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Holm multiple correction for large-scale gene-shape association mapping
Guifang Fu1Email author,
Garrett Saunders1 and
John Stevens1
© Fu et al.; licensee BioMed Central Ltd. 2014
Linkage Disequilibrium (LD) is a powerful approach for the identification and characterization of morphological shape, which usually involves multiple genetic markers. However, multiple testing corrections substantially reduce the power of the associated tests. In addition, the principle component analysis (PCA), used to quantify the shape variations into several principal phenotypes, further increases the number of tests. As a result, a powerful multiple testing correction for simultaneous large-scale gene-shape association tests is an essential part of determining statistical significance. Bonferroni adjustments and permutation tests are the most popular approaches to correcting for multiple tests within LD based Quantitative Trait Loci (QTL) models. However, permutations are extremely computationally expensive and may mislead in the presence of family structure. The Bonferroni correction, though simple and fast, is conservative and has low power for large-scale testing.
We propose a new multiple testing approach, constructed by combining an Intersection Union Test (IUT) with the Holm correction, which strongly controls the family-wise error rate (FWER) without any additional assumptions on the joint distribution of the test statistics or dependence structure of the markers. The power improvement for the Holm correction, as compared to the standard Bonferroni correction, is examined through a simulation study. A consistent and moderate increase in power is found under the majority of simulated circumstances, including various sample sizes, Heritabilities, and numbers of markers. The power gains are further demonstrated on real leaf shape data from a natural population of poplar, Populus szechuanica var tietica, where more significant QTL associated with morphological shape are detected than under the previously applied Bonferroni adjustment.
The Holm correction is a valid and powerful method for assessing gene-shape association involving multiple markers, which not only controls the FWER in the strong sense but also improves statistical power.
Bonferroni
QTL mapping
Multiple correction
Linkage Disequilibrium (LD)-based Quantitative Trait Loci (QTL) studies now involve large-scale numbers of genetic markers and play a significant role in identifying underlying genetic variants for complex quantitative traits such as morphological shape or human disease [1–5]. A major issue for LD based QTL mapping is in determining significance levels for the testing of multiple individual markers. Three reasons add to the complexity of this multiple testing correction. First, new genotyping techniques make it common to measure tens of thousands of markers. The more statistical tests that we perform for identifying significant gene-trait associations, the more likely we are to reject the null hypothesis when it is true. This problem is also called the inflation of the type I error [6, 7]. Second, high dimensional shape traits, often quantified by multiple principal components, dramatically increase the number of multiple tests by as much as three or more times [5, 8, 9]. Third, independence of test statistics is not guaranteed because correlations between markers lead to highly complicated and unknown dependency structures.
The Bonferroni correction, as one of the most popular multiple correction approaches, is known to be conservative and have low power for large-scale tests [10]. Permutations, although the current gold standard for assessing significance levels in genetic mapping studies with multiple markers, is extremely time consuming due to its computational burden, and may not work well if the population has family structure [6, 11–13]. Therefore, it is necessary to seek alternative approaches that can improve the power for largescale simultaneous individual marker tests while preserving control of the family-wise error rate (FWER) under nominal significance thresholds (e.g. α = 0.05) [14, 15].
In this article, we propose a uniformly more powerful sequentially rejective multiple testing approach that strongly controls the FWER for the LD based shape mapping model, by merging Holm's procedure [16] with the Intersection Union Test (IUT) [17]. The new procedure makes no assumptions on the joint distribution of the test statistics. The advantage of the Holm correction over the standard Bonferroni correction has been known to statisticians for over 35 years [16, 18–20] but has not yet gained traction in LD based QTL mapping.
A critical challenge in large-scale LD association tests is the increase in the false positive rate if selected markers are not in complete LD with each other. In this case, the power is likely reduced (or false negative rate inflates) if the correction for multiple comparisons is overly conservative or if independence is assumed for markers with strong LD associations with each other. Despite the fact that the false discovery rate (FDR) is very popular and has been extensively used in multiple hypothesis testing [21], the FWER, the probability of making at least one type I error, exerts a more stringent control over the FDR. Since FDR is controlled only for all selected markers and provides no promise of control for an arbitrarily selected subset of the significant markers, researchers may detect more spurious QTLs using the FDR in place of the FWER as they often consider only a subset of the significant results [22]. Therefore, we recommend controlling the FWER rather than FDR whenever only the most promising results are valued, such as in LD based QTL mapping.
Detecting a significant shape QTL requires two hypothesis tests [5], the first testing for the association between QTL and shape, and the second testing for the LD between the observable marker and underlying QTL. Currently, Bonferroni corrections are applied separately to two families of hypotheses, one family consisting of the first hypothesis test for all markers, and the other family consisting of the second hypothesis test for all markers. Only those markers showing significance within both families, after correcting for multiple tests, are identified as linked to a QTL. This amounts to performing an IUT with the two test statistics for each marker and applying a Bonferroni correction for multiple markers. Although the LD based QTL model has been successful in locating significant QTLs [5, 23, 24], two improvements can be made within the multiple hypothesis testing aspect. First, several gene-shape association tests were made separately for each principal component (PC). Since these PCs quantify the original high dimensional shape variations from different directions, the multiple testing correction should account for these separate PCs as well as for multiple markers. Currently, multiple PCs are not accounted for in the multiplicity correction. Second, we introduce the uniformly more powerful Holm adjustment on the p-values resulting from the IUT, which shows greater power than the Bonferroni approach.
The significance of the power advantage of the Holm method over the Bonferroni method is demonstrated through both simulations and a real leaf shape data of a natural population of poplar, Populus szechuanica var tietica. We detect more significant QTL than were previously detected in the literature while still ensuring strong control of the FWER. Since sample size, Heritability, and number of markers all determine the power, we illustrate the power differences for Heritabilities of 0.1 and 0.4, sample size small (100), medium (300), and large (500), and number of markers changing from 1, 10, 50, 100, 500 to 1,000.
Power simulation
We investigated a simulation study to quantify the power advantage of the Holm adjustment over the standard Bonferroni adjustment within the LD based QTL mapping model of [5]. The QTL, phenotype, and markers were generated under the assumptions of the alternative hypotheses in (3) and (4). The QTL was generated using an assigned probability of q = 0.7 for the major allele. For each individual i, Qi = l with l ∈ {1, 2, 3} was used to code the QTL genotypes of aa, Aa, and AA, respectively. The normally distributed phenotype dependent on the value of the QTL is generated as Y i |(Q i = l) ~ N (µl, σ). The means for the phenotype Y corresponding to the values of the QTL were set at µ1 = 8, µ2 = 10 and µ3 = 12. markers were then generated using the conditional probability of the marker genotype given the value of the QTL genotype for each individual. In general, for an LD based QTL mapping model, researchers genotype the marker first and then use the marker to generate a QTL based on the conditional probability of QTL genotype given marker genotype. However, for our purposes, we are interested in extending from single marker mapping to multiple marker mapping. Therefore, we derive the conditional probability of marker genotype given QTL genotype (see Table 1) from the Bayes Rule in Equation (1) and Table 2.
The theoretical conditional probabilities of marker genotype (columns) given QTL genotype (rows).
p 11 2 q 2
2 p 11 p 01 q 2
2 p 11 p 10 q ( 1 - q )
2 ( p 11 p 00 + p 10 p 01 ) ( 1 - q ) 2
2 p 00 2 ( 1 - q ) 2
p 10 2 ( 1 - q ) 2
2 p 10 p 00 ( 1 - q ) 2
The theoretical joint distribution probabilities of marker and QTL haplotypes.
p 11 2
2 p 11 p 10
2 ( p 11 p 00 + p 10 p 01 )
P ( M|QTL ) = P ( QTL ) P ( QTL ) .
Sample sizes of n = 100, 300, and 500 were used to represent small, medium, and large sample sizes, respectively. The number of markers per simulation was set at m = 1, 10, 50, 100, 500, and 1,000 to show the initial power under the single marker scenario and the corresponding decreasing power trend as the number of markers increases. Finally, the heritability was set at two values, H2 = 0.1 and 0.4, corresponding to high and low error variance [25]. The model error variance σ2 was computed using the heritability and genetic variance of the QTL. Power estimates were averaged over 1,000 simulations.
The simulation results, depicted in Figure 1 and shown in Additional file 1, demonstrate the power comparison of the Holm adjustment with the traditional Bonferroni adjustment. These results provide an experimental reference for researchers about how power varies among different sample size n, the number of markers m, and the degree of heritability (H2). As expected, the power under high heritability (B: H2 = 0.4) is much higher than that of the low heritability (A: H2 = 0.1) and the power under large sample size (n = 500, blue curves) is much higher than that of the small sample size (n = 100, green curves). Under high heritability (H2 = 0.4) and a larger sample size (n = 500), the power of the Holm multiplicity adjustment remains high, at least 99%, as the number of markers vary from 1 to 1,000. However, in practice it is often expensive to collect so many sample measurements, so these results are useful in deciding the opportunity costs in power for smaller sample sizes. It is worth noting that for moderate numbers of markers, the power increase of the Holm over the Bonferroni adjustment allows for maintaining the same power level of the Bonferroni adjustment while decreasing the sample size of the study or increasing the number of markers, a great advantage for researchers. For example, with a medium sample size of 300, the Holm correction maintains a power of 95% for 100 markers. Even when number of markers increase to 1, 000, the power achieved by the Holm correction is still as high as 80%.
Power comparison between the Holm adjustment and standard Bonferroni adjustment under different sample size, number of markers, and heritability ( A: H 2 = 0.1, B: H 2 = 0.4).
Although the power increase of the Holm adjustment improves moderately over the standard Bonferroni adjustment for the case of high heritability (H2 = 0.4) when the sample size is small (n = 100), these findings are comparable to seminal results found by previous multiplicity improvements over their competitors [16, 21]. For the worst case when the data has extremely large variance (H2 = 0.4) and relatively much smaller sample size (n = 100), the improvement of Holm over Bonferroni is not obvious. However, it is not an issue of multiple hypothesis testing but an issue of the least sample size necessary to guarantee a decent level of power.
All in all, the Holm method generally shows a valuable increase in power over the Bonferroni adjustment under the majority of simulated circumstances, including different combinations of sample size, numbers of markers, and Heritability. As long as the sample size is reasonably large in comparison to the variance to guarantee decent power, the improvement of the Holm correction over the Bonferroni is consistently meaningful.
Poplar leaf shape QTL mapping project
To show how the power advantage of the Holm approach leads to increased scientific discovery over the Bonferroni adjustment, we apply it to a real poplar leaf shape QTL mapping study [5]. The study design used a representative leaf from each of 106 poplar trees (i.e., Populus szechuanica var. tibetica belonging to the Tacamahaca section) that was randomly selected and photographed for shape QTL analysis. The trees were also genotyped for a panel of 29 microsatellite markers (16 of them were considered). A Radius Centroid Contour (RCC) approach was used to represent the leaf shape (phenotype) with a high dimensional curve. The first three principal components (PCs) were selected to capture the majority variation of leaf shape from different directions to quantify the original high dimensional shape curves respectively. Significant QTLs affecting the shape variability (i.e., affecting the most important PCs) were mapped through the statistical LD based QTL mapping model [5]. Previously, the standard Bonferroni adjustment was used to control the FWER for the multiple markers [5, Table 1]. However, the researchers did not consider the multiple testing correction issue introduced by multiple PCs and their reported results treated as a family of hypotheses only the multiple markers within each PC. After including the multiple PCs within the family of interest, we found slightly different results, even under the previously applied Bonferroni correction.
After applying our proposed Holm approach to provide a comprehensive multiple correction, not only including the multiple PCs in the correction but also including multiple markers within each PC, the Holm correction successfully detects all significant microsatellites that were detected by the Bonferroni correction. Further, the Holm correction detects one more marker, marker 10, that was not detected previously. Figure 2 demonstrates the bivariate plot of the two test statistics χ L 2 and χ D 2 . Those points corresponding to markers identified as significant under the Holm correction are in black dots. Those identified significant by the standard Bonferroni correction are marked with a ×. The red dot is the marker that is detected newly by Holm. All other (non-significant) empirical joint test statistic points for multiple PCs and multiple markers are plotted in gray. The new detected marker under the Holm correction is reasonable because it has similar test statistics value for the H0L : µ1 = µ2 = µ3 test but lower value for the H0D : D = 0 test, as compared to its nearest significant neighboring marker. It is well known that the critical threshold for the linkage tests are mostly somewhere around 10. Even if 1,000 multiple tests are considered, i.e., a significance level of 0.05/1000, the critical threshold of χ2 is at most 16.44. In this real shape data, the total number of tests that we performed is only 48 (16 markers and 3 PCs total) corresponding to the threshold of 10.752. Therefore, it is reasonable to call a marker significant with a test statistic value of 25 for H0D and a value for H0L is not lower than its nearest significant neighboring marker.
Bivariate plot of the two test statistics χ L 2 and χ D 2 . Those points corresponding to markers identified as significant under the Holm correction are in black dots. Those identified significant by the standard Bonferroni correction are marked with an ×. The red dot is the marker that is newly detected by the Holm correction. All other (non-significant) empirical joint test statistic points for multiple PCs and multiple markers are plotted in gray.
Figure 3 illustrates the genotypic shape effects according to the different genotypes (AA, Aa, aa) of the QTL identified by marker 10 on PC 3. It is evident that the effect of aa produces shorter leaf tips and more degrees of deltoidness at leaf base compare to the other genotypes. The effect of AA and Aa are very similar, which indicates a dominance effect. Although significant genotype differences can be observed visually, it is nevertheless not detected under the Bonferroni correction. This confirms the practical relevence of the increased sensitivity of the Holm correction over the Bonferroni. Figure 4 illustrates the RCC curves of leaf shape as a function of radial angle θ explained by the different genotypes (AA, Aa, aa) of the QTL identified by marker 10 on PC 3. It is evident that the RCC curve of aa has a higher peak when θ is close to π/2 but a lower dynamic pattern when θ is close to 3π/2, which matches the interpretations of above Figure 3 visualized from the leaf image domain. We believe that the advantages of our proposed approach will be more remarkable for a larger number of markers.
The genotypic shape effects according to the different genotypes (AA, Aa, aa) of the QTL identified by marker 10 on PC 3. This shows the increased sensitivity of the Holm approach as the effect of the aa QTL genotype is noticeably different from that of genotypes AA and Aa, but nevertheless, corresponds to information which was not detected under the Bonferroni correction.
RCC curves of leaf shape as a function of radial angle θ explained by the different genotypes (AA, Aa, aa) of the QTL identified by marker 10 on PC 3. This shows the increased sensitivity of the Holm approach as the effect of the aa QTL genotype is noticeably different from that of genotypes AA and Aa, but nevertheless, corresponds to information which was not detected under the Bonferroni correction.
Detecting significant genes that affect complex traits such as shape or disease through LD based QTL mapping has been popular in many disciplines [1–5, 26–33]. The new genotyping techniques make it possible to simultaneously consider tens of thousands of markers, bringing substantial challenges for multiple testing. In addition, high dimensional shape traits, often involving multiple PC components, have been widely used and add yet another demand for a powerful and computationally efficient approach to adjust for multiple tests [5, 8, 9].
These multiple tests require an adjustment on the resulting p-values in order to preserve control of the family-wise error rate (FWER) at a pre-specified level α. Making the alpha level more stringent will create less errors, but it may lower the chance of detecting more real effects [7]. The FDR has been widely used as the error rate of interest. Typically however, a subset of the significant results are directly reported and therefore the FWER is the more desirable form of error rate to control [22]. The current standard approach in LD based QTL mapping is to apply a Bonferroni adjustment to correct for multiplicity and preserve control of the FWER. As is well known, the Bonferroni correction is overly conservative for large numbers of tests, but the advantages of simplicity without independence assumptions on the corresponding family of tests continue to make it popular. Permutation, although has been the gold standard for assessing significance levels in studies with multiple markers, is extremely time consuming, computationally intensive, and may not work well if the population has family structure [6, 11–13].
In this article, we propose an uniformly more powerful multiple correction approach by integrating Holm [16] with the IUT test, which is assured strong control of the FWER under arbitrary dependencies among the test statistics. The advantage of Holm over Bonferroni actually has been recognized to statisticians for over 35 years [16, 18–20] but is new to LD based QTL mapping. The significance of the power advantage of the Holm correction over the Bonferroni, has been established theoretically [16]. This work demonstrates the power advantage in LD based QTL mapping empirically through both simulation study and real data. As long as the sample size is reasonablly large in comparison to the variance to guarantee a decent power, the improvement of the Holm correction over the Bonferroni is consistent and meaningful.
LD based QTL model
To map the rough location of the QTL regulating shape, we apply the mixture model of [5]. Under this model, QTL mapping is accomplished by statistically modeling the genotypic variation through not only the association between phenotype and the putative QTL, but also the LD between the putative QTL and marker. Since the marker genotype is observable, the probabilities of a putative QTL genotype can be inferred by the conditional probability of QTL genotype (A) given the marker genotype (M), as long as there exists LD between the marker and putative QTL [5].
The mixture model of [5] assumes each individual's phenotype Yi, i = 1, . . . , n, is a random variate from density f l (Y i |θ l ), where l ∈ {1, 2, 3} denote three distinct QTL genotypes. Each QTL genotype is assumed to induce a separate distribution of phenotypes. Typically, normal distributions are assumed for each f l (Y i |θ l ) with θ l = (µ l , σ). From these assumptions, the corresponding likelihood is expressed as [5]
L ( ω , μ , σ | Y , M ) = ∏ i = 1 n ∑ i = 1 3 ω l | i f l ( Y i | μ l , σ )
where ωl|i is the conditional probability of individual I having QTL genotype l given their marker genotypes, µl is the phenotypic mean for QTL genotype l, σ is the common variance for all genotypes, and fl(Yi|µl, σ) is the probability density of observations for individual I at QTL genotype l [5, 25, 34].
The probability of the marker's major allele (M) is denoted by p, and correspondingly 1 − p for the minor allele (m). Similarly, the probability of the QTL's major allele (A) is denoted by q, and correspondingly 1−q for the minor allele (a). Together, the marker and QTL form four haplotypes (MA, Ma, mA, and ma) with corresponding frequencies p11 = pq+D, p10 = p(1−q)−D, p01 = (1−p)q −D, and p00 = (1−p)(1−q)+D, respectively. Here, D is the linkage disequilibrium between marker and QTL. The conditional probabilities ω l|i of the QTL's various genotypes (AA, Aa, and aa) can be calculated upon the observed marker genotypes (MM, Mm, and mm) from the joint probabilities in Table 2[25, 5]. The EM algorithm is then applied to the likelihood in (2) to obtain maximum likelihood estimates for all parameters [5, 25].
Two hypothesis tests
Through the likelihood in (2), the hypotheses
H 0 L : μ 1 = μ 2 = μ 3 vs
H 1 L : one of the equalities above does not hold can be used to test if the QTL is significantly associated with phenotype Y (i.e. existence of QTL). Since all the unknown parameters in (2) were estimated by maximum likelihood estimates (MLEs), a log likelihood ratio statistic can be used to test the hypotheses in (3) [5]. The resulting test statistic ( χ L 2 ) is asymptotically distributed as a χ 2 2 under H 0 L for large enough samples.
On the other hand, linkage disequilibrium, denoted by D, between the marker and QTL can be tested by means of the hypotheses
H 0 D : D = 0 vs H 1 D : D ≠ 0 .
The test statistic used to judge whether or not the QTL is significantly associated with marker is [5, 35]:
χ D 2 * = n D ^ 2 p ^ ( 1 - p ^ ) q ^ ( 1 - q ^ )
= n r ^ 2 .
Here, r ^ 2 is the square of the correlation coefficient between the marker and QTL that has been used in most of the related literature, which has many good sampling properties [36, 37]. Under H 0 D , χ D 2 is asymptotically distributed as χ 1 2 , from which the tail probability (p-value) of the observed level of association can be determined [3, 23, 35, 38].
In general, the Intersection-Union test (IUT) is defined as [39]
H 0 : θ ∈ ∪ γ ∈ Γ Θ γ .
Here Γ is a finite or infinite set containing index of tests, θ is the unknown parameters under testing, and Θ γ specifies the statement of null hypothesis test for each index γ. Suppose that for each γ ∈ Γ, {x : T γ (x) ∈ R γ } is the rejection region for each test H 0 γ : θ ∈ Θ γ versus H 1 γ : θ ∈ Θ γ c . Then the rejection region for the IUT test is
∩ γ ∈ Γ { x : T γ ( x ) ∈ R γ } .
In the context of LD based QTL mapping, the tests of the above hypotheses (3) and (4) must be performed simultaneously to make the final conclusion, i.e., a significant QTL regulating shape is not detected unless both null hypotheses in (3) and (4) are rejected. H 0 D : D = 0 is used to test the LD between QTL and marker, and H 0 L : μ 1 = μ 2 = μ 3 is used to test the association between the phenotype and QTL, respectively. Thus, the IUT test with intersection rejection region but union null regions is appropriate for these two tests of each marker, resulting in a final set of m IUT p-values, where m is the number of markers tested. Then we integrate Holm into the IUT and perform multiplicity adjustment to these m IUT p-values, in place of the original Bonferroni correction that has been the current standard [5].
The Holm correction
The Holm multiplicity correction [16] applies a "sequentially rejective Bonferroni test" to all currently non-rejected hypothesis in a step-down manner. The first step of our proposed approach is to use an IUT to obtain m p-values. Then, we order the tests from the one with the smallest p-value to the one with the largest p-value as p(1), . . . , p(m) according to the usual order statistics notation. The smallest p-value, p(1), corresponding to the ordered hypothesis H(1), is then tested with the usual Bonferroni correction of α1 = α/m. If H(1) is declared significant, then the method continues by testing p(2) against α2 = α/(m − 1). So long as rejections continue to occur, p(i) is compared to α i = α/(m − i + 1) until finally p(m) is compared to α m = α. If for any i ∈ {1, 2, . . . , m} the hypothesis H(i) is not rejected, then the method stops and H(i), . . . , H(m) are retained, i.e., not rejected. Therefore, the procedure stops when the first non-significant test is obtained or when all the tests have been performed.
To be exact, let p(1), . . . , p(m), denote the ordered p-values corresponding to the ordered m hypotheses obtained from IUTs, H(1), . . . , H(m). The ordered p-values for the test of H(j) are then compared to the thresholds α j where
p ( j ) ≤ α j = α / ( m - j + 1 ) ,
and all testings will stop at the jth test for which the first non-rejection occurs, i.e., the j for which p(j) > α j . Because the denominators are m − j + 1 instead of m, Holm's procedure never rejects fewer hypotheses than the Bonferroni procedure does.
A multiple test procedure for testing hypotheses H1, . . . , H m is said to have multiple level of significance α (for free combinations) if for any non-empty index set I ⊆ {1, 2, 3, . . . , m} the supremum of the probability P ( ∪ A i c ) when H i are true for all i ∈ I is less than or equal to α where A i c denotes the event of rejecting H i . This is called strong control of the FWER. A method that only controls the FWER under the assumption that all nulls are true has weak control of the FWER.
Importantly, as proved in [16], strong control of the FWER is ensured under the Holm adjustment, no matter the dependency structure of the corresponding test statistics. A simple, but elegant proof of the strong FWER control of this approach, under arbitrary dependence structures of the test statistics, is given in [16]. The idea behind the proof is as follows. Let I denote the set of indices corresponding to the true null hypotheses, and let k denote the number of hypotheses in I, so that k ≤ m. The well known Boole's Inequality shows that the FWER (the probability of at least one type I error) is controlled by the Bonferroni method so long as at most α/k is applied to the testing of all k true nulls. Specifically,
P ( p i ≤ α / k , for some i ∈ I ) ≤ ∑ i ∈ I P ( p i ≤ α / k ) ≤ k α / k = α .
Given the nature of the sequential testing of the Holm adjustment, at any stage j of testing, the number of true nulls remaining to be tested (k) will always be less than or equal to the number of hypotheses remaining to be tested (m−j+1). Hence, any true null will always be tested by at least α/(m − j + 1) ≤ α/k, ensuring strong control of the FWER no matter how many or which nulls are true.
Just as with the Bonferroni method, Holm's method is a distribution free approach to the multiple hypothesis testing issue. More importantly it is uniformly more powerful than the Bonferroni method as it will compare P(2), . . . , P(m) to larger thresholds α i , i = 2, . . . , m than will the Bonferroni method. Therefore, it is clear that the Holm method should always be preferred over the Bonferroni method from a theoretical perspective. In the following sections, we will illustrate the benefit of Holm over Bonferroni from an application perspective.
This work was supported by a Utah State University VPR Research Catalyst Grant. Publication costs for this article were funded by the corresponding author's institution.
12863_2014_1255_MOESM1_ESM.pdf Additional file 1: Additional file 1 includes a single table showing the results of the power simulation as depicted in Figure 1. (PDF 55 KB)
GF initiated the project, supervised the main ideas, closely guided several details, provided the estimation programming, wrote and revised the manuscript. GS participated in the development of the Holm method, made programs for multiple testing, performed data analysis, and drafted the manuscript. JS involved in idea development discussions, checked the validation of the method, and revised the manuscript.
Department of Mathematics & Statistics, Utah State University, 3900 Old Main, Logan, UT, USA
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Service SK, Lang TDW, Freimer NB, Sandkuijl LA: Linkage-disequilibrium mapping of disease genes by reconstruction of ancestral haplotypes in founder populations. Am J Hum Genet. 1999, 64: 1728-1738. 10.1086/302398.PubMed CentralView ArticlePubMedGoogle Scholar
Martin ER, Lai EH, Gilbert JR, Rogala AR, Afshari AJ, Riley J, Finch KL, Stevens JF, Livak KJ, Slotterbeck BD, Slifer SH, Warren LL, Conneally PM, Schmechel DE, Purvis I, Pericak-Vance MA, Roses AD, Vance JM: SNPing away at complex diseases: Analysis of single-nucleotide polymorphisms around APOE in alzheimer disease. Am J Hum Genet. 2000, 67: 383-394. 10.1086/303003.PubMed CentralView ArticlePubMedGoogle Scholar
Goldstein D, Weale M: Linkage disequilibrium holds the key. Curr Biol. 2001, 11: 576-579. 10.1016/S0960-9822(01)00348-7.View ArticleGoogle Scholar
Reich D, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, Lavery T, Kouyoumjian R, Farhadian SF, Ward R, Lander ES: Linkage disequilibrium in the human genome. Nature. 2001, 411: 199-204. 10.1038/35075590.View ArticlePubMedGoogle Scholar
Dawson E, Abecasis GR, Bumpstead S, Chen Y, Hunt S, Beare DM, Pabial J, Dibling T, Tinsley E, Kirby S, Carter D, Papaspyridonos M, Livingstone S, Ganske R, Lõhmussaar E, Zernant J, Tõnisson N, Remm M, Magi R, Puurand T, Vilo J, Kurg A, Rice K, Deloukas P, Mott R, Metspalu A, Bentley DR, Cardon LR, Dunham I: A first-generation linkage disequilibrium map of human chromosome 22. Nature. 2002, 418: 544-548. 10.1038/nature00864.View ArticlePubMedGoogle Scholar
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Obtain population density and body size structure, using video material or image sequences as input. Functions assist in the creation of image sequences from videos, background detection and subtraction, particle identification and tracking. An artificial neural network can be trained for noise filtering. The goal is to supply accurate estimates of population size, structure and/or individual behavior, for use in evolutionary and ecological studies.


Cut back on our work schedule, who is going to pay the bills. Also, sorry but I can't make any contributions to the Kingdom hall because you told me to cut back on my work schedule.
They ramp up the rhetoric because they're unnerved that people are beginning to tune them out.
Soooooo glad I am OUT!!
Room 215 - "They ramp up the rhetoric because they're unnerved that people are beginning to tune them out."
Many times in the past, I've noticed that the ones who are losing tend to get the loudest.
Pretty sure that as they are crunching up the numbers, they are realizing that the trend is for them to go down.
Yes, they can continue to artificially massage the numbers so that they don't look as bad, but at the end of the day, there is only so much you can do. At some point, even the creative ways of counting time will not be enough to keep the numbers afloat.
Them what? Well i'm sure the Org will again resort to creative interpretation to excuse that. In fact, I think they have already. Didn't one of the Governing Body members say recently that the work of JWs is not to bring new converts anymore? Sorta like just run and maintain mode?
They be saying the end of the world is gonna come soon any day now for over 125 years how long do they think this can go on? The Rank and File are getting desensitized to the Watchtower corporation's sense of urgency and not responding like they used to back in the good old days before the internet.
The Governing Body is barking up the wrong tree if you ask me. They will never learn, they got such slow and delusional brains that they can't even see this type of harping is getting them deeper and deeper in debt. They cried wolf way too many times to be taken seriously, Assholes! Bye, bye, delusional thinkers who are in deep denial.
Guilt-mongering was the biggest trigger for my awakening.
In fact, I'm so used to it by now, it's almost superfluous.


Known for birthing the country's classic baked beans and for leading you along the Freedom Trail of authentic history and treasure, Boston also provides an impressive array of convenient and accessible shopping options for locals and tourists alike.
For a place to see and be seen, venture down Newbury Street to window shop (or splurge) at retailers like Chanel, Giorgio Armani and Burberry. It's rich history and culture consistently attracts high-end boutiques, pop-ups and restaurants.
Looking for something more laid back, take a stroll along the Freedom Trail and make a stop at Quincy Market where you'll find a mix of retailers spanning various price points. Little known fact – Quincy Market is the fourth most-visited tourist site in America, driving a mix of local shops, international brands and top restaurants. It's slated to become a year-round destination with a planned investment of $60M in renovations.
You can create your own experience while shopping in Boston. Shopping here provides any option you're looking for whether it's a staple, eccentric or extravagant piece. And as an added bonus, they won't charge you sales tax on your clothes.
Don't forget to download our Boston City Retail report to learn about its retail corridors and view its average asking prime retail rents, annual rent growth rates and average cap rate ranges.
Categories: Americas Retail, Retail Cities, Retail Transactions, Retailers and tagged Boston, city retail, Retail Corridors, retail real estate, Retail Research.


Whilst looking at the instrument panel and the speedo assembly last time, I noticed the board had some jumpers missing, which related to the external divisor pins for the IC that converts the front wheel pulses into a speedo signal. These were also used to feed the electric motors that power the odometer and tripmeter assembly. I wondered whether this was the kilometer or mile conversion area, or whether it was mechanical via the gearing.
I managed to get hold of a kilometer unit, and it turns out it is electronic after all.
If you compare the previous blog image with this board, you'll notice that the jumpers J1 & J2 are bridged, whereas in the mile version they are not used.
I'll be testing this out when I run the mile unit up on the fuel injection rig, the easiest way is to spin up the sensor and see how far the tripmeter travels in say two minutes, bridge the J1 & J2 connections, reset the tripmeter and see if the distance is 1.6x greater for the same time & rotation speed.


text:
/*
 * @file config.h
 *
 * bootloader definitions that configures the behavior and options
 * of the Boot loader
 * This file is relies on the parent folder's boot_config.h file and defines
 * different usages of the hardware for bootloading
 */

#pragma once

/************************************************************************************
 * Global platform definitions
 ************************************************************************************/

#define CONFIG_ARCH_CORTEXM4
#define CONFIG_ARCH_FPU
#define CONFIG_ARCH_IRQPRIO
#define CONFIG_ARCH_CHIP_STM32F302K8
#define CONFIG_STM32_STM32F302
#define CONFIG_USEC_PER_TICK 1000
#define CONFIG_IDLETHREAD_STACKSIZE 8192
#define CONFIG_STM32_NOEXT_VECTORS
#define CONFIG_STM32_ADC1
#define S2740VC_1_0

/************************************************************************************
 * Included Files
 ************************************************************************************/

#include <stm32.h>

#ifndef __ASSEMBLY__
#include <assert.h>
#include <string.h>
#endif

/************************************************************************************
 * Pre-processor Definitions
 ************************************************************************************/
/* Clocking *************************************************************************/

/* HSI - 8 MHz RC factory-trimmed
 * LSI - 40 KHz RC (30-60KHz, uncalibrated)
 * HSE - On-board crystal frequency is 8MHz
 * LSE - 32.768 kHz
 */

#define STM32_BOARD_XTAL        8000000ul

#define STM32_HSI_FREQUENCY     8000000ul
#define STM32_LSI_FREQUENCY     40000
#define STM32_HSE_FREQUENCY     STM32_BOARD_XTAL
#define STM32_LSE_FREQUENCY     32768

/* PLL source is HSE/1, PLL multipler is 9: PLL frequency is 8MHz (XTAL) x 9 = 72MHz */

#define STM32_CFGR_PLLSRC       RCC_CFGR_PLLSRC
#define STM32_CFGR_PLLXTPRE     0
#define STM32_CFGR_PLLMUL       RCC_CFGR_PLLMUL_CLKx9
#define STM32_PLL_FREQUENCY     (9*STM32_BOARD_XTAL)

/* Use the PLL and set the SYSCLK source to be the PLL */

#define STM32_SYSCLK_SW         RCC_CFGR_SW_PLL
#define STM32_SYSCLK_SWS        RCC_CFGR_SWS_PLL
#define STM32_SYSCLK_FREQUENCY  STM32_PLL_FREQUENCY

/* AHB clock (HCLK) is SYSCLK (72MHz) */

#define STM32_RCC_CFGR_HPRE     RCC_CFGR_HPRE_SYSCLK
#define STM32_HCLK_FREQUENCY    STM32_PLL_FREQUENCY
#define STM32_BOARD_HCLK        STM32_HCLK_FREQUENCY    /* same as above, to satisfy compiler */

/* APB2 clock (PCLK2) is HCLK (72MHz) */

#define STM32_RCC_CFGR_PPRE2    RCC_CFGR_PPRE2_HCLK
#define STM32_PCLK2_FREQUENCY   STM32_HCLK_FREQUENCY

 /* Timer Frequencies, if APBx is set to 1, frequency is same to APBx
 * otherwise frequency is 2xAPBx.
 * Note: TIM1,15-17 are on APB2, others on APB1 */

#define STM32_TIM18_FREQUENCY   STM32_HCLK_FREQUENCY
#define STM32_TIM27_FREQUENCY   STM32_HCLK_FREQUENCY

/* APB2 timer 1 will receive PCLK2. */

#define STM32_APB2_TIM1_CLKIN   (STM32_PCLK2_FREQUENCY)

/* APB1 clock (PCLK1) is HCLK/2 (36MHz) */

#define STM32_RCC_CFGR_PPRE1    RCC_CFGR_PPRE1_HCLKd2
#define STM32_PCLK1_FREQUENCY   (STM32_HCLK_FREQUENCY/2)

/* APB1 timers 2-4 will be twice PCLK1 (I presume the remaining will receive PCLK1) */

#define STM32_APB1_TIM2_CLKIN   (2*STM32_PCLK1_FREQUENCY)
#define STM32_APB1_TIM3_CLKIN   (2*STM32_PCLK1_FREQUENCY)
#define STM32_APB1_TIM4_CLKIN   (2*STM32_PCLK1_FREQUENCY)
#define STM32_APB1_TIM5_CLKIN   (STM32_PCLK1_FREQUENCY)
#define STM32_APB1_TIM6_CLKIN   (STM32_PCLK1_FREQUENCY)
#define STM32_APB1_TIM7_CLKIN   (STM32_PCLK1_FREQUENCY)

/* USB divider -- Divide PLL clock by 1.5 */

#define STM32_CFGR_USBPRE       0

/* Probes unused */
#define PROBE_INIT(mask)
#define PROBE(n,s)
#define PROBE_MARK(n)

/****************************************************************************
 * Pre-processor Definitions
 ****************************************************************************/

#define OPT_PREFERRED_NODE_ID ANY_NODE_ID

//todo:wrap OPT_x in in ifdefs for command line definitions
#define OPT_TBOOT_MS            2000
#define OPT_NODE_STATUS_RATE_MS 800
#define OPT_NODE_INFO_RATE_MS   10
#define OPT_BL_NUMBER_TIMERS    7

#define OPT_RESTART_TIMEOUT_MS 20000u

/* Reserved for the Booloader */
#define OPT_BOOTLOADER_SIZE_IN_K (1024*8)

/* Reserved for the application out of the total
 * system flash minus the BOOTLOADER_SIZE_IN_K
 */
#define OPT_APPLICATION_RESERVER_IN_K 0

#define OPT_APPLICATION_IMAGE_OFFSET OPT_BOOTLOADER_SIZE_IN_K
#define OPT_APPLICATION_IMAGE_LENGTH (FLASH_SIZE-(OPT_BOOTLOADER_SIZE_IN_K+OPT_APPLICATION_RESERVER_IN_K))

#define HW_UAVCAN_NAME "com.thiemar.s2740vc-v1"
#define HW_VERSION_MAJOR 1
#define HW_VERSION_MINOR 0

#define FLASH_BASE              STM32_FLASH_BASE
#define FLASH_NUMBER_PAGES      32
#define FLASH_PAGE_SIZE         STM32_FLASH_PAGESIZE
#define FLASH_SIZE              (FLASH_NUMBER_PAGES*FLASH_PAGE_SIZE)

#define PARAM_SIZE              (2 * FLASH_PAGE_SIZE)

#define APPLICATION_LOAD_ADDRESS (FLASH_BASE + OPT_APPLICATION_IMAGE_OFFSET)
#define APPLICATION_SIZE (FLASH_SIZE-OPT_APPLICATION_IMAGE_OFFSET-PARAM_SIZE)
#define APPLICATION_LAST_8BIT_ADDRRESS  ((uint8_t *)((APPLICATION_LOAD_ADDRESS+APPLICATION_SIZE)-sizeof(uint8_t)))
#define APPLICATION_LAST_32BIT_ADDRRESS ((uint32_t *)((APPLICATION_LOAD_ADDRESS+APPLICATION_SIZE)-sizeof(uint32_t)))
#define APPLICATION_LAST_64BIT_ADDRRESS ((uint64_t *)((APPLICATION_LOAD_ADDRESS+APPLICATION_SIZE)-sizeof(uint64_t)))

/* High-resolution timer
 */
#define HRT_TIMER               1       /* use timer1 for the HRT */
#define HRT_TIMER_CHANNEL       1       /* use capture/compare channel */

/* CAN ***************************************************************************
 *
 *   GPIO      Function                             MPU        Board
 *                                                  Pin #      Name
 * --------- --------------------------------     ----------------------------
 *
 *   PA[0]     ADC1_IN1                              7         IA
 *   PA[1]     ADC1_IN2                              8         IB
 *   PA[2]     ADC1_IN3                              9         IC
 *   PA[3]     ADC1_IN4                             10         VSENSE
 *   PA[4]     DAC1                                 11         VREF
 *   PA[8]     TIM1_CH1                             18         PWMA
 *   PA[9]     TIM1_CH2                             19         PWMB
 *   PA[10]    TIM1_CH3                             20         PWMC
 *   PA[11]    PA11/CAN_RX                          21         CAN_RX
 *   PA[12]    PA12/CAN_TX                          22         CAN_TX
 *   PB[6]     PB06                                 29         CAN_SILENT
 */

#define GPIO_CAN_SILENT (GPIO_OUTPUT | GPIO_PUSHPULL | \
                         GPIO_PORTB | GPIO_PIN6 | GPIO_OUTPUT_CLEAR)

#define GPIO_PWMA_DISABLED (GPIO_INPUT | GPIO_PORTA | GPIO_PIN8)
#define GPIO_PWMB_DISABLED (GPIO_INPUT | GPIO_PORTA | GPIO_PIN9)
#define GPIO_PWMC_DISABLED (GPIO_INPUT | GPIO_PORTA | GPIO_PIN10)

#define GPIO_PWMA_LOW (GPIO_OUTPUT | GPIO_PUSHPULL | GPIO_OUTPUT_CLEAR | \
                       GPIO_PORTA | GPIO_PIN8)
#define GPIO_PWMB_LOW (GPIO_OUTPUT | GPIO_PUSHPULL | GPIO_OUTPUT_CLEAR | \
                       GPIO_PORTA | GPIO_PIN9)
#define GPIO_PWMC_LOW (GPIO_OUTPUT | GPIO_PUSHPULL | GPIO_OUTPUT_CLEAR | \
                       GPIO_PORTA | GPIO_PIN10)

#define GPIO_PWMA_ENABLED GPIO_TIM1_CH1OUT_2
#define GPIO_PWMB_ENABLED GPIO_TIM1_CH2OUT_2
#define GPIO_PWMC_ENABLED GPIO_TIM1_CH3OUT_2

#define GPIO_ADC1_CH1 (GPIO_ANALOG | GPIO_PORTA | GPIO_PIN0)
#define GPIO_ADC1_CH2 (GPIO_ANALOG | GPIO_PORTA | GPIO_PIN1)
#define GPIO_ADC1_CH3 (GPIO_ANALOG | GPIO_PORTA | GPIO_PIN2)
#define GPIO_ADC1_CH4 (GPIO_ANALOG | GPIO_PORTA | GPIO_PIN3)

/************************************************************************************
 * Public Data
 ************************************************************************************/

#ifndef __ASSEMBLY__

#undef EXTERN
#if defined(__cplusplus)
#define EXTERN extern "C"
extern "C"
{
#else
#define EXTERN extern
#endif

/****************************************************************************
 * Public Functions
 ****************************************************************************/

/************************************************************************************
 * Name: board_initialize
 *
 * Description:
 *   All STM32 architectures must provide the following entry point.  This entry point
 *   is called early in the initialization -- after all memory has been configured
 *   and mapped but before any devices have been initialized.
 *
 ************************************************************************************/

inline static void board_initialize(void)
{
    putreg32(getreg32(STM32_RCC_AHBENR) | RCC_AHBENR_IOPAEN |
             RCC_AHBENR_DMA1EN | RCC_AHBENR_IOPBEN | RCC_AHBENR_ADC12EN,
             STM32_RCC_AHBENR);
    putreg32(getreg32(STM32_RCC_APB1ENR) | RCC_APB1ENR_CAN1EN |
             RCC_APB1ENR_DACEN,
             STM32_RCC_APB1ENR);
    putreg32(getreg32(STM32_RCC_APB2ENR) | RCC_APB2ENR_TIM1EN |
             RCC_APB2ENR_SYSCFGEN,
             STM32_RCC_APB2ENR);

    putreg32(getreg32(STM32_RCC_APB1RSTR) | RCC_APB1RSTR_CAN1RST,
             STM32_RCC_APB1RSTR);
    putreg32(getreg32(STM32_RCC_APB1RSTR) & ~RCC_APB1RSTR_CAN1RST,
             STM32_RCC_APB1RSTR);

    stm32_configgpio(GPIO_CAN_RX_2);
    stm32_configgpio(GPIO_CAN_TX_2);
    stm32_configgpio(GPIO_CAN_SILENT);
    stm32_configgpio(GPIO_PWMA_DISABLED);
    stm32_configgpio(GPIO_PWMB_DISABLED);
    stm32_configgpio(GPIO_PWMC_DISABLED);
    stm32_configgpio(GPIO_ADC1_CH1);
    stm32_configgpio(GPIO_ADC1_CH2);
    stm32_configgpio(GPIO_ADC1_CH3);
    stm32_configgpio(GPIO_ADC1_CH4);
    stm32_configgpio(GPIO_DAC1_OUT);
}

/************************************************************************************
 * Name: board_deinitialize
 *
 * Description:
 *   This function is called by the bootloader code prior to booting
 *   the application. Is should place the HW into an benign initialized state.
 *
 ************************************************************************************/

inline static void board_deinitialize(void)
{
}

/****************************************************************************
 * Name: board_get_product_name
 *
 * Description:
 *   Called to retrieve the product name. The returned value is a assumed
 *   to be written to a pascal style string that will be length prefixed
 *   and not null terminated
 *
 * Input Parameters:
 *    product_name - A pointer to a buffer to write the name.
 *    maxlen       - The maximum number of charter that can be written
 *
 * Returned Value:
 *   The length of characters written to the buffer.
 *
 ****************************************************************************/

inline static uint8_t board_get_product_name(uint8_t *product_name, size_t maxlen)
{
    assert(maxlen > sizeof(HW_UAVCAN_NAME)-1);
    memcpy(product_name, HW_UAVCAN_NAME, sizeof(HW_UAVCAN_NAME)-1);
    return sizeof(HW_UAVCAN_NAME)-1;
}

/****************************************************************************
 * Name: board_get_hardware_version
 *
 * Description:
 *   Called to retrieve the hardware version information.
 *
 * Input Parameters:
 *    major - A pointer to the major hardware version field.
 *    minor - A pointer to the minor hardware version field.
 *    unique_id - A pointer to the 16-byte unique ID field
 *    coa_length - A pointer to the 8-bit length field for the COA
 *    coa - A pointer to the COA field, with a maximum length of 255 bytes
 *
 * Returned Value:
 *   None
 *
 ****************************************************************************/

inline static void board_get_hardware_version(uint8_t *major, uint8_t *minor,
    uint8_t unique_id[16], uint8_t *coa_length, uint8_t *coa)
{
    *major = HW_VERSION_MAJOR;
    *minor = HW_VERSION_MINOR;
    *coa_length = 0u;

    memset(unique_id, 0, 16u);
    memcpy(unique_id, (void *)STM32_SYSMEM_UID, 12u);
}

/****************************************************************************
 * Name: board_indicate
 *
 * Description:
 *   Provides User feedback to indicate the state of the bootloader
 *   on board specific  hardware.
 *
 * Input Parameters:
 *    indication - A member of the uiindication_t
 *
 * Returned Value:
 *   None
 *
 ****************************************************************************/

typedef enum {
    off,
    reset,
    autobaud_start,
    autobaud_end,
    allocation_start,
    allocation_end,
    fw_update_start,
    fw_update_erase_fail,
    fw_update_invalid_response,
    fw_update_timeout,
    fw_update_invalid_crc,
    jump_to_app,
} uiindication_t;

inline static void board_indicate(uiindication_t indication)
{
}

/****************************************************************************
 * Name: board_should_wait_for_getnodeinfo
 *
 * Description:
 *   Returns 1 if the board should wait for a GetNodeInfo request before
 *   booting, or 0 if boot should proceed anyway.
 *
 * Input Parameters:
 *    None
 *
 * Returned Value:
 *    1 if the board should wait for GetNodeInfo, 0 otherwise
 *
 ****************************************************************************/

inline static uint8_t board_should_wait_for_getnodeinfo(void)
{
    return 1u;
}

#undef EXTERN
#if defined(__cplusplus)
}
#endif

#endif /* __ASSEMBLY__ */

redpajama_set_name: RedPajamaGithub


and Bill Watterson's The Indispensable Calvin and Hobbes and putting the stories together as best I could without words. That's the great thing about comic strips, they don't always need words. Certain "sequential art" historians and theorists (Scott McCloud, etc.) even put forth the idea that prehistoric cave paintings were comic strip precursors. And they sort of are, a collection of pictures that tell a story, with or without words.
But I didn't set out to do this comic without words. I just roughed it in, in my sketchy style, and noticed it worked perfectly well without any dialogue.
The joke behind this strip is, I think, something many parents, and children alike will recognize. And maybe not just them, because my husband saw what I was drawing and said, "That looks like something a kid would do. Or something I would do" He would too.
And the sarcastic, single bite response many children give makes for frustrating parenting, but good comedy. I even have this struggle with my baby (dog) Michelle. I cook her food myself, and if I chop up veggies and put it in with her meat, she will delicately pick round them, and place them on the floor for me to step in. Her own little form of civil doggy-disobedience. So I've taken to pureeing them. Pick around THAT, you sneaky pup.
Dogs aside, Bridget is like many children, much more excited by the prospect of egg rolls, french fries, and macaroni & cheese than she is asparagus, and swiss chard.


The block mould is a casting mould which means the mould is removed whilst the concrete is still wet allowing the mould to be used repeatedly the same day. The steel moulds are filled with concrete vibrated, turned over and removed leaving the blocks to cure.
Vibration is used to produce high density blocks with a lower water content. High structural strength can be achieved with lower cement content.


The next Centaur Media dividend will go ex in 14 days for 1.5p and will be paid in 29 days.
The last Centaur Media dividend was 1.5p and it went ex 7 months ago and it was paid 7 months ago.
How accurate are our Centaur Media forecasts?


text:
Item:3 General Debate - 13th Meeting, 42nd Regular Session Human Rights Council
13 Sep 2019 - - Briefing by the President of the Economic and Social Council
- Report of the Open-ended intergovernmental working group on the regulation, monitoring and oversight of the activities of private military and security companies
Followed by General debate under Agenda Item:3 Promotion and protection of all human rights, civil, political, economic, social and cultural right A/HRC/42/19, A/HRC/42/20, A/HRC/42/21, A/HRC/42/22, A/HRC/42/23, A/HRC/42/24, A/HRC/42/25, A/HRC/42/26, A/HRC/42/27, A/HRC/42/28, A/HRC/42/29, A/HRC/42/35, A/HRC/42/36
Item 3: Promotion and protection of all human rights, civil, political, economic, social and cultural rights, including the right to development- 13th Plenary Meeting
42nd Regular Session of the Human Rights Council.
H.E. Ms. Mona Juul, President of the Economic and Social Council (Introduction)
H.E. Ms. Nozipho Joyce Mxakato-Diseko, President-Rappoprteur of the intergovernmental working group on the regulation, monitoring and oversight of the activities of private military and security companies (Introduction)
Pakistan (on behalf of OIC), Mr. Junaid Suleiman
Denmark (on behalf of a group of States), Ms. Lone Thorup
Peru (on behalf of a group of States), Ms. Silvia Elena Alfaro Espinosa
Czech Republic (on behalf of a group of States), Mr. Michal Kaplan
Venezuela (Bolivarian Republic of) on behalf of NAM, Mr. Alexander Yanez
Finland (on behalf of the European Union), Ms. Sari Lehtiranta
Thailand (on behalf of ASEAN), Mr. Sek Wannamethee
El Salvador (on behalf of a group of States), Mr. Joaquín Alexander Maza Martelli
New Zealand (on behalf of a group of States), Ms. Michelle Angela McGillivray
Bolivia (Plurinational State of) on behalf of a group of States, Mr. Olmer Torrejon Alcoba
Switzerland (on behalf of a group of States), Ms. Barbara Fontana
Slovenia (on behalf of a group of States), Mr. Klemen Ponikvar
China (on behalf of a group of States), Mr. Chen Xu
Pakistan, Mr. Tahir Hussain Andrabi
South Africa, Ms. Nelia Barnard
Mexico, Ms. Socorro Flores Liera
Iraq, Ms. Suzan Ahmad Muhsen Muhsen
Austria, Ms. Elisabeth Tichy-Fisslberger
India, Ms. Mini Kumam
Cuba, Mr. Jairo Rodríguez Herndández
United Kingdom of Great Britain and Northern Ireland, Ms. Rita French
Cameroon, Mr. Côme Damien Georges Awoumou
Nigeria, Mr. Muhammad S. Isa
Nepal, Mr. Vijay Raj Tandukar
Australia, Ms. Katie Mead
Syrian Arab Republic, Ms. Rania Al Haj Ali
Venezuela (Bolivarian Republic of), Mr. Manuel José Hernández Bustamante
Ecuador, Mr. Alejandro Davalos
Estonia, Ms. Triinu Kallas
Iran (Islamic Republic of), Mr. Javad Kazemi
Russian Federation, Ms. Anastasia Bagdatieva
Republic of Korea, Mr. Jang-Keun Lee
Thailand, Mr. Sek Wannamethee
H.E. Ms. Mona Juul, President of the Economic and Social Council (Introduction) 00:02:51
H.E. Ms. Nozipho Joyce Mxakato-Diseko, President-Rappoprteur of IGWG on private military and security companies (Introduction) 00:19:32
Pakistan (on behalf of OIC), Mr. Junaid Suleiman 00:24:46
Denmark (on behalf of a group of States), Ms. Lone Thorup 00:27:34
Peru (on behalf of a group of States), Ms. Silvia Elena Alfaro Espinosa 00:30:00
Czech Republic (on behalf of a group of States), Mr. Michal Kaplan 00:32:17
Venezuela (Bolivarian Republic of) on behalf of NAM, Mr. Alexander Yanez 00:35:24
Finland (on behalf of EU), Ms. Sari Lehtiranta 00:37:50
Thailand (on behalf of ASEAN), Mr. Sek Wannamethee 00:40:55
El Salvador (on behalf of a group of States), Mr. Joaquín Alexander Maza Martelli 00:42:46
New Zealand (on behalf of a group of States), Ms. Michelle Angela McGillivray 00:45:51
Bolivia (Plurinational State of) on behalf of a group of States, Mr. Olmer Torrejon Alcoba 00:48:27
Switzerland (on behalf of a group of States), Ms. Barbara Fontana 00:50:18
Slovenia (on behalf of a group of States), Mr. Klemen Ponikvar 00:52:33
China (on behalf of a group of States), Mr. Chen Xu 00:54:32
Pakistan, Mr. Tahir Hussain Andrabi 00:57:25
South Africa, Ms. Nelia Barnard 01:00:00
Mexico, Ms. Socorro Flores Liera 01:02:09
Iraq, Ms. Suzan Ahmad Muhsen Muhsen 01:04:42
Austria, Ms. Elisabeth Tichy-Fisslberger 01:06:53
India, Ms. Mini Kumam 01:09:20
Cuba, Mr. Jairo Rodríguez Herndández 01:11:34
United Kingdom of Great Britain and Northern Ireland, Ms. Rita French 01:13:55
Cameroon, Mr. Côme Damien Georges Awoumou 01:16:16
Nigeria, Mr. Muhammad S. Isa 01:18:52
Nepal, Mr. Vijay Raj Tandukar 01:20:51
Australia, Ms. Katie Mead 01:22:58
Syrian Arab Republic, Ms. Rania Al Haj Ali 01:25:02
Venezuela (Bolivarian Republic of), Mr. Manuel José Hernández Bustamante 01:27:00
Ecuador, Mr. Alejandro Davalos 01:28:33
Estonia, Ms. Triinu Kallas 01:30:26
Iran (Islamic Republic of), Mr. Javad Kazemi 01:32:03
Russian Federation, Ms. Anastasia Bagdatieva 01:34:14
Republic of Korea, Mr. Jang-Keun Lee 01:36:10
Thailand, Mr. Sek Wannamethee 01:37:49
Netherlands 01:39:31
Georgia, Ms. Nino Bakradze 01:41:29
Greece, Mr. Thiseas Fragkiskos Poullos 01:43:03
Botswana, Ms. Bokani Edith Sesinyi 01:44:36
Azerbaijan, Mr. Emin Aslanov 01:46:01
Albania, Mr. Ilir Nezaj 01:47:12
Republic of Moldova, Ms. Cristina Cerevate 01:48:51
Namibia, Mr. Penda Naanda 01:50:41
United Republic of Tanzania, Ms. Lucy Darabe Diganyeck 01:52:31
Grenada, Mr. Robert Branch 01:53:58
Indonesia, Ms. Mia Padmasan 01:55:30
Armenia, Mr. Andranik Hovhannisyan 01:57:24
Marshall Islands, Ms. Teri Elbon 01:58:54
Suriname 02:00:39
Office of Ombudsman of Samoa (Video Message), Mr. Maiava Iulai Toma 02:02:51
Danish Institute for Human Rights, Ms. Katharina Rose 02:04:48
Soka Gakkai International (Joint Statement), Ms. Elisa Gazzotti 02:06:26
Association Comunità Papa Giovanni XXIII (Joint Statement), Ms. Anna Visentin 02:08:00
United Nations Association of China, Mr. You Baishun 02:09:36
World Evangelical Alliance, Mr. Brian Stille 02:11:30
Friends World Committee for Consultation, Ms. Lucy Hannah Halton 02:13:17
Iranian Life Quality Improvement Association, Ms. Maryam Erzi 02:14:54
Peace Brigades International Switzerland (Joint Statement), Ms. Kim-Mai Vu 02:16:37
Conectas Human Rights, Mr. Gustavo Huppes 02:18:17
Union of Arab Jurists, Mr. Elias Khouri 02:19:57
Right Livelihood Award Foundation (Joint Statement), Ms. Nikhrim Singh 02:21:36
British Humanist Association, Ms. Farah Lailaa Mohamed 02:23:14
Prevention Association of Social Harms (PASH), Mr. Majid Feizikhan 02:24:56
Organization for Defending Victims of Violence, Mr. Mahmood Golshanpazhooh 02:26:22
Addictions Professional Association (Joint Statement), Ms. Jennifer Hasselgard-Rowe 02:27:50
Traditional Medicine and Health Developers Society of the Iranians, Mr. Mohammad Azizkhani 02:29:41
Charitable Institute for Protecting Social Victims, Ms. Omeh Leila Enayati	02:31:18
International Association for Equality of women, Ms. Sahak Sanaie 02:33:02
China (Right of Reply) 02:35:04
India (Right of Reply) 02:36:13
Japan (Right of Reply) 02:38:31
Brazil (Right of Reply) 02:40:03
Pakistan (Right of Reply) 02:42:31
ECOSOC President & Reports of WG on PMSCs - 13th Meeting, 42nd Regular Session...
Republic of Moldova, UPR Report Consideration - 42nd Meeting, 34th Regular...
ID: Human rights in Central African Republic - 36th Meeting, 42nd Regular...
Democratic People's Republic of Korea, UPR Report Consideration - 25th Meeting,...
המזכיר הכללי של האומות המאוחדות מסר וידאו לרגל יום הזכרון הב…
Consideration of Hungary - 2436th Meeting, 83rd Session Committee…
Dang Dinh Quy (Viet Nam) and Security Council President on Libya…
António Guterres (UN Secretary-General) on the situation in Libya…
Karen Pierce (United Kingdom) on Middle East - Security Council…
Kelly Craft (United States) on Middle East - Security Council…
Danny Danon (Israel) on Holocaust Remembrance Day and Middle…

redpajama_set_name: RedPajamaCommonCrawl


Shaw Moisture Meters has a long and illustrious history of exporting to India where its ultra precision instruments have long been prized for their quality. It began exporting to India 30 years ago and the country remains one of its top six worldwide markets.
The firm, whose dewpoint meters measure in parts per billion, was originally set up to test the moisture content of wool in the Yorkshire textile industry in the immediate post-war years. Since then, Shaw Moisture Meters has specialised in measuring trace moisture in gases and compressed air and its products have found applications in numerous industries. In India the firm sells to many industrial companies including compressed air, electronics manufacture and power generation applications.
The company operates in India using a long-standing representative, although managing director Tim Peters has regular contact with both the representative and end customers to maintain all-important relationships. He stresses the importance of keeping those on the ground up to date with as much information and support as possible to retain close ties with customers.
"It's a growth market and we are seeing increasing levels of business," he says. "We have a strong presence there and it's improving. We have a massive plus in India because of our pedigree.
As many other exporters have discovered, having close ties with those whom you deal with is all-important in India – and very different from doing business in European countries.
Mr Peters cautions that one of the downsides of doing business in India is the amount of bureaucracy which is often involved.
"Many organisations seem to have taken British bureaucracy and tripled it," he adds. "We do more Letters of Credit for India than anywhere else and it is the preferred option for most of the nationalised industries. The extra paperwork creates a lot of additional work with the order processing and payments procedures.


Was a very great weekend. To drive with the tank. We seen a lot of clubs. The guide was very nice, friendly. Everything was in time. Brno is a great city for young people for great party's.
Excellent weekend! We enjoyed all of the activities and definitely would recommend Brno to anyone. Great value for money, a good place for a Stag do. Nightlife here is quality and We're looking forward to coming back! Thanks for an awesome Stag do!
Very good weekend, the shooting session was excellent! Our guide was really kind and looked after us through the weekend. We would definitely come back!
Great place to visit, night life was brilliant. Friendly atmosphere, the stag had a very good time. Our guide was friendly and approachable and showed us the best.
We all had a brilliant stag and also had a lovely attentive host! Very helpful with good local knowledge. Excellent bars!
A fantastic time in Brno. Thank you very much for looking after us. Professional, kind, friendly and fantastic value.


Justine Blau is a visual artist, creating works that explore the various languages and usages of photography, particularly in a vernacular context. She is interested in the role culture plays in shaping an environment or people's interactions. Many of her works deal with the complex and peculiar relationship humankind maintains with what we qualify as 'nature'.
Justine Blau was born in Luxembourg in 1977 and studied at Wimbledon College of Art, University of the Arts London, London, UK - MA Fine Art Sculpture.
What Color is the Red Planet, Really?


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Character (supporting cast) (1)
Specifically pre-Crisis in Infinite Earths (1)
See 26 other values
Marine Marauder I
0 - 13th July 2018
Miscellaneous Bonus: Once the Marine Marauder has used the Telepathic Sending Devices to establish a telepathic link with an animal or animals, the Devices will maintain the link even if the Marauder unmasks provided that the Marauder; 1) remains within Range of the animal and...
Psylocke
(Profile #1 - Early)
When the Marauders attacked the Morlocks, Betsy, now calling herself Psylocke, helped with relief efforts in the mansion. Her help was welcome, as some of the X-Men had been badly injured in the attack. While the able X-Men were hunting for the Marauders, Sabretooth breached...
Blockbuster aka Heat-Ray
(Fredric Woolrich)
Blockbuster agreed to plea-bargain in return for the name of his employer. As a result, he got a reduced sentence. He became a minor super-villain, whose activities included attacking money transfer trucks. He used part of his profits to keep his suit upgraded. Woolrich also...
Green Lantern Kho of the Khunds
Months later, Procanon Kaa and his rookies found a planet that had just been ravaged by the Silver Serpent space marauders. They could find but a single sapient survivor before Silver Serpent forces attacked them. Thulka Re died opening a breach among enemy forces. Kaa was...
(Before Ms. Marvel, part #1)
0 - 30th December 2017
It also seems that women were allowed in or near combat theatres during the Việt Nam war, rather than by 1994 as in the real world. This part is implied by Marauders member Arclight, though her role and status in that conflict are unclear. It is also possible, especially in the...
(Jack Monroe profile #3 - early Nomad)
0 - 3rd March 2015
Monroe eventually captured the maddening marauder. This victory made him realise that he needed to move out of Cap's shadow and strike out on his own. Wherever I may roam Roaming the US on his motorbike to act as a hero and create a Captain America-like reputation for himself,...
Thundra
0 - 8th March 2015
Thundra stayed on Earth-715 for 20 years, renewing her efforts to defend and expand the Sisterhood until the females claimed practically the entire world. The last holdings of males were in the Middle East. As she got older, Thundra fought mostly to defend the West of the Sisterhood...


Established in 2001 With years of experience. We specialize in HARLEY DAVIDSON / AMERICAN V-TWIN MOTORCYCLES. We take pride in our work. You'll find our honesty is unmatched. Were here for tomorrow so you can count on us working to keep your business.


Our range of products include glycerin filled pressure gauge and hydraulic pressure gauge.
We ALM engineering is one of the leading and most reliable organisation in the market. we bridge the gap between the quality and we are the most trusted suppliers since long.
Looking for Glycerin Filled Pressure Gauge ?


You can also find us on Facebook where you can join our Facebook public group and view posts of current astronomical events and space research. You will also receive reminders of our monthly lectures. Click the icon!


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"Just you wait, it won't be long, the man in black will soon be here, with his cleaver's blade so true, he'll make mincemeat out of you!"
87 years after its release and yet remarkably not a second of Fritz Lang's M feels dated. It's a cold, expertly crafted serial killer thriller and sits right along side another Lang masterpiece Metropolis as quintessential examples of cinema far ahead of its time. With some films it can be difficult to appreciate how influential they proved to be for elements of modern filmmaking because unfair or not, having already seen the future, going back to the past later on can feel redundant. M is not one of those films. Having fallen in love with cinematic serial killer storytelling thanks to the work of artists like Fincher, Demme and Hitchcock, I am able to soak in all that they clearly learned from a master like Lang, whom upon reflecting on his own career declared that M was his favorite of all his work. I can see why.


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The Zoological Survey of India (ZSI), founded on 1 July 1916 by the Ministry of Environment, Forest and Climate Change of the Government of India as a premier Indian organisation in zoological research and studies to promote the survey, exploration and research of the fauna in the country.

History

The annals of Zoological Survey of India (ZSI) reflect an eventful beginning for the Survey even before its formal birth and growth. The history of ZSI begins from the days of the Asiatic Society of Bengal founded by Sir William Jones on 15 January 1784. The Asiatic Society of Bengal was the mother institution not only to the Indian Museum (1875) but also to the institutions like the Zoological Survey of India and the Geological Survey of India. ZSI's establishment was in fact a fulfillment of the dream of Sir William Jones, the founder of the Asiatic Society of Bengal, whose vision encompassed the entire range of human knowledge. The Asiatic Society had started collecting zoological and geological specimens since 1796 and set up a museum in 1814. Nathaniel Wallich, the first Superintendent of the "Museum of the Asiatic Society", was in charge of the increasing collections of Geological and Zoological specimens; he had augmented the animal collections to the Zoological Galleries of the Museum.

The genesis of Zoological Survey of India was in 1875 with the opening of the Indian Museum. The new museum on its inception comprised only three sections: the Zoological, the Archaeological and the Geological. The zoological collections of the Asiatic Society of Bengal were formally handed over to the board of trustees of the Indian Museum in 1875.

Zoological Section of the Museum during the period from 1875 to 1916 steadily expanded, growing to the greatest collection of natural history in Asia. By the care and activity of the Curators of the Asiatic society of Bengal and the Superintendents of the Indian Museum, viz., John McClelland, Edward Blyth, John Anderson, James Wood-Mason, Alfred William Alcock and finally Thomas Nelson Annandale and his colleagues, the museum was richly endowed with a magnificent collection of animals, especially of the larger vertebrate groups. Further additions of both land and aquatic fauna to the valuable collections came through during several political and military expeditions, including a number of collections purchased, notably those of Francis Day of Indian Fishes, Lionel de Nicéville of butterflies, Dudgeon and Edward Ernest Green of moths, Jacob R. H. Neervoort van de Poll of beetles and Godwin Austen of mollusks.

The Zoological Gallery at the Asiatic society Museum under the care and charge of Nathaniel Wallich served the impetus for the formation of the Zoological Survey of India, which was later born as an independent organization on 1 July 1916. The excerpt from the 'Constitution of the Zoological Survey of India', released by the Government of India, Department of Education, Resolution no. 19-Museum, dated Shimla, 20 June 1916, states: "In March 1913, the Chairman of the Trustees of the Indian Museum forwarded a representation from the Superintendent of the Zoological and Anthropological Section of the Museum regarding the recognition of the Zoological Section as Zoological Survey. The Government of India, who had already under consideration the desirability of establishing on a sound basis a Zoological Survey of India, informed the Trustees of the Museum that they would be prepared to consider a scheme for such a survey on lines somewhat similar to the existing Botanical Survey of India and asked to furnish with the necessary details. The trustees accordingly submitted their proposals at the end of September 1913."

Thomas Nelson Annandale, who joined the Indian museum as Deputy Superintendent (1904), and later as the Superintendent (1907), after years-old struggle, achieved his aim in establishing the Zoological survey of India, and became its founder director and continued until his premature death in April 1924. Dr. Annandale was Honorary Secretary to the Trustees of the Indian Museum for several years; he was also the President of the Asiatic Society of Bengal in 1923.

Dhriti Banerjee became the very first women director of ZSI since its inception in 1916.

Divisions and sections at headquarters

Divisions & Sections

Regional Centers
North Eastern Regional Centre (NERC), Shillong, Meghalaya (Estd. 1959).
Western Regional Centre (WRC), Pune, Maharashtra (Estd. 1959).
Central Zone Regional Centre (CZRC), Jabalpur, Madhya Pradesh (Estd. 1960).
Desert Regional Centre (DRC), Jodhpur, Rajasthan (Estd. 1960).
Northern Regional Centre (NRC), Dehra Dun, Uttarakhand (Estd. 1960).
Southern Regional Centre (SRC), Chennai, Tamil Nadu (Estd. 1961).
Gangetic Plains Regional Centre (GPRC), Patna, Bihar (Estd. 1965).
High Altitude Regional Centre (HARC), Solan, Himachal Pradesh (Estd. 1968).
Marine Biology Regional Centre (MBRC), Madras, Tamil Nadu (Estd. 1973).
Andaman and Nicobar Regional Centre (ANRC), Port Blair (Estd. 1977).
Freshwater Biology Regional Centre (FBRC), Hyderabad, Telangana (Estd. 1979).
Sunderbans Regional Centre (SRC), Canning, West Bengal (Estd. 1979).
Estuarine Biology Regional Centre (EBRC), Ganjam, Orissa (Estd. 1980).
Western Ghats Regional Centre (WGRC), Kozhikode, Kerala (Estd. 1980).
Arunachal Pradesh Regional Centre (APRC), Itanagar, Arunachal Pradesh (Estd. 1983).
Marine Aquarium Cum Regional Centre (MARC), Digha, West Bengal (Estd. 1989).

National zoological collections
The Survey acquired the zoological collections of more than a century old from the former museum of the Asiatic Society of Bengal and the zoological section of the Indian Museum (18141875) in Calcutta.

Publications
Records of the Zoological Survey of India
Memoirs of  Zoological Survey of India
Occasional Papers
Fauna of British India
Fauna of India
Annual Report since 1961–62
State Fauna Series (20 States)
Conservation Area Series
Ecosystem Series
Wetland Series
Estuarine Series
Marine Series
Himalayan Series
Animal Discoveries (New species and New records)
Handbooks/Pictorial Guides
Special Publication Series
Status Survey of Threatened Animals
Bibliography of India Zoology (Discontinued)
Zoologiana (Discontinued) Vol. 1–5
Technical Monograph (Discontinued) Vol. 1–17
Bulletin of ZSI Vol. (Discontinued) Vo. 1–8

ZSI library
The library in Kolkata and regional centers have a total collection of approximately 1,35,000 volumes, which includes books, journals, monographs, reports of expeditions and fauna surveys, periodicals and other archaic literature on Zoology. The Kolkata library has around 400 titles of rare books. Some of the notable documents include the original publications of Carl Linnaeus and Fabricius, original paintings and drawings of renowned scientists, biogeographers and naturalists.

Gallery

See also
 List of zoo associations
 Botanical Survey of India (BSI)
 Forest Survey of India (FSI)
 Wildlife Institute of India (WII)
 Salim Ali Centre for Ornithology and Natural History (SACON)
 Survey of India (SI)
 Geological Survey of India (GSI)
 Anthropological Survey of India (AnSI)

References

External links

Executive branch of the government of India
Fauna of India
Natural history of India
Organizations established in 1916
1916 establishments in India
Organisations based in Kolkata
Nature conservation organisations based in India
Biodiversity

redpajama_set_name: RedPajamaWikipedia


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Home FEATURED Benedict Peters' Aiteo Group Settles For Force Majeure To Avoid More Loss
Benedict Peters' Aiteo Group Settles For Force Majeure To Avoid More Loss
Benedict Peters
Aiteo Eastern Exploration and Production Company Limited, a member of the Aiteo Group, led by billionaire businessman, Benedict Peters, obviously to prevent more loss and guard against the fulfillment of some business commitments, has opted for force majeure.
The company resorted to this as a result of the recent outbreak at their Nembe Creek Trunk Line.
According to The Punch, 'The NCTL, a major crude oil transportation channel used for export, evacuates crude to the Bonny Crude Oil Terminal. It is 100 kilometres long and has a capacity of 150,000 barrels per day at Nembe Creek.'
Force majeure, on the other hand, refers to a legal clause that allows companies to cancel or delay agreed deliveries due to unforeseen circumstances.
In giving their own side of the story, however, Aiteo, on Sunday, April 21, 2019, said, "We have been informed of a fire outbreak by our surveillance team comprising the JTF, FSS around NCTL Right of Way near Awoba today, April 21, 2019.
"Our Operations Emergency Response team was immediately activated and following its urgent intervention and containment action, we are constrained to shut in injection as well as other related operations into the NCTL. In accordance with standard procedure, we requested the other injectors to do the same."
Aiteo Group, YES INTERNATIONAL! Magazine gathered, is an integrated, global-focused Nigerian energy conglomerate founded in 2008. The company, with headquarters in Lagos and Port Harcourt, Rivers State, is the successor entity to Sigmund Communnecci Limited.
AITEO
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Opinion (7/7/18): Saraki, APC And The Future Of Nigeria, By Dele Momodu
Yes International! Magazine - July 8, 2018
APC To International Media, Observers: Don't Be Deceived By PDP!
Lai Mohammed: Why FG Is Determined To End All Forms Of Monopoly In Broadcasting
Yes International! Magazine - October 21, 2019
IMMIGRATION RECRUITMENT TRAGEDY: MORO SHUNNED LAID DOWN PROCEDURES – WITNESS
Yes International! Magazine - June 11, 2016


1.	Use a life course perspective to analyse the interactive relationship between individual and social factors determining life style and health outcomes.
2.	Review critical analyses of social interventions based on a Social Capital framework.


Chai Tulani connects with AliForTheGo and Christian JaLon for a new visual directed by APJ Films.
Upcoming Chicago artist Chai Tulani put together a creative new anthem featuring AliForTheGo and Christian JaLon. His new visual has scenic views overlooking downtown Chicago, which was captured by one of our favorite videographers known as Apj Films.


MAYDAY PARADE has released "Piece Of Your Heart," the first song from their upcoming album, SUNNYLAND!
Mayday Parade's new album SUNNYLAND will be released on Friday June 15. It can be pre-ordered at https://riserecords.lnk.to/sunnyland.


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Marina Thank you to Philip & Dorrie Jones and Marla Williams and friends for giving so generously to Marina in order for her to get her surgery done.
Ruel Thank you to all those who helped with the treatment of Ruel.
Ruel, our namesake, was found suffering from malnutrition in a hospital in Borongan, Eastern Samar in the Philipine Islands. His malnutrition was due to a cleft lip with cleft palate. Cleft
Jade Jade was operated on her lip on 23/10/12
Palate Feb 2013
Zhielah Mae Mariel Zhielah had her operation done at the beginning of October 2010, thankyou to all those who regularly give to our donation boxes.
Nino Nino's cleft palate was operated on by Operation Smile on 15th January 2010.
Thanks to those who support the Donation boxes that paid for this surgery.
John Mark John Mark was dropped off at Ruel House because his mother did not want him.
He is under nourished.We will process him for adoption.
Thank you to all those who came to the Veira fundraising concert in the UK, helping to pay for his treatment.
John John has had his lip operation. unfortunately we cannot currently operate on his cleft palate because we suspect he has heart problems.
Thank you to the Smile Train for sponsoring this child. $450 is still needed to sponsor his surgery.
Daniel cleft lip and palate
John Paul Completed January 2012
Manita Manita has now had her surgery completed and she is back with her family.
We are continuing to monitor Manita. At her last check up we found she has a slight swelling on her head so she will need futher monitoring.
Thank you to Harry and Martha Bart
We have decided to move our children's home in Romblon to be more accessible for the families that need it most.We have had two years in a beautiful... read more
'The Shack' movie night
You're Invited to a private screening ofTHE SHACKCome along to The Shack on Wednesday, 28th June for a relaxing night out and a chance to Give a Smil... read more
My wife and I are pleased to endorse the work of the "Ruel Foundation." The foundation has its roots in Eastern Samar, as Ruel is a native son of Eastern Samar. Many of the children from this region are being helped and cared for by the foundation. We look forward with anticipation to working with David and his team in the coming years.
Lieutenant General Rupert Ambil (PDF)Former Governor of E.Samar
The Ruel Foundation is simple in concept and compassionate in spirit. These qualities resonate deeply throughout the Christian Gospel. Jesus spoke simply to children and treated the poor and broken with compassion. The "Foundation" makes it possible for us to do likewise.
Francis P. CarollArchbishop of Canberra and Gouldburn


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The neurons in our gut help the immune system keep inflammation in check
Complete the form below and we will email you a PDF version of "The neurons in our gut help the immune system keep inflammation in check "
The immune system exercises constant vigilance to protect the body from external threats—including what we eat and drink. A careful balancing act plays out as digested food travels through the intestine. Immune cells must remain alert to protect against harmful pathogens like Salmonella, but their activity also needs to be tempered since an overreaction can lead to too much inflammation and permanent tissue damage.
New research from Rockefeller University's assistant professor Daniel Mucida, head of the Laboratory of Mucosal Immunology, shows that neurons play a role in protecting intestinal tissue from over-inflammation. Published in Cell, the findings could have treatment implications for gastrointestinal diseases such as irritable bowel syndrome.
See Also: Migrating immune cells promote nerve cell demise in the brain
"Resistance to infections needs to be coupled with tolerance to the delicacy of the system," says Mucida, who led the research together with co-first authors Ilana Gabanyi, a postdoctoral associate, and Paul Muller, a graduate student. "Our work identifies a mechanism by which neurons work with immune cells to help intestinal tissue respond to perturbations without going too far."
Opposites react
Different populations of macrophages are among the many types of immune cells present in intestinal tissue. Lamina propria macrophages are found very close to the lining of the intestinal tube, while muscularis macrophages are in a deeper tissue layer, more distant from what passes through the intestine.
Using an imaging technique developed by Marc Tessier-Lavigne's Laboratory of Brain Development and Repair that allows scientists to view cellular structures three-dimensionally, the researchers looked in depth at the differences between the two populations. In addition to variations in how the cells look and move, they noticed that intestinal neurons are surrounded by macrophages.
When Mucida and colleagues analyzed the genes that are expressed in the two macrophage populations, they found that lamina propria macrophages preferentially express pro-inflammatory genes. In contrast, the muscularis macrophages preferentially express anti-inflammatory genes, and these are boosted when intestinal infections occur.
Learn More: Head injury causes the immune system to attack the brain
"We wanted to know where this signal was coming from that induced this different response to infection," says Mucida. "We came to the conclusion that one of the main signals seems to come from neurons, which appear in our imaging to almost be hugged by the muscularis macrophages."
How the gut-brain axis halts inflammation
In other experiments, the scientists found that muscularis macrophages carry receptors on their surface that allow them to respond to norepinephrine, a signaling substance produced by neurons. The presence of the receptor might indicate a mechanism by which neurons signal to the immune cells to put a stop to inflammation.
The researchers also observed that the muscularis macrophages are activated within one to two hours following an infection—significantly faster than a response would take if it were completely immunological, not mediated by neurons. They believe that was because these deeply embedded macrophages receive signals from neurons, they are able to respond rapidly to an infection, even though they are not in direct contact with the pathogen.
"We now have a much better picture of how the communication between neurons and macrophages in the intestine helps to prevent potential damage from inflammation," says Mucida. "It's plausible that a severe infection could disrupt this pathway, leading to the tissue damage and permanent gastrointestinal changes that are seen in diseases like irritable bowel syndrome. These findings could be harnessed in the future to develop treatments for such diseases."
The Rockefeller University press release
Gabanyi I et al. Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages. Cell, Published Online January 14 2016. doi: 10.1016/j.cell.2015.12.023


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Introducing Hopkins Dining: A new dining experience coming in fall
/ Published April 25, 2022
We're excited to announce the new Hopkins Dining program coming to Johns Hopkins University this fall! Hopkins Dining was created in response to the university's decision to transition to a self-operated dining model, providing the institution with more freedom in developing a program that is focused on enhancing the student experience and implementing more sustainable food practices. Leaders of the new program will also seek to cultivate meaningful relationships with students, faculty, and staff to create a dining experience that's especially tailored to their wants and needs. Though several changes are underway, many of the current dining staff that you've come to know and love will be joining the Hopkins Dining family. As we prepare for the official launch of Hopkins Dining this fall, here are a few things that you can look forward to with the new program:
A Fresh Look
When students arrive to campus this fall, they will notice an updated appearance in our dining locations. Our facilities will undergo a much-needed facelift this summer to provide a fresh look and customer-friendly experience when visiting each location. In addition to updated facilities, keep an eye out for new employee uniforms, signs, and branding to enhance your dining experience.
A Student-Centered Experience
We understand that food plays an integral role in the well-being and success of our students. Because of this, our goal is to provide students with a well-rounded dining experience that's focused on nutrition, community, enrichment, and fun! Students can expect to see a wide array of dining events including food holidays, cultural events, and sustainable initiatives.
Sustainability & Local Partnerships
In alignment with the university's commitment to sustainability, Hopkins Dining plans to continue existing sustainable practices while also fostering new opportunities to enhance the program. Beyond our day-to-day practices, we've made sure that our local partners also align with our intentional mission of a sustainable, authentic, and inclusive new program. Through our supply chain partnerships, for example, we've selected Gold Crust Bakery which uses all solar energy to power their facility. We're thrilled to also welcome new supply partners including Gluten-Free Bakery Girl, Chesapeake Bay Roasting Company, and more!
A Team of Experts
In recent months, we've been working to develop a robust group of experts who are dedicated to providing you with a quality dining experience. Our team is working diligently to ensure a seamless dining operation when you return next fall. Julie Allbrooks, senior administrative coordinator, says, "It's the people in the Dining Program and JHU at large that make me love working here. The high level of creativity, talent, and personal drive for excellence is a common thread running through nearly everyone I have worked with while at JHU. I am excited to provide support to Dining Programs staff as they roll out new innovations and transformations to the Dining Program for the entire JHU community."
We want to connect with you! Be sure to follow us on Facebook, Instagram, and Twitter (@hopkinsdining) to stay updated on all things campus dining. We're also excited for the fall launch of our Dining Digest newsletter, delivering the latest Hopkins Dining news—including events, specials, and announcements—to your inbox each month. Finally, students can expect new feedback programs that will allow them to connect with our dining team in real-time.
Our team is excited to launch Johns Hopkins into a new era of dining experiences. Can't wait to experience the new Hopkins Dining? Visit our website to learn more about how you can enroll in a meal plan just in time for next year. As we aim to create a program that is focused on the student experience, we're looking forward to seeing you in the fall, receiving your input, and evolving into a dining program for the whole JHU community!


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