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Dosage-sensitive genes in evolution and disease
Alan M. Rice1 &
Aoife McLysaght1
For a subset of genes in our genome a change in gene dosage, by duplication or deletion, causes a phenotypic effect. These dosage-sensitive genes may confer an advantage upon copy number change, but more typically they are associated with disease, including heart disease, cancers and neuropsychiatric disorders. This gene copy number sensitivity creates characteristic evolutionary constraints that can serve as a diagnostic to identify dosage-sensitive genes. Though the link between copy number change and disease is well-established, the mechanism of pathogenicity is usually opaque. We propose that gene expression level may provide a common basis for the pathogenic effects of many copy number variants.
Gene dosage matters
At the evolutionary level, gene duplication is an important and common process [1]; at the population level, copy number variation is the most abundant kind of genetic variation per base-pair [2]; and at the individual level, gene expression is often noisy [3]. All of these observations add up to the conclusion that for many of our genes there is good tolerance for changes in dosage. Indeed, Sewell Wright argued that even the very phenomenon of genetic dominance is suggestive of a tolerance of gene dosage changes [4]. However, for a significant fraction of the genome alteration of gene dosage has deleterious effects. This is most plainly seen in the association of copy number variants (CNVs) with human disease, including heart disease, cancers, diabetes and neuropsychiatric disorders, among others [5,6,7,8]. This dosage sensitivity reflects the generally linear relationship between gene copy number and protein product in most cases [9, 10].
A dramatic but transient form of dosage alteration occurs during every cell cycle where there is a drastic disruption to the relative ratios of gene copy number, with early-replicating DNA regions being twice as abundant as late-replicating regions during S-phase. Dosage sensitivity would predict that this should be compensated, and indeed elaborate mechanisms exist to mitigate this imbalance—it was recently discovered that in eukaryotes histone-mediated dosage compensation mechanisms dampen expression from early-replicating loci during cell replication, thus rebalancing the gene products with those from late-replicating loci [11, 12]. By contrast, in bacteria the differential ratio of early- and late-replicating genes is used as a cell cycle signal [12]. These systems have deep differences, but in both cases we see that even a transient change in relative gene dosage has noticeable consequences.
Dosage sensitivity
There are several different ways in which gene dosage can matter (Fig. 1). Haploinsufficiency, where a hemizygous state does not produce sufficient gene product for correct function, proposed by Wright as a source of dominant negative effects [4], is perhaps the most intuitive of the dosage constraints and has long been recognised as a cause of human disease [13], 22q11 deletion syndrome being just one well-studied example [14]. A recent large survey of human genetic variation identified over 3000 genes in the human genome with a near-total absence of loss-of-function alleles, suggesting that many of these are in fact haploinsufficient; over 70% of these were not previously associated with disease [15].
Various types of dosage sensitivity. Dosage sensitivity can be due to any of several different mechanisms. a For some proteins there is a minimum amount of active product required for normal function (haploinsufficiency). A hemizygous deletion or other loss of function allele will reduce the amount of active product below the threshold for functionality. b Some proteins form inappropriate interactions at high concentration, such as protein aggregation. These aggregates may themselves be toxic, or may phenocopy a deletion by removing the proteins from availability. c Dosage-balanced genes have constrained relative stoichiometry, for example the ratio of gp6 protein to gp7 protein in phage HK97 must be correct in order to achieve correct protein complex assembly. If gp6 is present in excess it preferentially forms large homomers, thus becoming unavailable to form the complex with gp7. d A simplified, hypothetical example of concentration-dependent activity based on the splicing of pyruvate kinase M, where the concentration of the splicing regulator determines its location of binding, which in turn determines which isoform is produced. Panel d is a modified from [25]
By contrast, why the presence of a surplus copy of a perfectly good gene should be deleterious is less obvious. Charcot-Marie-Tooth disease, a hereditary neuropathy, was one of the first human diseases shown to be due to duplication of a dosage-sensitive gene, PMP22 [16, 17]. The fact that some phenotypically normal individuals carry both a duplication and a compensatory deletion of this gene supports the dosage sensitivity model rather than any other regulatory or structural effects as the underlying mechanism behind the disease condition [18]. In some cases, especially for intrinsically disordered proteins, the basis of pathogenicity may lie in an increased propensity for low-affinity off-target interactions at high concentrations [19, 20]. For example, extra copies of the α-synuclein gene (SNCA) are associated with early-onset Parkinson's disease, possibly due to greater protein concentration increasing the likelihood of protein aggregation [21, 22]. Though, mechanistically speaking, why protein aggregates should have such devastating effects remains unclear [23].
Yet other genes are sensitive to both increases and decreases in copy number: many developmental morphogens act in a concentration-dependent manner [24]; whether pyruvate kinase M (PKM) is spliced into the adult or embryonic isoform depends on the concentration of hnRNP proteins, with high concentrations in cancer cells resulting in the ectopic production of the embryonic form [25]; and some sets of genes have constrained stoichiometry such that deviations from the normal ratio is deleterious, that is, they are dosage balanced [26]. Members of protein complexes may be particularly dosage balanced as deviations from the correct ratios of subunits can disrupt the biochemistry of protein complex assembly in non-linear ways, such that a 50% decrease in the amount of one component can result in a greater than 50% decrease in the amount of active product. Similarly, and somewhat counter-intuitively, even an increase in one of the components can result in a decrease in the amount of complete protein complex produced [20,28,29,30,31,, 27–32].
The dosage balance model contends that, for genes that are in stoichiometric balance, any perturbation of their relative ratios is deleterious [26, 32, 33]. Under this model, sets of dosage-balanced genes can only change copy number in concert or not at all. There are multiple lines of evidence for this model, including: the copy number of different components of the ribosome co-vary to retain stoichiometric balance [34]; in some cases an artificially induced overexpression phenotype can be rescued by the overexpression of an interacting partner [35]; and genes whose products form protein complexes are not normally duplicated [36].
Dosage-sensitive genes are duplicated by polyploidy or not at all
The knowledge that some genes in the genome are sensitive to copy number changes, should they occur, suggests a model where these genes have persistent sensitivity to evolutionary dosage changes, whereas other genes have no such sensitivity. The tendency of a gene to be duplicated or not is referred to as 'duplicability'. The observation that duplicability is a relatively stable property of a gene, with some genes consistently found as singletons and others repeatedly independently duplicated across distant lineages [37], supports the existence of ancient and persistent dosage constraints on genes. However, it is useful to remember that these dosage constraints are not a limit on the absolute number of copies of a gene, but on the ratio of a gene product to other components of the cell, either in terms of overall concentration or in terms of specific interacting partners [26,39,, 27, 38–40]. So, the non-duplicability of dosage-sensitive genes relates to one-by-one duplication or loss and not to concerted events. Indeed, if a given set of dosage-balanced genes were to be linked on a chromosome, then a single segmental duplication including all of them may not be deleterious [41].
By definition, even genes that are not normally 'duplicable' are duplicated by whole genome duplication (WGD; or polyploidy). This event creates no deleterious imbalance, because, even though all of the genes are duplicated, the ratios remain unchanged. During the subsequent period of extensive gene loss that has followed every known polyploidy event [42] deletion of some, but not all, of a set of dosage-balanced genes would be deleterious, being imbalanced. This leads to the prediction that such genes should be preferentially retained through this period of purging of paralogs [43]. Consistent with expectations based on dosage sensitivity, we and others have observed that genes that are not generally duplicable by small-scale duplication (SSD) are in fact disproportionately retained after polyploidy [44,45,46,47,48]. The patterns of general duplicability by SSD and of retention after WGD are so contrasting as to result in almost completely non-overlapping groups of genes.
The dosage balance model prediction that WGD paralogs (termed 'ohnologs' [42, 49]) should be enriched for dosage-sensitive genes is supported by the observation that most ohnologs are unduplicated even in lineages that diverged prior to the WGD event and do not experience subsequent duplications except if by another WGD event [44, 47]. This duplication constraint extends into recent population polymorphism: we found that ohnologs are rarely observed in CNVs in healthy individuals, whereas genes that are frequently copied by SSD also commonly have benign CNVs [47]. In other words, the general trend is that genes that can be individually duplicated, are; by contrast dosage-sensitive genes are duplicated by polyploidy, or not at all.
CNVs and dosage sensitivity
The existence of CNVs has been long known, but since they were recognised as a significant category of genetic variation 13 years ago [50] our understanding of how they are generated and their phenotypic consequences has grown. Like any kind of genetic variation, the global distribution of CNVs is determined by demography and selection [51,52,53]. Many CNVs are selectively neutral [2], sometimes even when present as homozygous deletions [54]. Instances of positive selection include adaptations to diet [55] and pathogen resistance [56]. However, a significant number of CNVs are deleterious and associated with disorders [57, 58], including developmental delay [6], hearing loss [59], heart disease [7] and neuropsychiatric conditions [60, 61].
Obviously, any CNV changes the copy number of genes contained within its breakpoints, but it is not necessarily the case that the phenotype of any given CNV is due to gene dosage changes as the CNV will also potentially disrupt genes, uncouple genes from their regulatory sequences, or alter chromosome three-dimensional organisation [62,63,64,65,66,67,68] (Fig. 2). Nonetheless, dosage sensitivity of the encompassed genes is the most popular hypothesis to explain pathogenic CNVs, with multiple examples known [69]. This view was supported by an evolutionary analysis of gene duplication and loss across mammals where we found that genes in pathogenic CNVs have much more conserved copy number than genes observed in CNVs in healthy individuals [48]. This observation is uniquely explained by copy number constraints on the enclosed genes rather than any other model of CNV pathogenicity.
Multiple different ways in which a CNV can have a pathogenic effect. a CNVs cause duplication and/or deletion of the enclosed genes. If one or more of those genes is dosage-sensitive then there will be a consequent phenotype, usually deleterious. b, c Alternatively, CNVs with breakpoints within a gene disrupt the gene by truncation (b) or formation of chimeras (c). Gene truncation will usually result in loss of function, but may alternatively result in a gain of function, dominant negative effect. Chimeric genes have unpredictable effects, and may be pathogenic. d Topologically associating domains (TADs) are structural units in the three-dimensional organisation of the genome and play a large role in mediating gene–enhancer interactions and other aspects of gene expression regulation. TADs are isolated from each other by TAD boundaries, which are determined by protein binding sites. CNVs encompassing TAD boundaries create new TADs. These can result in rewiring of gene enhancer interactions including the isolation of a gene from its regulator or the placement of a gene under the regulation of an inappropriate enhancer. Disruption of TADs has been associated with human disease [64,65,66, 68]
Dosage sensitivity and genome evolution
Not surprisingly, dosage-sensitive genes have also played an enormous role in the evolution of gene content and gene expression of sex chromosomes. Not only did they precipitate the evolution of elaborate dosage compensation mechanisms [70,71,72], but they also have shaped gene content through both purifying selection and relocation of dosage-sensitive genes to autosomes [73,74,75,76,77]. For other dosage-sensitive genes that did not relocate to autosomes, especially members of large protein complexes, we and others have shown that the expression of sex-chromosome-linked genes and their autosomal interacting partners has evolved so as to maintain stoichiometric balance [78, 79].
Because dosage-sensitive genes are refractory to duplication events, and because duplications are often long, encompassing multiple genes [80], the simple presence of dosage-sensitive genes has incidental effects on neighbouring genes. The likelihood that a duplication of a given gene also includes a dosage-sensitive gene should decrease with the physical distance between them. Using ohnologs as a proxy for dosage-sensitive genes, we found evidence in support of this model, as the closer a gene is to an ohnolog the less likely it is to be duplicated [81]. This effect is sufficiently strong to create SSD and CNV deserts in the human genome [81].
One of the principal mechanisms of generation of CNVs is by non-allelic homologous recombination (NAHR; recombination events between different loci with high sequence similarity) [82]. Approximately 10% of the human genome is subject to recurrent CNVs due to the existence of NAHR hotspots [83]. These hotspots are created by the presence of segmental duplications (low-copy repeat sequences) that are at least 95% identical at the DNA level, at least 10 kb long, and located between 0.05 and 10 Mb apart [84]. At least 2129 known recurrent pathogenic CNVs occur at NAHR hotspots [85] and in at least two cases new human disease-associated NAHR hotspots were created by recent lineage-specific segmental duplication events [17, 86]. In both cases there is an as yet unproven claim that the duplication event was itself adaptive, thus compensating for the risk of disease in offspring [86, 87]. It remains unknown how the propensity of segmental duplications flanking dosage-sensitive genes to generate pathogenic CNVs has impacted upon genome evolution. One might expect purifying selection to destroy the NAHR hotspots around dosage-sensitive genes, perhaps by genome rearrangement events that eliminate the proximity of the segmental duplications.
Evolutionary patterns are an informative trait to identify human disease genes
One of the recurrent pathogenic CNVs in humans occurs at 22q11, resulting in 22q11 deletion syndrome, which has a variable phenotype including heart defects, developmental disorders and schizophrenia [14]. Similarly, recurrent NAHR at 16p11.2 generates duplication and deletion CNVs, both of which are pathogenic, but which have different, 'mirrored' phenotypes impacting metabolism, developmental delay and neuropsychiatric traits [88, 89]. At both 22q11 and 16p11.2 there is a large CNV but also a smaller, 'critical' CNV with the same phenotype. As such, in each case the phenotype is considered to be due to dosage sensitivity of some of the genes within the smaller regions. However, even within the critical regions the number of genes is still quite large, numbering 28 and 26 for 22q11 and 16p11.2, respectively. An important challenge is to identify the most likely candidate genes for the phenotype from among these.
Evolutionary analysis provides a powerful method for pinpointing the dosage-sensitive genes within these and other CNV regions. Our detailed inspection of the evolutionary copy number conservation of the genes in the 22q11 deletion syndome region revealed that orthologs of 16 out of the 28 genes are present (never lost) across 13 mammalian genomes analysed [48]. Similarly, in the 16q11.2 region, 13 out of the 26 genes in the critical region have completely conserved copy number (1:1 orthologs) in all mammalian genomes analysed (Fig. 3). These completely conserved genes fit the profile expected of dosage-sensitive genes, and as such are attractive candidate genes for the syndrome.
Evolutionary conservation of copy number of genes in the 16p11.2 recurrent CNV region. The genes in the 16p11.2 region are illustrated across the top, with Mbp co-ordinates indicated above and gene names below. The critical region (dashed outline) indicates a smaller CNV that exhibits the same phenotype as the larger CNV and so is considered sufficient for the syndrome. For each of the mammals, if the ortholog is duplicated it is represented by a green dot, and if not found (presumed deleted) it is represented by an orange dot. Otherwise the copy number is unchanged with respect to human. Where a given gene has 1:1 orthologs across all 13 mammals tested this is indicated by a red vertical stripe. Genes in the region that were not amenable to this analysis are indicated by greyed-out names. Copy number conservation data are from [48]. BOLA2, SLX1 and SULT1A are part of a human-specific duplication with paralogs present on both flanks of the critical region and which increased the susceptibility to NAHR [86]
Trisomies are chromosomal abnormalities that are at least conceptually comparable to large CNVs. Trisomy 21, which results in Down's syndrome, is the most common human trisomy, occurring in approximately 1 in 700 live births [90]. The next most common human trisomies, 18 and 13, can survive briefly post-birth and result in Edward's syndrome and Patau syndrome, respectively. Other trisomies occur but are inviable [91]. The high frequency of trisomy 21 reflects the fact that it results in a relatively mild syndrome.
The pathogenic effects of the trisomy are likely to be due to a combination of the effects of the specific genes on the chromosome [47, 90] and general expression dysregulation [92]. In yeast the phenotype of an aneuploidy is largely independent of the identity of the chromosome [93], suggestive of a general disruption, not specific to the biochemical function of particular genes. Why human trisomy 21, 18 and 13 in particular are unusually viable is probably related to the low number of genes encoded on each chromosome. However, as with pathogenic CNVs, it is likely that only a subset of these are dosage sensitive. There is a very interesting correlation with the number of ohnologs (here again, a proxy for dosage-sensitive genes) and trisomy severity. Human chromosome 21 has the most common (least severe) trisomy and the smallest number of ohnologs. Similarly, chromosomes 18 and 13 have the next smallest numbers of ohnologs, and the next highest trisomy incidences, respectively (Table 1). By contrast, none of the mouse trisomies is viable (only mouse trisomy 19 survives 1–4 weeks post-birth [94]). However, there is a similar correlation between the number of ohnologs and the gestational survival of trisomies (Table 2). At least for human chromosome 21 we found that this number of ohnologs is surprisingly small even given its small number of genes [47]. Three-quarters of previously reported Down's syndrome candidate genes were independently discovered by this evolutionary analysis, but other genes were also identified as under evolutionary constraint that were not previously recognised to have an association with the syndrome. Thus, we argued that these genes, distinguished by their characteristic pattern of evolutionary copy number conservation, are interesting candidate genes for Down's syndrome [47]. Though aspects of the syndromes are clearly related to the specific genes on the chromosome, the correlation with number of genes encoded and perhaps specifically with the number of ohnologs suggests a general relationship with the extent of the burden of dosage-sensitive genes.
Table 1 Human autosomes with common trisomies, in ascending order of number of ohnologs
Table 2 Mouse autosomes in ascending order of number of ohnologs
Gene expression burden as a possible explanation for duplication phenotypes
As mentioned earlier, we and others found that genes that are successfully duplicated by SSD are usually not retained after WGD, and vice versa [46, 47, 81, 95, 96]. Curiously, these contrasts also carry over into the differences in gene expression level and coding sequence length. Whereas in human the median expression for SSD paralogs is 13.4 RPKM (reads per kilobase of transcript per million mapped reads) and the median CDS length is 1206 nucleotides, these values are much higher for ohnologs (23.7 RPKM and 1557 nucleotides, respectively). A similar pattern is seen in paramecium [97].
These contrasting patterns of expression for SSD paralogs and ohnologs could be explained if there are very different consequences of duplicating one (or a few) highly expressed gene(s) by SSD, compared to balanced duplication of all genes simultaneously by WGD. These different consequences might arise not only because some genes have dosage constraints (such as the requirement to maintain balanced ratios between specific gene products) and thus cannot be duplicated individually [38, 47, 98], but also because an extra copy of a highly expressed gene may be costly in terms of cellular resources [99,100,101].
This latter idea is consistent with observations from yeast where it was shown that overexpression of highly expressed genes has a greater negative effect than of less highly expressed genes [35]. The reported experiments linked the deleterious phenotype to the protein burden rather than the protein biochemical function (the phenotype was recapitulated when the protein sequence was replaced by green fluorescent protein (GFP)) but did not dissect the nature of that burden.
WGD defies this cost, as can be seen plainly in the readiness with which plant genome ploidy increases [102], an extreme example being oilseed rape which has a 72-fold increase since the origin of angiosperms owing to multiple WGD events [103]. This makes intuitive sense if the WGD increases and draws down cellular resources evenly, with no net difference compared to the pre-WGD genome. It has previously been shown that the greater the proportionate increase in copy number, the greater the phenotypic consequence; that is, adding one extra copy to a haploid is more dramatic than adding one extra copy to a diploid [30]. Thus, the greater the number of copies of a given gene, the lesser the impact of one more copy. One could therefore predict that the effects of SSD in a genome with a history of multiple WGD events, like that of oilseed rape, would be much reduced compared to an outgroup.
Is gene expression a zero-sum game?
The idea of a cost associated with gene expression has rich theoretical support and experimental evidence [99,100,105,101, 104–106]. Furthermore, highly expressed genes are expected to be particularly dosage sensitive [35, 97]. Protein expression is a significant fraction of a cell's energy budget [99, 100, 107]. The cost of expression can be expanded to include a model where overexpression of one locus is not merely a waste, but actually sequesters cellular resources away from other genes. Clearly the number of RNA polymerases available for transcription and the number of ribosomes available for translation are both finite, but are they sometimes limiting? Experiments in Escherichia coli found the rather surprising result that overexpression of one locus could lead to a depletion of ribosomes [104]. Other experiments showed that the cost of overexpression is not due to protein biochemical function or amino acid usage, but can be fully explained by the cost of the process of gene expression [101]. Rather than simply requiring resources, overexpression of some genes should naturally titrate out polymerases, ribosomes and other cellular resources so that they become unavailable for other genes. In other words, a duplication of a 'greedy', highly expressed gene might exert a deleterious effect by indirectly lowering the expression of other genes. This model views gene expression as a 'zero sum game', where an increase in one gene may cause decreased output from another. This is consistent with a recent model of human disease dubbed the 'omnigenic' model, where regulatory changes to any gene expressed in a disease-relevant tissue may contribute to disease whether or not there is a direct mechanistic link to the disease phenotype [108]. The authors of the omnigenic model suggest that gene regulatory networks are so interconnected as to allow changes in any expressed gene to affect any other.
Under the 'zero sum' model the barriers to duplication, that is, the costs of duplication, will sometimes lie not in the biochemical function of the gene that has been duplicated (though this is undoubtedly the case in many instances) but in the cost of the process of gene expression in terms of both energy (the cell spends seven ATPs for every amino acid of a protein) and the sequestration of the cell machinery such as polymerases and ribosomes. If RNA polymerases and ribosomes are limiting factors in the amount of gene expression possible from a given cell, then titration of these macromolecules by the doubling of a long, highly expressed gene would have knock-on consequences for the expression of other highly expressed genes, which may become reduced to pathogenic levels. Notably, this cost would not be incurred in WGD because all components of the system, including expression machinery, are duplicated equally, and all ratios remain constant.
Outlook – Gene expression as a keystone to understanding copy number constraints?
This view of gene dosage sensitivity may sit alongside other more well-established modes of dosage sensitivity [30]; however, it is currently speculative. In particular one must query whether duplication of one highly expressed locus would have sufficient impact on cellular resources when expressed at physiological levels to have any effect. The costs ought to matter more in rapidly proliferating cells, which may limit this to microbial organisms [100], but they may also be relevant for quickly growing tissues. This is an interesting area to explore as it has the potential to explain some common trends in evolutionary gene duplication by different mechanisms and link this propensity to disease phenotypes of human CNVs and trisomies.
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We thank Laurence Hurst, Yoichiro Nakatani and all members of the McLysaght research group for valuable discussions. This work is supported by funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/European Research Council grant agreement 309834.
Smurfit Institute of Genetics, Trinity College Dublin, University of Dublin, Dublin 2, Ireland
Alan M. Rice & Aoife McLysaght
Alan M. Rice
Aoife McLysaght
Correspondence to Aoife McLysaght.
Rice, A.M., McLysaght, A. Dosage-sensitive genes in evolution and disease. BMC Biol 15, 78 (2017). https://doi.org/10.1186/s12915-017-0418-y
DOI: https://doi.org/10.1186/s12915-017-0418-y
Dosage-sensitive Genes
Dose Sensitivity
Copy Number Variation (CNVs)
Ohnologs
Pathogenic CNVs
In the Light of Evolution
BMC Biology Reviews


text:
Ep 15: Cactus Flower
Get the podcast: Listen here at PopD | Go to iTunes
Lucy says: # Pops ~ Lucy's rating breakdown: Structure: 3, Comedy: 5, Romance: 2
Jenny says: # Pops ~ Jenny's rating breakdown: Structure: 3, Comedy: 5, Romance: 2
Release Date: December 16, 1969 Director: Gene Saks Writers: I.A.L. Diamond. More info at IMDb.
Comedy, Podcast, Romance
Historical Survey Part 3
18 responses to "Ep 15: Cactus Flower"
when i first downloaded the podcast it was around an hour. then as i listened it cut off mid-sentence at around 47 mins. i think darth vader took over iTunes:)
Micki says:
(-: I'm going to try and listen to the podcast today. Structure 3 and Romance 2? I want to hear why.
By my reckoning (and I am vastly amused by this), there were four men, two women, and SEVEN on-screen romance connections with two off-screen romance connections. Stephanie wins the Most Swingingest Award for having romantic connections with Julian,?Igor, Sr. Chavez, Harvey — oh yeah, and that guy who broke her heart, and the married guy she dated for a long time. Up the off-screen romances to four.
Something like that should have looked like a Tinker Toy cannister, but they brought it off.
As far as warm and fuzzy feelings at the end, Toni and Igor get them . . . although, maybe not as many as if it were a straight romance. I was one of the few who could forgive Julian, but I think that's my weird romantic chemistry, and the fact that I think I could forgive Walter Matthau for almost anything up to an STD.
(-: Look forward to the podcast!
Merry says:
This sounds a bit like My Best Friend's Wedding, where I couldn't respect Julia Whosis for trying to break up her best friend's wedding because she suddenly couldn't bear that he was happy with someone else.
Lucy says:
Stephanie – sometimes this happens with iTunes, and I never know why. Here's what you do:
Unsubscribe to PopD. You won't lose anything you've downloaded.
Delete #15 and throw original file in the trash/recycle bin when iTunes prompts.
Resubscribe; the latest episode will re-download.
I wonder if there's a better way to do this in the new iTunes? I'll research it, but for now, this should work.
Micki wrote:
I was one of the few who could forgive Julian, but I think that's my weird romantic chemistry, and the fact that I think I could forgive Walter Matthau for almost anything up to an STD.
Micki – have you seen A New Leaf? Go watch that, and report back. 🙂
I haven't watched this in forever, but do remember something screwy about the romance. Enjoyable but not right. Looking forward to the podcast so you can remind me of it.
@Lucy: I've looked for A New Leaf, but it's just not available here. (-: I have to say, I'm doubly curious, now that you think Walter is a sociopath in it. I'm devoting an awful lot of brain time lately to my very strange passion for Walter Matthau . . . .
Good podcast. I liked the idea that Julian was the Master of the Universe, constantly defeated by these good people. Although, he does get his goodie in the end. Another a-ha moment: "(Watch him?) build lie upon lie without any motivation beyond selfishness." OK, I can see that as a flaw (in hindsight).
I have a question for y'all: what are some interesting ways to complicate a plot if there are no lies?
It's very interesting that all the men are cartoons in this movie, while the women are very full of character. Is *that* a product of the times? Who wrote this movie, anyway? I think in Bringing Up Baby, both are cartoons. Was there one where the men were well defined, but the women were kind of props? Perhaps . . . the one with Billie Holiday? I mean she was GREAT, but she was still very cartoonish. Then again, so was William Holden.
I think this is a terrible sin against men . . . so many media representations show them as concerned only with their work, and their cars, and their garages, and a great set of boobs, that it's very easy for women to buy into that. To not make their men think, or let them be emotional 12-year-olds, because everyone knows, "oh, boys will be boys."
Although, when there's a long silence, and I ask my husband, "What are you thinking?" he invariably answers, "Nothing." So . . . maybe men are cartoons after all?
(-: Jking, can't be true. Men are primarily responsible for most of the great literature, movies, music, government, etc in the world, so it can't be true. What's up here?
Sorry, went off the deep end. I should stick to the movies.
I really enjoyed the podcast. Lots of the recurring ideas in the duscussion are starting to bring my thoughts about romantic comedy into focus.
One question – as a non-writer I'm not sure I understand the meaning of "broke the protagonist. " Sorry if I missed the definition in the podcast.
I agree with your ratings for Cactus Flower. It was definitely a far stronger comedy than romance. The writing is so sharp in this and I'm a sucker for snappy dialogue. While that makes it fun to watch neither of the romances leave me with that vicarious warm happy glow.
Micki, your comment reminded me of something I meant to talk about – you said "It's very interesting that all the men are cartoons in this movie, while the women are very full of character. Is *that* a product of the times?"
My somewhat cynical take on this is from a feminist perspective. Women are acknowledged to be smarter and better people which is supposed to distract from the fact that men have so much more power in the society. This attitude fits with my memory of the times pretty much. And I agree with you, it doesn't do much service to men or women to depict men so cartoonishly.
Did you see that recent Atlantic that tried to posit women were taking over the world? And, they pointed out themselves, there were about three women involved in that issue . . . .
I think any art needs to refine a personality down — to portray people in all their glory and quirks is actually pretty distracting. But, there's a difference between 2-D and 3-D (and real people, who are in the fifth dimension or maybe the twilight zone (-:). Any art is going to reduce this to a few understandable brush strokes. But . . . there's a difference between the brushstrokes of a Neolithic artist and the unpracticed strokes of someone who doesn't know where the stroke has to go . . . .
@Lucy – thanks for the tips re: the podcast. Didn't work but I did get to listen to the end by going directly from here. I'll worry about iTunes later.
Lucy/ Jenny – thank YOU BOTH for figuring out who this movie belonged to. I was so confused. I got the cactus flower [Stephanie]/ Daisy [Toni] thing and then couldn't figure out why Toni was with Julian – yada yada. The lies kept derailing me.
One thing that I kept coming back to and likely I've gone off the rails is that it sometimes felt like a farce or something [Toni asking to meet the wife, wanting to make sure the kids were okay, etc] wrapped or at the core of a romance [Julian and Stephanie]. The problem was the farce was driving the story, not the romance.
Now, I too am curious about New Leaf. I did mention I also watched First Monday In October to counter balance this because he's a much better character in that and just great writing.
@Micki — I got shot at work the other day.
By an engineer who had meant to aim his nerf machine gun at another engineer, but still. Men are boys.
90% of my co-workers are men, most of them have a Ph.D in Genius and most of them spend a lot of time discussing deeply convoluted topics involving lots of diagrams and TLAs. Then they hop on one of the scooters (no, not kidding) and scoot down the hall to their next meeting.
I've never seen /any/ of my female co-workers use the scooters or bring nerf guns to work. Men are still boys at heart; I'm not sure women are still girls at heart. (Possibly we're all still young and perky though?)
That said, I still think the cartoonish representation of characters is lazy writing. If the author could throw in even /one/ opposing trait, it would give these two-dimensional characters a bit of shading.
I wonder if the cartoonish quality we are talking about really serves the comedy in this case. Julian begins the movie as the Master of his Universe. He is the guy with all of the power. We laugh at his struggles at the hands of Toni & Stephanie – which are ultimately due to the careless way he has wielded his power with lies and taking their place in his life for granted. It is very satisfying to us to see him paid back for treating these nice women unfairly. Our trouble with him as a character comes if we don't think he has suffered enough, lost enough power to become more relateable and sympathetic.. If he we think he has earned Stephanie then we are ok with him as the hero of the story. If not, then we aren't satisfied and he has really just been the temporary focus of the comedy more than a hero we can root for.
I think I may have accidently answered my own earlier question about Breaking the Protagonist there – right?
I second whoever it was in the other post that rooted for a Toni/Stephanie/Igor threesome.
Yeah, whose movie is this? I wouldn't have guessed it was Ingrid's (except for the title drop plot) for most of the movie. And you can't root for her to end up with the ass that she ends up with. Mostly I just waited for Toni to get with Igor already.
@Merry: I think I might be a little boy at heart, because I wish I had a scooter . . . . Not so crazy about the guns, although I know of a lot of women who love them.
The "whose movie is it" question kind of worries me. This movie is a bit ambiguous. Stephanie is the heart, Julian is the catalyst and the one who makes everything happen. I would say Julian changes the most — he goes from loving the moment to realizing his love for Stephanie, and he goes from being a confirmed bachelor to someone who wants to get married (albeit, to two women in one week . . . ).
However, this isn't just a movie about the laffs. There are some really basic human ideas at the bottom of it, and all the laughs come from those things. Bringing Up Baby — I really didn't care about the characters. Cactus Flower — I did care about the women, and it felt right that Julian and Stephanie got together at the end.
BTW, is this a new meme for the era? The switcheroo romance? I can't believe it is, but then again, I can't think of an earlier literary example (well, except for some of Georgette Heyer's works — Jenny mentioned that one, right? Cotillion?) Are there any movies that exploited that?
I had that problem, too. I thought it was great that they were trying something different, but an awful, withholding, selfish heroine was not a good way to go.
glee says:
LATimes article on "The Apartment" and its 50th anniversary can be found here: http://www.latimes.com/entertainment/news/la-ca-apartment-20100905,0,3264289.story
and a columnist's take on Rom Com: http://www.latimes.com/entertainment/news/la-et-rom-com-20100907,0,6669779.story
Ell says:
I'm even more confused about this movie after somebody said the protagonist's goals drive the action. 'Cause Toni drives the action–she wants to be able to marry Julian without guilt, and every time Julian's got her latest attempt covered with his latest REaction (as opposed to action), she comes up with a new wrinkle. But Toni's definitely not the protagonist. Catalyst? Given that Julian's ostensible goal is to marry Toni so she won't kill herself and real goal seems to be to keep her as his mistress, it gets complicated.
As for who the movie belongs to… I'm imagining a Julian played differently (yeah, I know, I keep doing that) with body language and so on to indicate just a hint of awareness that what he's doing is dodgy–he still chooses the lie but at least he hesitates–THAT Julian owns the movie. This one doesn't.

redpajama_set_name: RedPajamaCommonCrawl


text:
The Bilingual Brain | MIT Technology Review
Saima Malik-Moraleda, a fifth-year doctoral student in the Harvard/MIT program in the biosciences and technologies of speech and hearing, tries to help answer this question. In the process, she hopes to uncover ways to ease some of the cultural and political tensions that surround bilingualism, especially in cultures where certain languages have distinct political connotations. As a member of the McGovern Institute lab of Ev Fedorenko, PhD '07, which studies how brains create language, Malik-Moraleda is studying bilingual brains in a new way.
Neurobiologists generally focus on the relative involvement of different regions of the brain in bilingual activity. Malik-Moraleda goes even further by studying neural networks, the specific pathways by which information travels in the brain. Instead of simply observing which regions of the brain light up during a particular activity, it uses what's called a localized approach, tracking the reactions of specific sets of neurons within or sometimes between those regions.
Malik-Moraleda herself speaks Spanish, Kashmiri, Catalan, English, Urdu, Hindi and French, and she is learning Arabic. She has always been aware of the cultural issues raised by bilingualism. Her mother is Spanish and her father is from Kashmir, a disputed region of South Asia claimed by both India and Pakistan. Growing up, she spent the school year in Girona, a city in the Spanish region of Catalonia, and traveled with her father to Kashmir during the summer holidays.
Splitting his year between the two places revealed to Malik-Moraleda how differently they deal with bilingualism. Both areas are culturally different from surrounding areas and have historically fought for independence, so residents often speak a region-specific language as well as the primary language of the surrounding country(ies). On street signs in Barcelona, for example, "you're going to see Catalan first, then Spanish, then English," says Malik-Moraleda. But while Catalans prefer Catalan and tend to speak Spanish only when necessary, in Kashmir, she says, parents generally discourage their children from learning even Kashmir. Instead, they urge them to speak the most commonly used languages, Urdu or English, to better prepare them for school and a career.
As a polyglot child, seeing his relatives neglecting Kashmir bothered Malik-Moraleda. More than sadness or anger, she felt confusion – why, if given the chance, wouldn't someone seize the opportunity to speak two languages? "It always upset me," she says. She decided to pursue a career discovering how bilingual brains really work so she could show her community that bilingualism could have valuable benefits too.
Do beer and wine affect cholesterol levels?
9 surprising signs of an unhealthy gut.


text:
Vivek Kaul
About Vivek Kaul
Bad Money
Easy Money: Book 1
India's Big Government
Econ Central
Why Robots Are Not Going to Screw Humans-At Least Not Yet
If you are the kind who reads the inside pages of newspapers carefully, you would know that these days stories around robots replacing human jobs are quite common. Most of these stories are written in a way that suggest that doomsday is upon us.
But is it as straightforward as the newspapers and the media makes it out to be? I really don't agree. I had first written about this issue a few months back in the weekly Letter that I write, but given the importance of the issue, I am sharing my thoughts with the Diary readers as well.
In the recent past, there have been a spate of headlines in the media on the capabilities of robots having reached a stage wherein they can take on human jobs. Here are a few news items, along these lines, which I have come across over the last few months.
1) In May 2016, the shoemaker Adidas announced that it would start manufacturing shoes in its home country of Germany after nearly two decades. But it shall use robots and not human beings to do the same. The company calls its robot factory the speed factory. A second such factory is being planned in the United States as well.[i]
2) In another similar case, Foxconn, a company which manufactures mobile phones for both Samsung and Apple, is replacing 60,000 workers with robots.[ii]
3) In July 2016, HfS Research, a research firm based in the United States, predicted that by 2021, India's information technology companies will lose around 6.4 lakh jobs to automation. This is something that high ranking officials of Indian IT firms have also said.
4) In mid-September 2016, the textile major Raymond said that it was planning to slash 10,000 jobs across its manufacturing centres all across India and replace them with robots and technology. The company currently employs 30,000 employees.[iii] Hence, robots are likely to replace one-third of its workforce.
5) Driverless cars have already arrived. As Ruchir Sharma writes in The Rise and Fall of Nations—Ten Rules of Change in the Post-Crisis World: "The most common job for American men is driving, and one forecast has driverless smart cars and trucks replacing them all by 2020."[iv]
6) And if all this wasn't enough, on October 3, 2016, the World Bank President Jim Yong Kim said in a speech: "Research based on World Bank data has predicted that the proportion of jobs threatened by automation in India is 69 percent, 77 percent in China and as high as 85 percent in Ethiopia."[v]
These are just a few examples of the expectation that robots will take over human jobs that I have come across over the last few months. As can be seen, this threat looms not just over India but over large parts of the developed as well as the developing world.
As Rutger Bergman writes in Utopia for Realists: "Scholars at Oxford University estimate that no less than 47 per cent of all American jobs and 54 per cent of those in Europe are at the high risk of being usurped by machines. And not in a hundred years or so, but in next twenty years." He then quotes a New York university professor as saying: "The only real difference between enthusiasts and skeptics is a time frame."[vi]
Indeed, the threat of robots taking over human jobs is nothing new. So what makes the threat this time around so different from the previous ones? As Yuval Noah Harari writes in Homo Deus—A Brief History of Tomorrow: "This is not an entirely new question. Ever since the Industrial Revolution erupted, people feared that mechanisation [which is what robots are after all about] might cause mass unemployment. This never happened, because as old professions became obsolete, new professions evolved, and there was always something humans could do better than machines. Yet this is not a law of nature and nothing guarantees it will continue to be like that in the future."[vii]
The question is: What has changed this time around?
Human beings essentially have two kinds of abilities: a) physical ability b) cognitive abilities i.e., the ability to think, understand, reason, analyse, remember, etc. As Harari writes: "As long as machines competed with us merely in physical abilities, you could always find cognitive tasks that humans do better. So machines took over purely manual jobs, while humans focussed on jobs requiring at least some cognitive skills. Yet what will happen once algorithms outperform us in remembering, analysing and recognising patterns?"
Hence, the robots used until now essentially replaced the physical things that human beings did in factories. The trouble is that now the robots have also started thinking (in the form of algorithms) and hence, many more human jobs are on the line. Harari feels that "as algorithms push humans out of the job market, wealth might become concentrated in the hands of the tiny elite that owns the all-powerful algorithms, created unprecedented social inequality."
This argument along with the evidence offered before seems to be pretty convincing, if seen in isolation. But there is a lot more to this than just the evidence that is currently being offered. As Sharma writes: "While the robotics revolution could come faster than most previous technology revolutions, it is likely to be gradual enough to complement rather than destroy human workforce. A huge gap still exists between the size of the world's industrial robot population—about 1.6 million—and the global industrial labour force of about 320 million humans. Most of the industrial robots are currently unintelligent machines, committed to a single task like turning a bolt or painting a car door, and indeed half of them work in the car industry."[viii]
As per the International Federation of Robots, South Korea currently has the highest penetration of robots. The country has 437 robots per 10,000 employees. Japan and Germany come in second and third with 323 robots and 282 robots per 10,000 employees, respectively. China has 14 robots per 10,000 employees.[ix]
The point is that there aren't as many robots going around as there are made out to be. Also, it is worth remembering here that large parts of the Western world and Japan are currently seeing their population decline. China will also soon reach that stage as well. Hence, in that sense the robots will arrive at the right time replacing the decline in the labour force. As Daniel Kahneman the Noble Prize winning psychologist (he won the Economics prize) told John Markoff, a journalist, who covers science and technology for The New York Times: "You just don't get it…In China, the robots are going to come just in time."[x]
The point is that when it comes to big predictions like robots taking over human jobs, there are always a few ifs and buts. The trouble is that these ifs and buts are not being highlighted as much as the core argument of robots taking over human jobs, currently is.
Other than these factors there is a basic law in economics which goes against the entire idea of robots totally destroying human jobs. It's called the Say's Law. One of my favourite books in economics is John Kenneth Galbraith's A History of Economics—The Past as the Present (In fact, anyone who wants to understand economics should mandatorily make Galbraith a part of his readings). In A History of Economics, Galbraith writes about the Say's Law.
This law was put forward by Jean-Baptise Say, a French businessman, who lived between 1767 and 1832. As Galbraith writes: "Say's law held that out of the production of goods came an effective aggregate of demand sufficient to purchase the total supply of goods. Put in somewhat more modern terms, from the price of every product sold comes a return in wages, interest, profit or rent sufficient to buy that product. Somebody, somewhere, gets it all. And once it is gotten, there is spending up to the value of what is produced."
Say's Law essentially states that the production of goods ensures that the workers and suppliers of these goods are paid enough for them to be able to buy all the other goods that are being produced. A pithier version of this law is, "Supply creates its own demand."
As Bill Bonner writes in Hormegeddon—How Too Much of a Good Thing Leads to Disaster: "French businessman and economist, Jean-Baptiste Say, discovered that "products are paid for with products," not merely with money. He meant that you needed to produce things to buy things."
So what does this mean in the context of robots destroying human jobs? If robots destroy too many human jobs, many people won't have a regular income. If these people do not have a regular income, how are they going to buy all the products that robots are going to produce? And if they are not going to buy the products that robots are producing, how are these companies driven by robots going to survive?
This is a basic question that none of the analysts, who are predicting doom on the basis of robots taking over human jobs, have bothered to ask. For capitalism to survive, it is essential that human beings work and earn an income, only then can they go around buying everything that is being produced.
The basic problem with the robots taking over human jobs argument is best explained through this example. As Bergman writes: "When Henry Ford's grandson [Henry Ford II] gave labour union leader Walter Reuther a tour of the company's new, automated factory, he jokingly asked, "Walter, how are you going to get those robots to pay your union dues?" Without missing a beat, Reuther answered, "Henry, how are you going to get them to buy your cars?""[xi]
Also, another point that most analysts seem to miss is that if and when robots actually do start destroying many human jobs, it is stupid to assume that the governments will sit around doing nothing. There will be huge pressure on them to react and make it difficult for companies to replace human beings with robots.
To cut a long story short, it will be interesting to see how the robots taking over human jobs trend evolves in the years to come, but it will not be as straightforward as it is currently being made out to be. If we are still in business, we will surely keep a lookout!
The column originally appeared in Equitymaster on January 25, 2017
[i] Agence France-Presse, Reboot: Adidas to make shoes in Germany again – but using robots, May 25, 2016
[ii] J.Wakefield, Foxconn replaces '60,000 factory workers with robots', BBC.com, May 25, 2016
[iii] TNN and Agencies, Raymond to replace 10,000 jobs with robots in next 3 years, September 16, 2016
[iv] R.Sharma, The Rise and Fall of Nations—Ten Rules of Change in the Post-Crisis World, Allen Lane, 2016
[v] Speech by World Bank President Jim Yong Kim: The World Bank Group's Mission: To End Extreme Poverty, October 3, 2016
[vi] R.Bergman, Utopia for Realists—The Case for a Universal Basic Income, Open Borders and a 15-Hour Workweek, The Correspondent, 2016
[vii] Y.N.Harari, Homo Deus—A Brief History of Tomorrow, Harper, 2016
[viii] Sharma 2016
[ix] Ibid
[x] A Conversation With John Markoff. Available at https://www.edge.org/conversation/john_markoff-the-next-wave. Accessed on October 12, 2016
[xi] Bergman 2016
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West Sacramento Yellow Cab Company offers the most dedicated and quickest Taxi Cab Service for any of your transportation needs in this suburb. We proudly originated from this town, and we still proudly serve our West Sacramento customers; so we would love the local residents to support our company. We connect the local resident commuters to Downtown Sacramento and to rest of the world by making daily trips to the Sacramento, Oakland, and San Francisco airports, and to the Greyhound and Amtrak stations. We offer service in older and the newer parts of the city. We provide locals rides to all the shopping centers like Wal-Mart, Target, Raleys and Safeway. Our customers from local hotels like Ramada Inn, Holiday Inn Express, Hampton Inn and Suites, Motel 6, and others businesses get a discounted rate if rides are booked in advance. We proudly service all of our customers to the local River Cats stadium and events at recreation center.
West Sacramento Yellow Cab is affiliated with its sister company Exotic Limos also based in the W. Sac. To proudly serve the citizens of West Sacramento with limo rental services, they offer special discounted rates for our Hummer, Escalade, Lincoln limos and Party buses. They offer wine tours to local Clarksburg wineries and trips to Napa and Amador wineries as well. The extensive limo fleet can be used for any event or service.


text:
ZWIENER, PHILLIP
Alba Berlin 7 Forward
Height: 2.01 Born: 23 July, 1985 Nationality: Germany
Totals 3 0 11:23 0 0/0 0/1 0/0 0 2 2 0 0 1 0 0 2 0 -2
Averages 3 0 3:47 0 0% 0% 0% 0 0.7 0.7 0 0 0.3 0 0 0.7 0 -0.7
12 vs Real Madrid 0:10
Average 0:10 0 0% 0% 0% 0 0 0 0 0 0 0 0 0 0 0
3 at Tau Ceramica 8:54 0/1 1 1 1 -1
5 at Union Olimpija 2:19 1 1 2 -1
2 Totals 11:13 0 0/0 0/1 0/0 0 2 2 0 0 1 0 0 2 0 -2
Average 5:36 0 0% 0% 0% 0 1 1 0 0 0.5 0 0 1 0 -1
Index rating 0 Real Madrid vs. ALBA Berlin 3/12/2009
Points 0 Real Madrid vs. ALBA Berlin 3/12/2009
Offensive rebounds 0 Real Madrid vs. ALBA Berlin 3/12/2009
Defensive rebounds 1 Cedevita Olimpija Ljubljana vs. ALBA Berlin 11/27/2008
Total rebounds 1 Cedevita Olimpija Ljubljana vs. ALBA Berlin 11/27/2008
Assists 0 Real Madrid vs. ALBA Berlin 3/12/2009
Steals 0 Real Madrid vs. ALBA Berlin 3/12/2009
Blocks 0 Real Madrid vs. ALBA Berlin 3/12/2009
Minutes 8 Baskonia Vitoria-Gasteiz vs. ALBA Berlin 11/5/2008
Grew up with Bremen Roosters (Germany) juniors.
Made his debut with Bremen Roosters during the 2002-03 season, in the German Bundesliga II.
Signed for the 2005-06 season by Alba Berlin Basketball Team.
Signed for the 2010-11 season by TBB Trier.
Signed for the 2012-13 season by Eisbaren Bremerhaven.
Signed for the 2014-15 season by EWE Baskets Oldenburg.
Won the 2007-08 German National Championship with Alba Berlin Basketball Team.
Won the 2006 and 2009 German National Cup with Alba Berlin Basketball Team.
Played the 2011, 2012 and 2104 German All Star Game.
Played has been member of the German U-18 and U-20 National Team.
Member of the German National Team.
Played at the 2008 Olympic Games.
Played at the 2013 European Championships.
Has been member of the German University National Team.
Played at the 2007 World University Games.
2008-09 Alba Berlin 3 0 0 0/0 0 0/1 0 0/0 0 2 0 0 0
Totals 3 0 0 0/0 0 0/1 0 0/0 0 2 0 0 0
Averages 3 0 0 0/0 0 0/1 0 0/0 0 0.7 0 0 0
2005-06 Alba Berlin 4 3 0.8 1/3 33.3 0/1 0 1/2 50 3 2 0 0
2006-07 Alba Berlin 4 1 0.3 0/0 0 0/1 0 1/2 50 0 0 1 0
2007-08 Alba Berlin 7 21 3 7/12 58.3 2/5 40 1/2 50 11 4 1 0
2009-10 Alba Berlin 5 9 1.8 3/7 42.9 1/1 100 0/0 0 2 2 2 0
2014-15 EWE Baskets Oldenburg 10 46 4.6 12/30 40 4/18 22.2 10/11 90.9 21 6 12 1
Totals 30 80 2.7 23/52 44.2 7/26 26.9 13/17 76.5 37 14 16 1
Averages 30 80 2.7 23/52 44.2 7/26 26.9 13/17 76.5 1.2 0.5 0.5 0
2002/03 Bremen 18 41 2.3 16/26 61.5 1/2 50 6/10 60 10 7 1 0
2003/04 Bremen 29 221 7.6 82/140 58.6 2/17 11.8 51/65 78.5 83 13 19 3
2004/05 Bremen 29 419 14.4 138/242 57 9/32 28.1 116/150 77.3 137 15 46 4
2005/06 Alba Berlin
23 43 1.9 14/36 38.9 2/2 100 9/16 56.3 26 3 5 1
17 53 3.1 8/22 36.4 5/11 45.5 22/25 88 25 4 6 3
34 93 2.7 22/46 47.8 8/21 38.1 25/36 69.4 50 12 18 5
13 38 2.9 8/12 66.7 4/12 33.3 10/16 62.5 12 1 2 1
2009/10 Alba Berlin 27 72 2.7 19/38 50.0 6/19 31.6 16/24 66.7 31 11 17 0
2010/11 Trier 30 384 12.8 122/249 49.0 17/50 34.0 89/120 74.2 139 11 33 3
2011/12 Trier 31 381 12.3 138/297 46.5 13/46 28.3 66/91 72.5 129 9 54 5
2012/13 Bremerhaven 34 325 9.6 90/208 43.3 18/52 34.6 91/112 81.3 122 21 50 4
2013/14 Bremerhaven 32 322 10.1 84/179 46.9 30/65 46.2 64/75 85.3 117 14 66 8


text:
El caballo islandés es una raza de caballo que se desarrolló en Islandia. Aunque estos equinos sean pequeños, a veces parecidos a los ponis, la mayor parte de los registros los consideran como caballos propiamente dichos.

Características
Es la única raza indígena de Islandia, pero se fue difundiendo en muchas partes del mundo, y también existen poblaciones considerables en otras partes de Europa y de Norte América. En Islandia se usa en las labores agrícolas, en muestras equinas, en la hípica y también para el consumo de su carne.

El caballo islandés es resistente y sufre pocas enfermedades. La legislación islandesa prohíbe que los ejemplares exportados regresen a la isla, para prevenir posibles contagios. Tiene además la característica de conocer dos maneras de andar suplementarias además de las tradicionales paso, trote, canter y galope.

Historia

Nacida de los ponis de los escandinavos entre los siglos IX y X, la primera referencia a esta raza se encuentra en el XII, cuando estos caballos eran objeto de culto en la mitología nórdica.

Su aspecto actual se debe a siglos de selección natural y genética. En 1780 una gran parte de su población autóctona falleció debido al Móðuharðindin, una erupción del volcán Laki.

La primera Sociedad del Caballo Islandés se creó en la isla en 1904. Hoy la raza está representada por organizaciones en 19 naciones, reunidas en la Federación Internacional de las Asociaciones del Caballo Islandés.

Véase también
Fauna de Islandia

Notas

Enlaces externos

Razas de caballo
Razas autóctonas de Islandia
Ponis

redpajama_set_name: RedPajamaWikipedia


mHealth is not a separate industry, but rather it's the future of a healthcare industry that's evolving to care for patients differently, putting them first to deliver services better, faster and less expensively.
Ageing populations and chronic illness are driving regulatory reform. Public sector healthcare is seeking better access and quality, and it's looking to the private sector for innovation and efficiency. mHealth improves access and quality, and offers dramatic innovation and cost reduction.
The foundations of industrialisation of healthcare are already in place — electronic medical records, remote monitoring and communications. 'Care anywhere' is already emerging. The platform for mHealth is set.
Healthcare, like other industries, is getting personal. mHealth can offer personal toolkits for predictive, participatory and preventative care.


text:
Customer 360 Transformation
The Importance
of Changing Mindsets
Introducing 360 Perspectives, a Series on How to Connect Silos and Put the Customer at the Center of Your Business
New Editorial Series
Introducing 360 Perspectives
Catch weekly coverage of customer-first businesses.
How to Plan the Ultimate Sales Kickoff: 5 Things You Need
Plan A Sales Kickoff
5 Things You'll Need
These meetings are an incredible tool.
Retail Trends: How to Engage Shoppers at the Edge
Engage Shoppers at the Edge
And, set yourself up for success this decade.
Jan 21, 2020 By Katherine von Jan
360 Perspective: How to Design Customer-Centric Business Processes
This post is part of a regular series called 360 Perspectives, featuring customers, partners, and experts unraveling the complexities of what it takes to change mindsets, connect silos, and put the customer at the center of their business. Your business processes are your company's habits —... Read More
CEO, Customer Engagement, Customer Experience, Best Practices
Jan 21, 2020 By Gary Brandeleer
4 Ways to Drive Customer Engagement With Connected Field Service
Every customer has felt the pain of scheduling a field service appointment: you're put on hold, slotted into next week's schedule, and told someone will come between 8 a.m. and 6 p.m. In short, you're subject to the inefficiencies of a reactive model in field service management. Why can't customers... Read More
Customer Service, Customer Experience, Digital Transformation, Service, Service Cloud
Jan 20, 2020 By Ruthie Miller
How to Develop a Sustainability Plan For Your SMB
Sustainability is always on our minds here at Salesforce — but what about the rest of our community? Recently Salesforce Research surveyed 1,300+ Dreamforce attendees to find out. We learned that employees of small and medium businesses (SMBs) feel strongly about their employers' sustainability... Read More
Small Business, Startups, Sustainability
How to Improve Field Service Scheduling and Planning
For decades, whiteboards were one of the most useful tools in field service scheduling and planning. Dispatchers manually mapped schedules based on input from staffing managers and identified an available field worker with little-to-no-visibility into the full mobile workforce. Unfortunately, this... Read More
Customer Service, Service Cloud, Customer Experience, Mobile, Omni-channel
Jan 17, 2020 By Matt Jaffe
The future of work is coming — and it will change the business world as we know it. But what does the future of work hold? How can we prepare for it? And beyond that, how can we succeed and thrive in it? Now, in the newest installment of Salesforce's Make Change series, hear from 18 C-suite leaders... Read More
CEO, Careers, Leadership
Jan 17, 2020 By Keara Cho
The Top Email Nurture Journeys Every SMB Marketer Should Build
Ever build 20 email marketing campaigns to find out only one works? The key to a successful marketing campaign is segmenting your target audience correctly and being customer-obsessed. But your job is not just to drive people to websites and have them fill out a form to become a lead; it's to be... Read More
Best Practices, Email Marketing, Small Business
Jan 16, 2020 By Erik Wagner
Disrupt or Be Disrupted: 4 Ways Providers Can Improve Patient Engagement
When a patient is hurt or sick, they simply want to get better. But there are many steps in between — make an appointment, fill out forms, see a doctor, get a prescription or referral — that the path to wellbeing often becomes burdensome. To add insult to injury (no pun intended), there's always... Read More
CEO, Customer Experience, Health Cloud, Healthcare & Life Sciences
Jan 15, 2020 By Lynne Zaledonis
I've been attending enterprise sales kickoffs (SKOs) for 20 years. Along the way, I've learned these meetings can be an incredible tool – or they can fall incredibly flat in engaging and inspiring sales reps. Sales leaders, you know what I'm talking about: those kickoffs that feel like a wall of... Read More
Best Practices, Sales, Sales Cloud
Jan 15, 2020 By Casey Coleman
How Empowering Employees With Technology Can Deliver Back to the Community
With industries around the globe raising the bar on innovations that drive personalized experiences, many government organizations also feel pressure to deliver better customer service in order to maintain public trust and credibility. As a result, they are seeking ways to leverage disruptive... Read More
Customer Experience, Digital Transformation, Industry Report
State of the Connected Customer
Here's how to stay ahead of changing customer expectations


text:
Golf >
DreamBig Gold Series Golf Camp to take place at Orchard
ABS-CBN Sports on Nov 15, 2019 05:44 PM
Golf Coaches from topmost schools in the US NCAA Division 1 will be present at DreamBig Gold Series Golf Camp and Tournament to be held at Orchard Golf & Country Club on December 17 and 18, 2019.
When the DreamBig Gold Series Golf Camp and Tournament opens at Orchard Golf & Country Club on December 17 and 18, 2019, junior golfers living in the Philippines will not only be able to hone their talents and get the chance to be scouted by world-class coaches. They will also enjoy huge savings and other conveniences of having the golf camps travel to Manila instead of them going abroad to join them.
Headlined as The Road To U.S. College Golf, the Dream Big golf camp will be preceded by the first-ever Future Champions Golf (FCG)-Dream Big Golf Challenger Series on December 16 and 17, a qualifier for the FCG Callaway World Championship. The winner of each age division in the Orchard tournament will qualify for direct entry to the FCG Callaway World Junior Golf Championship 2020 that will take place at Rancho Mirage, California on July 13 to 15, 2020.
Golf Coaches from topmost schools in the US NCAA Division 1 – UCLA (University of California – Los Angeles), Columbia University and UC Berkeley – will run the two-day golf clinic and oversee the 2-day FCG Golf Tournament.
Open to all junior golfers aged 12 to 18 years old, interested junior golfers and their parents have a choice of participating in both the tournament and the golf camp, or just one of the two activities.
"Either way they will be getting a tremendous advantage if they choose to join the tournament and the camp in Manila. The cost of the trip, the tuition and the accommodations abroad is quite prohibitive for players who want to bring their game to a whole new level. But now, Golf Coaches from topmost schools in the US NCAA Division 1 – UCLA (University of California – Los Angeles), Columbia University and UC Berkeley – are coming and will run the two-day golf clinic here. The savings will be tremendous," said Akshay Maliwal, Founder and CEO of DreamBig Events, who will stage the twin activities.
Maliwal said participants will save over USD 5000 by joining the camp in Manila and enjoy other advantages as well. The expenses abroad for camp tuition, airfare, board and lodging for athlete and chaperone, local transport expenses, and miscellaneous costs will add up to USD 5,900 and the athlete has to set aside seven days for travel and the camp itself.
"In contrast, taking advantage of the Gold Series Golf Camp and Tournament in Manila will cost only USD 870 and will take out just three days from the athletes' schedule. Airfare and travel costs are eliminated, as well as board and lodging. Over and above that, the Manila camp includes a qualifying tournament in the package – something that the camps abroad do not offer. With just one event, athletes have the opportunity to qualify for the Callaway Junior Tournament – the top tournament for junior golfers – and hone their skills at the camp as well. They have better access and opportunities to interact closely with the US coaches here; whereas interaction with coaches at similar camps in the US, is extremely limited," Maliwal said.
At the camp, campers will experience guided range and short game sessions that will allow them to sharpen their practice and pre-tournament routines. They will be given instruction that will help them expand their course management skills and prepare them for competition, as well as expose them to US coaching styles and competition at a higher level. The camp is limited to 30 participants only to enable personalized and customized instruction for each athlete.
"This is a once in a lifetime opportunity for young golf talents in the Philippines to put their country in the world map of junior golf. We have worked hard to bring this camp to Asia and the Philippines in particular because we believe in the wealth of talents here," Maliwal said.
Interested Junior Golfers may register here.
Mickelson struggles with driver in 2020 debut at La Quinta
Pinoy Junior golfers impress NCAA D1 Coaches
DreamBig helping Asian junior-athletes make it to US schools
FCG World Championship 2020 qualifier to be held in Manila
2020 Don Celso Tuason Cup showcases Valley Golf's rise


Latest news and a form enabling you to join this campaign can be found at the foot of this page.
This page was created to inform shareholders in Foresight 4 VCT Plc – a Venture Capital Trust with a patchy performance record. Foresight took over the management of Advent 2 VCT in 2004 and renamed it Foresight 4. In 2012 there were mergers with Foresight Clearwater VCT and with Foresight 5 and the Acuity VCT 3 – the latter two forming a separate class of "C" shareholders within Foresight 4.
In 2015, the share classes were amalgamated but the "C" share class holders were not pleased with the terms. ShareSoc published this blog note at the time on that subject.
The last published accounts (to March 2016) show a further substantial reduction in the net asset value of the company.
The current directors are Philip Stephens (Chairman), Peter Dicks and Simon Jamieson.
Foresight4-Letter (a pdf document – click on to access).
Updates 12/09/2016 and 24/9/2016. Note that subsequent to the above, Foresight 4 VCT and Foresight 3 VCT announced that they had entered into discussions on a merger with the intention of achieving cost savings from the establishment of a single, enlarged VCT (with Foresight 4 forming the legal base). That is likely to result in changes to the board of Foresight 4 but it may not resolve all of the issues raised in the aforementioned letter and Foresight 3 has similar problems.
Update 30/9/2016 – the result of the AGM is reported in this blog post.
In summary the directors only just managed to get re-elected!
Update 20/10/2016 – Foresight 4 VCT announced major changes. Surely a victory for investors and ShareSoc. See this blog post for more information.
Update 26/05/2017 – We recommend (with reservations) that shareholders vote in favour of the resolutions to merge Foresight 3 & 4 and to raise additional funds of £50 million, and possibly up to £100 million, (including a possible over-allotment facility for an additional £50 million). Click here to read the full update.
Update 16/06/2017 – Following the Foresight 4 AGM, ShareSoc member Roger Lawson wrote to the Chairman with his questions about NED, Mr Gray. Mr Gray denied any knowledge of business connections at the meeting, hence the need to send the Chairman the details in writing. Click here to read the letter.
If you wish to make a voluntary contribution to support the activities of ShareSoc please go to this page of our web site: Donations. Another way to support us is to become a full member of ShareSoc, which involves paying a modest annual membership fee and brings you numerous benefits, as well as supporting our cause.
Update 10/9/17 – ShareSoc isuues new voting recommendations for 2017 AGM. Click here to see the blog.


text:
In a continuation of the recent developments between Germany and Turkey the German finance minister is reported to have compared Turkey to the previous East Germany. The problems developing between the two countries have led to Germany considering political measures including travel warnings.
The following story is reprinted with permission of dpa-news.de
dpa news: (2017-07-22)
Berlin/Istanbul (dpa) - Turkish President Recep Tayyip Erdogan tried to reassure German investors Friday even as Berlin appeared to strengthen its resolve in a war of words and ideals, sharpening travel warnings and threatening sanctions.
Erdogan denounced recent German pronouncements as "black propaganda," "defamation," and "evil slander" as he rejected claims that Turkey was investigating German firms on terrorism charges.
"We are their guarantee. We are their security," said Erdogan on German firms, insisting business would continue as usual. "We have until now worked with them on a win-win basis," he added.
However, Erdogan indicated that Turkey would not release any German prisoners, including one man seized during a human rights conference in Istanbul.
"They must know that our judiciary is more independent than theirs," Erdogan said, adding that Turkey would not be threatened.
His remarks came after German Finance Minister Wolfgang Schaeuble told Bild newspaper that Turkey was no longer a country under the rule of law and compared it to communist East Germany.
"Turkey is now arresting people arbitrarily and is no longer upholding consular standards - it reminds me of what it used to be like in the GDR," he said, referring to the former German Democratic Republic.
German Foreign Minister Sigmar Gabriel this week had also warned that any German travelling to Turkey was at risk of arrest and threatened that export guarantees could be withdrawn.
On July 5, Turkish authorities detained six human rights activists - including Idil Eser, director of Amnesty International's Turkey branch, Ali Gharavi of Sweden and Peter Steudtner from Germany - at a conference in Istanbul. They were held for terrorism-related offences.
The detention of Steudtner, who had no previous affiliation with Turkey, prompted the latest round of tensions between the two trading partners.
Four other human rights workers were detained as part of the raid but then released on Tuesday, under restrictions. However, a fresh warrant was again issued for their capture late on Friday.
"We have a duty to protect our citizens and businesses," said Merkel's chief of staff, Peter Altmaier. Two German journalists, including Deniz Yucel, a correspondent for Die Welt newspaper, remain in Turkish custody on terrorism charges.
In a further escalation, Hans-Georg Maassen, the head of Germany's domestic intelligence service, said Friday that Turkey's covert operations on German soil had made the country an "adversary" to Germany.
"Since the coup attempt last summer and the changes to Turkey's domestic policies, we have viewed Turkey not only as a partner, but also - in light of its covert operations in Germany - as an adversary," Maassen said Friday.
The Turkish intelligence service MIT is alleged to have spied on suspected supporters of exiled cleric Fethullah Gulen - currently resident in the US - and other, Germany-based critics of the Turkish government.
Turkish Prime Minister Binali Yildirim said it was important to act with "prudence," adding that neither country had anything to gain by further harming their relationship, while recalling that Turkey and Germany have a long-standing link that dates back to World War I.
Earlier, Turkey's Foreign Ministry had accused Berlin of "blackmail" and said that it was a "double standard" to grant asylum to supporters of Gulen and the Kurdistan Workers' Party (PKK) while simultaneously demanding the release of German prisoners in Turkey.
Mustafa Yeneroglu, a lawmaker for President Recep Tayyip Erodgan's ruling Justice and Development Party (AKP), expressed outrage at a Bild headline that read "Turkey crisis: Is Erdogan arresting holiday-makers now?"
"Rabble-rousing Bild headline not only intimidates potential holiday-makers, but also (incites hatred) #racism #mediamanipulation," Yeneroglu wrote on Twitter.
German media reported Friday that Germany had suspended arms deliveries to Turkey, a member of the NATO military alliance, but this could not be independently verified.
Since the coup attempt last year, Turkey has jailed more than 50,000 people for alleged links to the Gulenists and purged some 150,000 people from the civil service and military.
Dozens of media outlets have been shuttered, as have private businesses and civil society groups. Around 165 media workers are jailed in Turkey.
Europe made a deal with Turkey more than a year ago that has helped reduce the number of new refugees arriving to EU nations.
Material with permission of dpa-news.de
Story reprint published by journalistfrei.de: July 25, 2017, 05:26 CET UTC +02:00


text:
<?php
class Table_tabletypeController extends Zend_Controller_Action {
	const REDIRECT_URL_ADD = '/table/tabletype/add';
	const REDIRECT_URL_ADD_CLOSE= '/table/tabletype/index';
	public function init()
	{
		header('content-type: text/html; charset=utf8');
		defined('BASE_URL')	|| define('BASE_URL', Zend_Controller_Front::getInstance()->getBaseUrl());
	}
	public function indexAction(){
		$db_table_type=new Table_Model_DbTable_DbTablesType();
	    $db=$db_table_type->getAllRowTablType();
	    $this->view->rows=$db;
		$frm = new Table_Form_FrmTableType();
		$this->view->form = $frm->Frm_table_type();
	}
	public function addAction(){
		if($this->getRequest()->isPost()){
			$data =$this->getRequest()->getPost();
			$db = new Table_Model_DbTable_DbTablesType();
			try{
				if(isset($data['btnsave'])){
					$data_table = $db->addTableType($data);
					Application_Form_FrmMessage::Sucessfull('ការបញ្ចូលជោគជ័យ', self::REDIRECT_URL_ADD);
				}
				else if(isset($data['btnsave_close'])){
					$data_table = $db->addTableType($data);
					Application_Form_FrmMessage::Sucessfull('ការបញ្ចូលជោគជ័យ', self::REDIRECT_URL_ADD_CLOSE);
				}
			} catch (Exception $e) {
				Application_Form_FrmMessage::message("INSERT_FAIL");
				Application_Model_DbTable_DbUserLog::writeMessageError($e->getMessage());
			}
		}
		$frm = new Table_Form_FrmTableType();
		$this->view->form = $frm->Frm_table_type();
	}
	public function editAction(){
				if($this->getRequest()->isPost()){
						$data =$this->getRequest()->getPost();
						$db = new Table_Model_DbTable_DbTablesType();
						try{
							 if(isset($data['btnsave_close'])){
								$data_table = $db->updateTableType($data);
								Application_Form_FrmMessage::Sucessfull('ការបញ្ចូលជោគជ័យ', self::REDIRECT_URL_ADD_CLOSE);
							}
						} catch (Exception $e) {
							Application_Form_FrmMessage::message("INSERT_FAIL");
							Application_Model_DbTable_DbUserLog::writeMessageError($e->getMessage());
					}
		}

		$id=$this->getRequest()->getParam('id');
		$db=new Table_Model_DbTable_DbTablesType();
		$row=$db->getTableTypeById($id);
		//print_r($row);exit();
		$frm = new Table_Form_FrmTableType();
		$this->view->form = $frm->Frm_table_type($row);
	}

}

redpajama_set_name: RedPajamaGithub