophilos" experts will make a real success of this magnificent event. So far, I want to thank them very much for the big amount of help and information that I have from them, and for what is already a big success "Eivissa 2002", "World capital of Racing Pigeons".
In the near future there will be a website http://www.eivissagrandprix.com especially for this event and all the information of the "columbophilos" of Eivissa.
All Pictures © Gary Hardy (1988 & 1989)
Demolition News to Ruffle Feathers
I want to congratulate and thank as well GEN-GOB (Grup de Estudis de sa Natura-Grup Ornitologic Balear) especially its president Joan Carles Palerm and the speaker Mariano Marí for their courage and the extraordinary job they are doing for the ecological legality here in Eivissa.
Last week, the tribunals in Palma de Mallorca proved them right over the lawsuit they had versus the Sant Antoni Town Hall, about the legality of a big villa built on top of a hill in a protected area (ANEI - Area Natural de Especial Interes). The Town Hall has been condemned to demolish this house two years since it was built, even though there was a big opposition at the time and the house was denounced by GEN when it was starting to be built.
This is the second time that a similar thing has happened. There's a second house condemned by the tribunals to be demolished because of its illegal licence given from this institution. If demolition has to go ahead, the cost to the town, paid with public money, will be about 8,414,500 euros (1,400,000,000 pesetas) as compensation to the owners.
Part Two Of Five


You may have played many versions of Tetris, but you've probably never played one like Tetris Effect. The latest iteration of the falling-block puzzler comes from Tetsuya Mizuguchi's Enhance Experience and combines music, sound, vibration, and visuals into something that becomes almost transcendent. It does have a late-game difficulty spike that's worse for those that aren't playing in VR, but this is still a masterfully presented new entry in a long-running series.
The main campaign of Tetris Effect is Journey, an engrossing series of connected boards each with their own diverse art style, music, and ruleset. Each board is unique and I was constantly surprised by what they offered. One might see you starting underwater as a beautiful particle-effect whale swims around you, while the next will be a desert landscape with a meandering caravan of camels that, halfway through, transitions to a realistic-looking version of the moon complete with an astronaut tooling around in a lunar vehicle. Some don't have music at all, instead opting for a soundscape drawn from the sounds of wind. Another had me inadvertently creating a jazz jam with the sound effects created by rotating, moving, and dropping pieces.


It might seem hard to understand, but IT technology and processes play a very important role in the success of your business. Business Intelligence of Puerto Rico offers IT solutions specifically designed for your business and customers. We are the perfect support for your technology department. We provide consulting, licensing, infrastructure update and much more.


text:
Шпо́лка — річка в Україні, в межах Шполянського, Звенигородського і Катеринопільського районів Черкаської області. Ліва притока Гнилого Тікичу (басейн Богу).

Опис
Довжина 53 км, сточище 605 км². Долина завширшки до 3 км, завглибшки до 40 м. Заплава двобічна, завширшки до 300 м. Річище слабозвивисте, завширшки до 10 м. Використовується для водопостачання, зрошування і риборозведення. На Шполці споруджено декілька ставків і 2 водосховища: Ватутінське та Юрківське.

Розташування
Шполка тече в межах Придніпровської височини. Витоки розташовані біля села Терешки. Спершу тече на південний схід, в місті Шпола повертає на південний захід і захід, далі тече переважно на захід, у пригирловій частині — на південний захід. Впадає до Гнилого Тікичу між смт Єрки та смт Катеринопіль.

Притоки: Холківка, Гарбузинка, Княжа, Чичир , Безіменна (праві); Князька, Киселіва (ліві).

Над річкою — міста Шпола і Ватутіне.

Джерела

 Екологічна ситуація (в районі р. Шполка, м. Ватутіне) // Бурій В. М. Твоє Ватутіне від А до Я / Валерій Бурій.- Черкаси: Витоки, 2003.- С. 8.
 Шполка // Бурій, В. Ватутінезнавство: події, факти, персоналії [Текст] / В. Бурій. — Черкаси: Вертикаль, 2015. — С. 241—242.

Малі річки України
Річки Черкаської області
Річки Шполянського району
Річки Звенигородського району
Річки Катеринопільського району
Шпола
Населені пункти над Шполкою
Статті про річки Черкаської області без зображення в картці

redpajama_set_name: RedPajamaWikipedia


Penrith Motorcycle Centre is Western Sydney's Number 1 Kawasaki, MV Agusta and Royal Enfield Motorycle Dealership. Specialising in New & Used Motorcycles for Sale.
They stock a huge range of motorcycle accessories and apparel. You can choose from brands like SHOEI, Shark Helmets, Dri Rider, Oneill & Ixon & much more.
New & Used Bikes for Sale and Motorcycle Finance and Insurance on all New Bikes.
At Penrith Motorcycle Centre, their Motorcycle Service & Spare Parts Department operates Monday through Saturday. Onsite they have dedicated, service technicians that are able to get your motorcycle back on the road, as quickly as possible.