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The venom preceded the stinger: Genomic studies shed light on the origins of bee venom – EurekAlert

Posted: November 30, 2023 at 8:34 pm

image:

Components of the venom cocktail used by wild bees such as the Banded Mud-Bee (Megachile ericetorum) are evolutionarily older than their sting.

Credit: Bjrn von Reumont

FRANKFURT. Venoms have developed in many animal groups independently of each other. One group that has many venomous species is Hymenoptera, an insect order that also includes aculeates (stinging insects) such as bees, wasps and ants. Hymenoptera is very species-rich, with over 6,000 species of bees alone. And yet, despite the great ecological and economic importance of hymenopterans, very little is known about the evolutionary development of their venoms.

By means of comparative genomics, researchers led by Dr. Bjrn von Reumont, who is currently a visiting scientist in the Applied Bioinformatics Working Group at the Institute for Cell Biology & Neuroscience of Goethe University Frankfurt, have now examined systematically and for the first time how the most important components of the venom of bees and other hymenopteran taxa developed in the course of evolution. The toxins are complex mixtures composed of small proteins (peptides) and a few large proteins and enzymes. Stinging insects actively inject this poisonous cocktail into their prey or attackers with the help of a special sting apparatus.

In the first step, the researchers identified which of the peptides and proteins in the venom were most prevalent in hymenopterans. To do this, they drew on information from protein databases, although this was sparse. In addition, they analyzed the proteins in the venoms of two wild bee species the violet carpenter bee (Xylocopa violacea) and the great-banded furrow-bee (Halictus scabiosae) as well as of the honeybee (Apis mellifera). They found the same 12 families of peptides and proteins in all the hymenopteran venoms analyzed. These are evidently a common ingredient in these venom cocktails.

In collaboration with colleagues from the Leibniz Institute for the Analysis of Biodiversity Change (LIB), the Technical University of Munich (TUM) and the LOEWE Center for Translational Biodiversity Genomics (LOEWE TBG), the research team then searched for the genes of these 12 peptide and protein families in the genome of 32 hymenopteran taxa, including sweat bees and stingless bees, but also wasps and ants such as the notorious fire ant (Solenopsis invicta). The differences in these genes, in some cases only the exchange of single letters of the genetic code, helped the scientists to determine the relationship between the genes of different species and later with the help of artificial intelligence and machine learning to compile a lineage of the venom genes.

The surprising result was that many of the venom genes analyzed are present in all hymenopterans. Evidently the common ancestor of all hymenopteran taxa already possessed these genes. This makes it highly probable that hymenopterans are venomous as an entire group, concludes von Reumont. For other groups, such as Toxicofera, which includes snakes, anguids (lizards) and iguania, science is still debating whether the venoms can be traced back to a common ancestor or whether they evolved separately.

Within Hymenoptera, only the stinging insects bees, wasps and ants have an actual stinger to administer the venom. The evolutionary old parasitic sawflies, by contrast, use their ovipositor along with their eggs to inject substances that alter their host plants physiology: The sirex wood wasp (Sirex noctilio), for example, not only introduces a fungus into the plant, which facilitates the colonization of the wood by its larvae, but also its own poisonous cocktail with the venom proteins examined in the study. The purpose of these proteins is to create suitable conditions in the plant for the larvae. This means that the sirex wood wasp can also be classified as venomous, says von Reumont.

New venom components in bees are the gene for the peptide melittin and genes for representatives of the newly described protein family anthophilin-1. The fact that melittin is encoded by just one single gene came as a surprise to the researchers, as von Reumont explains: Not only are there many different variants of melittin, but the peptide also accounts for up to 60 percent of the dry weight of bee venom. That is why science previously assumed that there must be many gene copies. We were able to disprove this quite clearly. Because they found the melittin gene only in bees, the researchers also invalidated the hypothesis that it belongs to a group of venom genes postulated for stinging insects called aculeatoxins. Von Reumont is convinced: This shows us once again that genome data are the only way to draw meaningful conclusions about the evolution of venom genes.

The Frankfurt study is the first one to show for an entire insect group with around one million species where venom genes originated and how they have developed. It provides a starting point for tracing the evolution of venom genes in the ancestors of Hymenoptera as well as specializations within the group. However, to be able to perform comparative genomics on a large scale, analysis methods for the partly very large protein families must first be automated.

Experimental study

Animals

Prevalent bee venom genes evolved before the aculeate stinger and eusociality

23-Oct-2023

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The venom preceded the stinger: Genomic studies shed light on the origins of bee venom - EurekAlert

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Integrating genomic and multiomic data for Angelica sinensis provides insights into the evolution and biosynthesis of … – Nature.com

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Genome assembly and annotation

The widely cultivated A. sinensis cultivar Qinggui1 was selected for genome sequencing (Fig.1a). We generated a total of 376.4Gb Single Molecule Real-Time (PacBio SMRT) sequences and 60.8Gb paired HiSeq reads (PE150), along with 325.0Gb effective chromosome conformation capture (Hi-C) reads (TableS1). The assembly was initialized by PacBio SMRT sequences, which were corrected with high-quality paired HiSeq reads. A genome size of 2.16Gb was obtained after the final assembly. The Hi-C interaction matrices showed a distinct separation pattern of 11 blocks that could be used to cluster and orient the contigs and anchor them to 11 chromosomes (Fig.1b and Tables1 andS2). The size of the genome that we assembled was similar to the size estimated by flow cytometry13. Mapping the short reads back to the assembly led to a correction of 29,533 single-base errors and 9426 small Indels. The identification of 1,588,740 heterozygous SNPs showed a low level of heterozygosity in this self-fertilized plant. Evaluation by the Benchmarking Universal Single-Copy Orthologs (BUSCO) method19,20 showed >99% completeness of the genome (TableS3). These results confirm a high-quality genome assembly. Please refer to Table1 and Data availability for detailed information on the genome assembly.

a Morphology of the sequenced plant. b Hi-C map of chromosomes. c a-b. SNP and indel density and distribution identified between A. sinensis (GS) and A. sinensis (QH); c Density and distribution of LTR retrotransposons (purple: LTR; blue: Copia-type; dark green: Gypsy-type); d Gene density and distribution; e Colinear gene pairs within the genome. The colors of linking lines indicate the number of one-to-one gene pairs in the collinearity blocks: 40, green: 20, blue: 10, gray: 5. This figure was prepared by using shinyCircos110.

Approximately 80.24% of the assembly (1.66Gb) was identified to be repetitive sequences, which was higher than estimates in another Apiaceae family member, coriander (70.59%) (Fig.1c, TableS4). Long terminal repeats (LTRs), primarily consisting of Gypsy and Copia subtypes, were most abundant. The other repeats were categorized as DNA transposons (3.65%), long interspersed nuclear elements (LINEs; 1.26%), short interspersed nuclear elements (SINEs, 0.03%), and uncharacterized repeats (19.77%) (TableS5).

We predicted a total of 41,040 protein-coding genes (TableS6) using ab initio methods, protein homology, and RNA-seq reads from different tissues. Of them, 98.3% were mapped to the chromosomes, and most were distributed in the terminal regions (Fig.1c). Using the iTAK pipeline21, we predicted 2,996 transcription factor (TF) genes in the A. sinensis genome. The top five TF families were MYB/MYB-related (209), AP2/ERF-ERF (172), bHLH (166), C2H2 (154), and NAC (135). Compared with those in other Apiaceae plants, GeBP, HSF, GARP-G2-like, C2C2-GATA, C2C2-Co-like, HB-WOX, and Trihelix families were expanded whereas C2C2-YABBY, B3-ARF, and GRAS genes dramatically decreased in A. sinensis (Fig.S1). The genome that we assembled in this study included more TF genes in most TF families than that in the published A. sinensis (GS) genome (Fig.S1).

Despite the increasing number of sequenced genomes of medicinal plants, systematic studies of their evolutionary relationships are relatively scarce. To explore the phylogenetic position of A. sinensis in the Apiaceae family and its evolutionary relations with other species, we selected typical representative families/orders and medicinal plant species of rosids and asterids according to the Angiosperm Phylogeny Group classification (APG V4) classification system22 and constructed a phylogenetic tree using one-to-one homologous gene families. These 20 representative angiosperms included 12 well-known medicinal plant species (TableS7) from 14 families and 12 orders, representing the major botanical taxonomic groups of core eudicots.

Among these species, Vitis vinifera was chosen for its important evolutionary position and its wide use as a model and basal plant for plant evolutionary research23. Arabidopsis thaliana and Solanum lycopersicum are well-studied model eudicot plants24,25. Theobroma cacao and Camellia sinensis are two of the most important beverage crops and are rich in secondary metabolites such as caffeine26,27. C. sinensis is also one of the basal species of asterid plants27. Populus trichocarpa was selected as a model plant for the study of lignin biosynthesis and phenylpropanoid metabolism28, which is also one of the most important metabolic pathways in A. sinensis related to the bioactive metabolites of ferulic acid, lignans, and coumarins. Cannabis sativa is one of the most valuable agriculturally important crops in nature and is also used to produce well-known drugs - tetrahydrocannabinol (THC) and cannabidiol (CBD)29. Ophiorrhiza pumila, belonging to the family Rubiaceae, is an important herbaceous medicinal plant and can accumulate camptothecin (CPT)30. Scutellaria baicalensis, Salvia miltiorrhiza, Taraxacum mongolicum, Artemisia annua, Lonicera japonica, Panax notoginseng, Panax ginseng, Angelica sinensis, and snapdragon (Antirrhinum majus L.) are widely used as traditional Chinese medicines with thousands of years of history in China. In addition, we also included Daucus carota, Apium graveolens, and Coriandrum sativum, which are important members of the Apiaceae family, to examine the evolutionary relationships within the family and the evolutionary status of A. sinensis.

We identified a total of 2133 one-to-one orthologous gene families shared by all the species (Fig.S2). Using these orthologs, we constructed a phylogenetic tree by the concatenation method. As expected, the topology of the tree was consistent with the APG V4 classification. In the Apiales order, Araliaceae was grouped with Apiaceae, and Araliaceae was considered to be the ancestral family. Divergence time estimates showed that these two families separated around 58 MYA. Within the Apiaceae family, A. graveolens and D. carota diverged approximately 23 MYA, which is much earlier than the divergence of A. sinensis (QH) and its sister clade C. sativum (12 MYA) (Fig.2a).

a Molecular phylogenetic tree of 20 representative angiosperm species constructed using 2133 concatenated conserved protein sequences by the ML and BI methods. b Phylogenetic tree of A. sinensis and other Apiaceae species, inferred by estimating divergence time using 3188 single-copy ortholog sequences. P. notoginseng was used as an outgroup. The numbers in green and red colors indicate gene family expansion and contraction compared with the most recent common ancestors, respectively. Estimated divergence times (MYA, million years ago) are indicated at each node. The Venn diagram shows the proportion of gene families under the unchanged (blue), expansion (red) and contraction (green) scenarios. c KEGG pathway enrichment analysis of expanded gene families in the A. sinensis (QH) genome. Only the enriched KEGG pathways with p values<0.05 are displayed. d Distribution of 4DTv distances of syntenic orthologous genes of Apiaceae species. The black arrows mark the WGD events. e The KS distribution for orthologous gene pairs within Apiaceae species. V. vinifera was used as the model organism for evolutionary analysis. The shape of the curve and the position of the peak are almost identical between A. sinensis (QH) and A. sinensis (GS). The highlighted peak regions represent two WGD events.

To further investigate the evolutionary relationships among Apiaceae species, we clustered approximately 91.3% (206,682) of the genes from five Apiaceae species and one outgroup species (P. notoginseng) into 29,108 orthologous groups and extracted 3189 single-copy genes (TableS8). We constructed a phylogenetic tree based on the concatenated sequence alignment of these single-copy gene families (Fig.2b). C. sativum showed the most marked gene expansion. A. sinensis (QH) and A. sinensis (GS) were clustered together and C. sativum was their closest relative. A. sinensis (QH) had more expanded and fewer contracted gene families than A. sinensis (GS) (Fig.2b).

We identified 3698 genes as members of significantly expanded gene families (P<0.01) in A. sinensis (QH) and mapped them to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for functional enrichment analysis. We detected 33 significantly enriched pathways (P<0.05), and the top enriched metabolic pathways included Glycosphingolipid biosynthesis, Zeatin biosynthesis, Benzoxazinoid biosynthesis, Oxidative phosphorylation, Sesquiterpenoid and triterpenoid biosynthesis, Biosynthesis of unsaturated fatty acids, Selenocompound metabolism, and Indole alkaloid biosynthesis (Fig.2c and TableS9). Some of the enriched KEGG pathways were involved in plant volatile biosynthesis, such as Sesquiterpenoid and triterpenoid biosynthesis and Phenylpropanoid biosynthesis, which suggested that these genes may contribute to the adaptive phenotypic diversification of A. sinensis species.

Whole-genome duplications (WGDs) are widely recognized as a major source of species diversification in many eukaryotic lineages based on various lines of evidence31. To identify potential WGD events, we calculated the nucleotide divergence at fourfold synonymous third-codon transversion positions (4dTv) and the synonymous substitution rates (Ks) for collinear gene pairs within each species. In addition to the five members of the Apiaceae family, namely, D. carota, A. graveolens, C. sativum, A. sinensis (GS), and A. sinensis (QH), we also included the model plant V. vinifera in our study.

The intragenomic paralogous genes of the Apiaceae species exhibit three distinct peaks in their 4dTv distributions (Fig.2d). The last peak (), shared with V. vinifera, signifies an ancient Whole Genome Triplication (WGT) event common to all eudicot plants. The first two peaks indicate two recent lineage-specific Whole Genome Duplication (WGD) events that took place prior to the divergence of the family members within the Apiaceae family. This observation aligns with a previous study which suggested that A. sinensis has undergone three polyploidy events13. By comparing the peak positions across species, we inferred a sequence of WGD events: A. sinensis experienced the most recent event, followed by C. sativum and then A. graveolens. This sequence corroborates our phylogenetic tree and divergence time estimates, thereby enhancing the consistency of our findings.

Ks values of homologous genes from different genomes can be used to estimate the time of species divergence32. In this study, we compared the Ks peak values within each species and identified two distinct peaks at Ks 0.5 and 1.0, corresponding to two WGD events (Fig.2e). The peak positions of A. sinensis (QH) and A. sinensis (GS) were nearly identical (see TableS10 for complete peak values), suggesting similar evolutionary histories for these two varieties. However, the peak at around 1.7 is not evident, likely due to the loss or divergence of ancient duplicate genes following the earliest WGD event. The order of the peak values aligned with the phylogenetic relationships of carrot, celery, coriander, and Angelica. This implied that the order of WGD events happened in these species was carrot, celery, coriander, and Angelica which was also consistent with the previous 4dTV analysis.

A total of 41,040 high-confidence genes were predicted, which is 2,163 fewer than the published genome annotation of 43,202 genes. To evaluate the integrity of the gene set, both gene sets were first compared using the same BUSCO version and parameters. A proportion of complete genes of 96.41% was found in A. sinensis (QH), while A. sinensis (GS) had only 88.10%. Second, common databases, including the InterproScan33, Gene Ontology (GO)34, KEGG35, SwissProt36, TrEMBL, KOG, and nonredundant protein NCBI databases, were used to functionally annotate these two gene sets. Approximately 95.76% of the genes were annotated in A. sinensis (QH), while only 90.38% were annotated in A. sinensis (GS). Third, OrthoFinder (v2.5.4)37 was used to cluster these two gene sets for further analysis. The percentage of genes in orthologous groups was 94.9% in A. sinensis (QH), while it was only 82.6% in A. sinensis (GS). The species-specific gene number was 2,111 in A. sinensis (QH) and 7,496 in A. sinensis (GS). In summary, we provided a better reference gene annotation for A. sinensis species.

The genomic differences between A. sinensis (QH) and A. sinensis (GS) were investigated. Highly collinear relationships were evident between these two genomes (Fig.3a, b). A large inversion was also observed along homologous chromosomes Chr09 (A. sinensis (QH)) and chr04 (A. sinensis (GS)), which is highlighted by a red arrow in Fig.3a and a red square in Fig.4b. Good collinearity was found in this region between A. sinensis (QH) and A. graveolens, suggesting that A. sinensis (GS) had an assembly error in this region or that this is an inherent feature of the A. sinensis (GS) genome. Relatively good collinearity was observed at the genome level between A. sinensis and A. graveolens. Furthermore, reciprocal translocations were observed along chromosomes 05 and 07 in A. sinensis (QH), as well as along chromosomes 09, 11, and 10 in A. graveolens (Fig.3b). This phenomenon was consistent between A. sinensis (GS) and A. graveolens, further confirming the occurrence of translocations between these chromosomes. The collinearities between A. sinensis (QH) and other species in Apiaceae are displayed in Fig.S3.

a Macrosynteny between A. sinensis (QH) and A. sinensis (GS) was verified using MUMmer98 (version 4.0). Each dot represents a homologous block. Blue and green colors indicate different orientations of the sequences, while the red arrow refers to intrachromosomal inversions. The plot was generated using Dot (https://dot.sandbox.bio/). b Genome collinearity analysis among A. sinensis (QH), A. sinensis (GS), and A. graveolens. MCScanX86 was used to identify collinear gene blocks among these three genomes. The red square highlights intrachromosomal inversions between A. sinensis (QH) and A. sinensis (GS). The color of linking lines indicates the number of one-to-one gene pairs in the collinearity blocks: orange (40), green (20), and gray (5). c The genome distribution of genes with strong functional effects between A. sinensis (QH) and A. sinensis (GS). d KEGG pathway enrichment analysis of genes with strong functional effects.

a Changes in metabolites between NG and EF samples. The horizontal axis shows log2-fold changes, and the vertical axis shows log2 absolute content changes. The dot colors represent the different compound classes. Numbers in brackets indicate the number of compounds upregulated in NG and EF samples. b Heatmap of the contents of metabolites Coumarins and lignans and Terpenoids and phthalides with different contents between the NG and EF groups. The data were normalized by the Z score in rows. The red and blue arrows indicate the upregulated and downregulated metabolites, respectively (VIP1 and LOG2 (fold change) 1 or 1). c Heatmap showing differential gene expression related to coumarin, lignan and lignin biosynthesis between NG and EF samples in Angelica roots. The red and blue arrows indicate the upregulated and downregulated genes (LOG2 (fold change) 1 or 1 and p 0.05), respectively. Only the genes with FPKM5 in at least one sample are shown.

A total of 1.227 million SNPs and 242,250 Indels were detected in syntenic blocks between the two A. sinensis genomes. The distributions of SNPs and indels were similar but uneven across the whole genome (Fig.1c). Most of the genetic variations were located in the intergenic regions. Of these, 38,862 SNPs and 8887 indels were located in the coding regions, affecting 9,547 and 5,125 genes, respectively. Within coding regions, 909 genetic variations (affecting 686 genes) were annotated as having a strong effect on gene function, with frameshifts or changes at the start or stop codon (Supplementary Data1). These genes were not evenly distributed across the whole genome (Fig.3c) and enriched in the KEGG pathways of biosynthesis of various secondary metabolites, such as Indole alkaloid, Betalain, Isoquinoline alkaloid and Sesquiterpenoid, and triterpenoid biosynthesis (Fig.3d). The numbers of SNPs and indels were higher on chromosomes 10 and 11 than those on other chromosomes (Fig.1c and TableS11).

To understand the biosynthesis of various bioactive components in Angelica roots, we conducted nontargeted metabolomics profiling on normally growing and early-flowering Angelica roots. More than 716 high-confidence metabolites were detected and identified, including 39 flavonoids, 12 terpenoids, 47 alkaloids, 74 phenolic acids, 10 phthalides, 31 coumarins, and 24 lignans (Supplementary Data2), of which 299 compounds were determined as differential metabolites using univariate and multivariate statistical methods with the parameters of FC2 or 0.5 and VIP (variable importance in projection) 1, including 145 upregulated and 154 downregulated metabolites.

The class of metabolites appeared to have completely different metabolic patterns in the Angelica roots between NG (normal growth) and EF (early flowering and bolting) samples. The Angelica roots in NG samples were rich in organic acids, amino acids and derivatives, saccharides and alcohols, and nucleotides and derivatives, while the Angelica roots in EF samples were rich in phenolic acids, LPC, LPE, coumarins, lignans, flavonols, and flavonoids (Fig.4a). In particular, the differential production of these bioactive compounds in NG and EF Angelica roots showed that some phthalides and coumarins were more highly accumulated in NG roots than in EF roots, whereas most lignans accumulated at higher levels in EF roots than in NG roots (Fig.4b). It demonstrated the higher medicinal value of NG roots than EF roots since these phthalides and coumarins displayed more important bioactivities in experimental and clinical studies.

Transcriptome analyses of these Angelica roots under different developmental conditions also unveiled the differentially expressed metabolic genes in their biosynthesis pathways in line with metabolomics data (Fig.4c). The metabolic genes putatively involved in the biosynthesis of lignans and coumarins, both of which are derived from the phenylpropanoid pathway that often leads to the biosynthesis of well-known lignin and flavonoids, were upregulated in EF roots compared with NG roots (Fig.4c). In contrast, most genes putatively involved in phthalide and coumarin biosynthesis were expressed at higher levels in NG roots than in EF roots, consistent with their higher pharmaceutical values (Fig.4c).

Although the common shared metabolic enzymes and pathways involving lignin, coumarins, lignans, and flavonoids are well known, the specific genes/enzymes involved in the production of many coumarins and lignans are poorly understood13,38,39. This new Angelica genome assembly provided more than 100 metabolic genes that encode all known enzyme homologs involved in the biosynthesis of coumarins and lignans (Supplementary Data3). The phenylpropanoid pathway genes, including phenylalanine ammonia lyase (PAL), cinnamate 4-hydroxylase (C4H), 4-coumaroyl-CoA ligase (4CL), hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyltransferase (HCT), caffeic acid O-methyltransferase (COMT), caffeoyl-CoA O-methyltransferase (CCoAOMT), etc., contributing to lignin biosynthesis via HCT and CCR genes, via dirigent protein (DIR), or via flavonoid synthesis by CHS and for coumarin biosynthesis from different products of 4CL by cinnamic acid 2-hydroxylase (C2H), p-coumarate 3-hydroxylase (C3H) with HCT, or feruloyl-CoA hydroxylase (F6H), were all assembled and annotated in our genome to provide insights on the biosynthesis of various pharmaceutically important products (Fig.5a). Lignans have unique antitumor activities and reduce lifestyle-related diseases40. Lignans were also enriched in Angelica roots, particularly of EF status, in which a subset of biosynthesis genes and contents of lignans and derivatives were upregulated, including dirigent protein (DIR), pinoresinol-lariciresinol reductase (PLR), and secoisolariciresinol dehydrogenase (SIRD) for the biosynthesis of pinoresinol and lariciresinol, secoisolariciresinol, and matairesinol aglycones and their glycosides as products of UGT71/74 glycosyltransferses40 (Fig.5a).

a Putative biosynthesis pathways of coumarins, lignin, lignans and flavonoids. The numbers in parentheses indicate the number of genes. Different background colors represent the synthetic pathways of different products. The PT genes are highlighted in red. The genes in different gene families are listed in Supplementary Data3. b Rootless phylogenetic tree of PT genes. The tree shows the grouping of PT genes according to the type of substrate (ah). The orthologous genes in A. sinensis (QH) and A. sinensis (GS) are highlighted. The genes in the c and d subtrees had relatively high expression levels.

Prenyltransferase (PT) catalyzes the prenylation of umbelliferone into linear or/and angular furanocoumarin biosynthesis34,35. PTs are involved in the biosynthesis of chlorophyll, vitamin E, heme, phylloquinone, and various secondary metabolites by prenyl modifications of chlorophyllide a/b, vitamin E, heme B, and many metabolites, such as 1,4-dihydroxyl-2-napthoic acid, p-hydroxylbenzoic acid, flavonoids, phloroglucinol, homogentisate, and coumarins, with different prenyl donors, such as isoprenyl diphosphate, dimethylallyl diphosphate, and geranyl diphosphate (Fig.5b). Despite the divergent functions of these PTs, they involved in coumarin biosynthesis that evolved most likely via convergent evolution since coumarins mainly occur in a few unrelated plant families, such as Fabaceae, Moraceae, Apiaceae and Rutaceae34,35. This finding is also supported by a previous study19, which showed independent evolution of coumarin biosynthesis-related PTs in these families. Furthermore, these PTs that catalyze both linear (demethylsuberosin, e.g., PsPT1 and PcPT1) and angular (osthenol, e.g., PsPT2) furanocoumarin biosynthesis are clustered together in one clade for Apiaceae species (Fig.5b), likely resulting from gene duplications followed by neofunctionalization and positive selection38,41.

As two major pharmaceutically important components in Angelica roots, ligustilide and butylidenephthalide are generally regarded as essential contributors to the main medical functions of Angelica roots42,43,44,45. However, their biosynthesis pathways remain elusive. The oxidation or transfer of isoprenoids or condensation of malonyl CoAs with other acyl CoAs by type III polyketide synthases (PKSs) or their combinations could be involved in the biosynthesis of these phthalides46,47. We therefore examined the A. sinensis genome together with transcriptome and metabolite profiling for the biosynthesis of ligustilide and butylidenephthalide and other monoterpene volatiles that contribute to the medicinal functions of Angelica roots.

To more clearly profile bioactive components in Angelica roots, volatile terpenoids, and phthalides were examined by using headspace solid-phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS). The volatiles of early-flowering (EF) and normally growing (NG) roots showed notable differences. In addition to the higher levels (~47% of total volatiles) of Z-ligustilide and Z-butylidenephthalide and their E- type isomers as major components in NG roots, the EF roots of A. sinensis also contained fewer phthalides (34% of total volatiles), as well as much less abundant monoterpenes, such as -pinene and E--farnesene, (Figs.6a, b). These data indicated that early bolting and flowering also negatively impacted volatile accumulation in Angelica roots.

a Headspace solid-phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) analysis of the contents and composition of volatiles in Angelica roots from early-flowering (EF) and normally growing (NG) plants. b Differential content analysis of the volatiles in Angelica roots between EF and NG plants. c Enzymatic reactions in the mevalonate (MVA) and methylerythritol phosphate (MEP) pathways in plants and synthesis of short-chain prenyl diphosphates. The MVA pathway is shown in light red; the MEP pathway is shown in light green. Abbreviations and full names are given in TableS16. Data are expressed as the meansSDs from at least three independent experiments with triplicates. Differences between NG and EF samples are considered significant when **P<0.01 and *P<0.05 in Students t test.

Genome analyses revealed that three key gene families involved in the MEP pathway toward monoterpene synthesis, MCT, HDS, and HDR, were expanded in the A. sinensis genome in comparison with the Arabidopsis and grapevine genomes (Supplementary Data4). A. sinensis genome sequences revealed an extremely enhanced monoterpene pathway during the evolution of several genera in the Apiaceae family (Supplementary Data4), which is consistent with the diverse and enriched monoterpene volatile profiles in these plants (Fig.6a).

Transcriptome data showed that genes involved in glycolysis and the pentose phosphate pathway were downregulated in EF Angelica roots, which also negatively affected the mavalonic pathway (MVP) and 2-C-methyl-erythrose 4-phosphate (MEP) pathway, leading to the biosynthesis of mono-and sesquiterpenoids (Fig.6c). The DXS, MDS, CMK, and HDR genes involved in the plastic MEP pathway, one IPPI and two GPPS genes for monoterpenoid biosynthesis were significantly downregulated in EF Angelica roots compared with NG Angelica roots (Fig.6c).

A. sinensis is a triennial medicinal plant that typically flowers in its third year but can flower early in May of its second year (Fig.7a). As Angelica roots contain a wide range of terpenoid volatiles at abundant levels, they are also regarded as major components contributing to clinical functions48. Terpenoid synthase family genes play key catalytic roles in plant terpenoid biosynthesis. A total of 28 putative TPS genes in the A. sinensis genome belonging to five TPS subfamilies (TPS-a, TPS-b, TPS-c, TPS-e/f, and TPS-g) were identified (Fig.7b). The TPS-b family was expanded in both A. sinensis (15) and C. sativum (20), and the expansion of TPS-b genes in the A. sinensis genome was mainly due to tandem duplication (Ks<0.1). There were 5 more TPS genes in A. sinensis (QH) than in A. sinensis (GS), which indicated that the completion of A. sinensis (QH) was better than that of A. sinensis (GS). We detected 8 TPS genes that were expressed in Angelica roots (FPKM1 at any samples), and most of them had higher expression levels in NG roots than in EF roots (Fig.7b).

a Plants were sown simultaneously and grown in the same environment. Samples were taken at the same time for observation and analysis. EF early flowering, NG normal growth. We highlight the highly lignified Angelica root of the EF plant and the normally developed storage root of the NG plant on the right side. b Five TPS subfamilies (TPS-a, TPS-b, TPS-c, TPS-e/f, and TPS-g) were clearly identified. The genes from A. sinensis (QH) and A. sinensis (GS) are highlighted by red and green dots, respectively. The heatmap of gene expression is illustrated.

To further verify the possibility that PKSs are involved in the biosynthesis of the polyketide derivatives ligustilide and butylidenephthalide in A. sinensis, we analyzed genes that are involved in the biosynthesis of acetyl-CoA and malonyl CoA, which are used as substrates for type II and III PKSs for the production of polyketides (Fig.8a)46,47. Acetyl-CoA carboxylase (ACC) is the main enzyme catalyzing the conversion of glycolysis pathway-derived acetyl-CoA into malonyl CoA, which is a key intermediate for fatty acid, polyketide, and flavonoid biosynthesis47. Plant ACC is composed of two subunits, the biotin carboxylase and carboxyl transferase subunits47. The coding genes for two ACC subunits, BCCP2 (CAC1) (4) and CAC2-CAC3 (5), were expanded in the A. sinensis genome in comparison with the Arabidopsis and grapevine genomes, respectively (TableS12). Consistent with lower Z-ligustilide and Z-butylidenephthalide levels in EF Angelica roots, at least two ACC subunit genes were downregulated in EF roots compared with NG roots (Fig.8b).

a The malonyl-CoA biosynthesis metabolic pathway. b Heatmap displaying the expression of typical ACC genes in Angelica roots between EF and NG plants. c The overall expression (FPKM) of ACC and PKS genes in Angelica roots between EF and NG plants. d Phylogeny of polyketide synthase genes (PKSs). The heatmap displays the gene expression in Angelica roots between EF and NG plants. The color of gene IDs shows the source of different species: red: A. sinensis; blue: A. thaliana; black: seed sequences. The red stars highlight the upregulated genes, and the blue stars highlight the downregulated genes.

PKS consists of a large gene family encoding multifunctional enzymes that catalyze condensation of malonyl CoAs or malonyl CoA with other acyl CoAs to generate diverse polyketides46,47. In particular, type III PKS (TKS) catalyzes linear tetraketide-CoA synthesis with hexanoyl-CoA and malonyl CoA and might provide a backbone for Z-ligustilide and Z-butylidenephthalide biosynthesis49. A previous study showed that a TKS olivetolic acid cyclase (OAC) catalyzed a C2C7 intramolecular aldol condensation with carboxylate retention in the linear tetraketide-CoA to form olivetolic acid in Cannabis sativa49. OAC was structurally similar to Z-ligustilide and Z-butylidenephthalide, with only differences in the position of the olefinic link and hydroxyl group49. A multifunctional protein (MFP) could handle the switch of olefinic links and hydroxyl groups in the lipid metabolism process50. It has thus been proposed that Z-ligustilide and Z-butylidenephthalide are synthesized via a similar mechanism through the PKS pathway, although the exact enzyme or gene responsible for their biosynthesis remains unknown. In the A. sinensis genome, PKSs also formed a large gene family of 120 members, among which the type III PKS genes are expanded (TableS13 and Fig.8d).

Transcriptome analyses showed that four PKS genes, namely, As05G08873, As11G04238, As10G03800, and As08G02849, were highly expressed in Angelica roots (Fig.S4), and in particular, we also found that some of the PKS genes were repressed in EF Angelica roots as compared with NG roots (Fig.8d), indicating that these PKSs might be involved in the biosynthesis of phthalides. The overall expression of ACC and PKS genes in Angelica roots was lower in EF plants (Fig.8c). Further studies with isotope-labeled substrates in tracer experiments, together with enzyme and molecular approaches, are needed to unveil the mechanism underlying the biosynthesis of Z-ligustilide and Z-butylidenephthalide in A. sinensis.

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Conspiracy Theories, Some with Antisemitic Roots, Crop Up in 2023 … – ADL

Posted: November 28, 2023 at 12:39 pm

The 2023 shareholder season heralded a new element of shareholder proposals: conspiracy theories. The National Center for Public Policy Research (NCPPR) and National Legal and Policy Center (NLPC) each filed such proposals; both are self-described conservative watchdog organizations. NCPPRs primary focus is public policy research and education, while NLPC promotes ethics in government, advocating for limitations on big government.

NCPPR filed at least seven shareholder proposals containing conspiracy theories or conspiratorial language, demanding a congruency report" on relationships between companies and "globalist organizations -- a demand that could be interpreted as an antisemitic dog whistle. In the supporting statement of its shareholder proposals, NCPPR claims these companies work with globalist organizations, namely the World Economic Forum, who "openly advocates for transhumanism, abolishing private property, eating bugs, social credit systems, The Great Reset and a host of other blatantly Orwellian objectives."

NCPPR filed these proposals at Alphabet/Google, Pfizer, Bank of America, Boeing, Marriot, Merck and Johnson & Johnson. Three of these proposals (at Alphabet, Marriott and Merck) made it onto the proxy ballots, while three companies successfully petitioned the SEC to have the proposals excluded (Johnson & Johnson, Pfizer, Bank of America) and one was withdrawn by NCPPR (Boeing).

NLPC also filed a similar proposal with Johnson & Johnson, though the company successfully argued it should not be included on the proxy ballot.

"Globalist" is a term used by many on the right and the far right. It has been used by mainstream personalities and politicians to refer to people or entities that support multilateralism and cross-border cooperation, but in extremist contexts, "globalist" is used by white supremacists and other antisemites as an antisemitic dog whistle, wielding it as a codeword for Jews or as a pejorative term for people whose interests in international commerce or finance ostensibly make them disloyal to the country in which they live.

Primary conspiracy theories

Several prominent conspiracy theories surfaced repeatedly in these proposals. The first, the Great Reset, is a conspiracy theory that can be used to espouse antisemitism. It warns that "global elites" used the pandemic (or other newsworthy events) to advance their interests and push a globalist plot to destroy American sovereignty and prosperity in favor of a global totalitarian regime. Adherents sometimes promote antisemitism as part of the conspiracy theory. Before it was adopted by conspiracy theorists, the phrase originally referred to an initiative introduced by the World Economic Forum.

The second primary conspiracy theory focuses on transhumanism, the idea that humans can transcend the physical limitations of our bodies -- perhaps even death itself. In its more conspiratorial form, proponents believe a "Satanist" or elite cabal of humans, on a mission to replace humans with machines/governments, are modifying bodies and DNA via secretly inserted chips. It can be and often is seen in conjunction with Great Replacement and Great Reset theory. This conspiracy theory has both antisemitic and anti-LGTBQ undertones, due to the associations proponents make with Satanist transhumanists alleged connections to George Soros and numerous references to the globalists behind the mov. Anti-LBGTQ authors such as Jennifer Bilek claim that transgender folks especially are the vanguard of this foundationally anti-humanity movement to transform the essence of what it means to be a person.

This kind of conspiratorial activism was also evident in the 2023 NCPPR shareholder proxy guide, in which the organization claims, We sometimes forget the UN is the institutional originator of climate nonsense and that the US government and by extension, the American taxpayer is the largest funder of the most prevalent globalist organization on Earth, whose very explicit purpose is to be the one-world government that globalists are trying to bring to fruition.

The NLPC also echoes this sentiment in a blog post attacking Brian Moynihan, Bank of America CEO and detailing their shareholder activism: Moynihan has been more than willing to place Bank of America in a globalist posture, subjugating shareholders interests under those of the World Economic Forum agenda of transhumanism, abolition of private property, consumption of bugs, social credit systems, and other Great Reset priorities. Paul Chesser, director of the Corporate Integrity Project for NLPC gave remarks at the Bank of America annual general meeting promoting fear of a one world government, a conspiracy theory with roots in the 1990s.

NCPPRs 2022 proxy voter guide is much more explicit, going so far as to detail the organizations understanding of these conspiracies, with subheadings about transhumanism and the Great Reset. Ethan Peck, a Free Enterprise Institute fellow (project of NCPPR), also commented while presenting a 2022 proposal that [Pfizer CEO Albert] Bourla is a globalist leech... And he is using shareholder money to finance his free trips to Davos where he advances the transhumanist agenda.

At this time, there is no evidence to suggest that either organizations agents espouse overt antisemitism, or that these proposals were filed with antisemitic intentions. However, the conspiracies espoused fit neatly into a broadly conspiratorial world view, and in some cases may serve as on ramps to more overtly antisemitic concepts. These conspiracies were once the mainstay of the darker corners of blogs and message forums, and it is of note that they have moved into the mainstream discourse about cultural norms a development antisemites undoubtedly welcome.

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10 of The Wildest Fictional Drugs from Transmetropolitan – Screen Rant

Posted: at 12:39 pm

Summary

Few works of fiction capture the true essence of gonzo as it was pioneered by Hunter S. Thompson quite like the Vertigo Comics series Transmetropolitan by Warren Ellis and Darick Robertson. The series follows a journalist named Spider Jerusalem who is a pretty clear Hunter S. Thompson analogue. Jerusalem lives in The City where he writes a column for the newspaper The Word thats titled I Hate It Here. The column focuses on his perception of modern day life as it exists in this futuristic, transhumanist, cyberpunk landscape.

Along with being a gonzo journalist with a point of view that captivates readers, Spider Jerusalem is similar to Hunter S. Thompson in one other way: drug consumption. In this future world, there is no shortage of increasingly weird drugs Spider can get his hands on, and the futuristic healthcare ensures that he likely wont die of any sort of drug overdose, meaning he and those around him can really push their bodies and minds to the limit. While there are certainly far more than just two handfuls of drugs to choose from, here are just 10 of the wildest fictional drugs from Transmetropolitan!

Transmetropolitan was more than just a 60 issue comic series, but also had two graphic novels that allowed fans to read Spider Jerusalems columns just as someone would in-world (with the accompaniment of Darick Robertsons outstanding artwork, of course). Those graphic novels were titled I Hate It Here and Filth of the City, respectively, and they - along with some other Transmetropolitan specials - were collected in Tales of Human Waste. Within this epic of journalistic depravity, Spider Jerusalem recounts a time when he accidentally took Alter Gum, thinking it was just regular gum that could help him cut down on his smoking.

Apparently, no one told Spider that Alter Gum was a serious drug that gave users temporary dissociative identity disorder, and he found that out by losing his mind, running around The City completely naked while wielding a sword.

Dead Celebrities isn't a drug that Spider Jerusalem indulges in himself (at least, not in this issue), but is one he sees other people doing on television during a quiet winter night inside his apartment. Apparently, every winter, a new group of teenagers digs up the corpses of long-dead celebrities, tear off and chop up pieces of their bodies, and ingest them.

Evidently, there are rich deposits of old drugs and crystallized adrenaline in these corpses, and they have the capacity to give people a high thats worth desecrating the body of a famous person.

Another As-Seen-On-TV drug, Disconekt, isnt taken by Spider on-panel, but is rather being advertised on television. The TV spot reveals that Disconekt is a prescription drug thats meant to numb the senses and make life in The City more tolerable for the millions of miserable citizens barely making it through the day. Not only that, but its advertised as a way to calm the collective anger of those citizens, and will keep peoples heads from bursting with rage.

Transmetropolitan is borderline totalitarian, and Disconekt is less of a recreational drug derived from the advanced technology of the era, and more of a way to control the masses by the current political party in power (championed by the President who Jerusalem nicknamed the Smiler, and who is a main antagonist throughout the series).

Freak Green - also seen during a television news report - is given to children by their parents to make them tougher and more equipped to survive in the cruel world in which this series takes place. In an interview, a mother of a child addicted to Freak Green boasts that her son fights the puppy for his morning fix and that it has given him impressive grip strength.

Not only is this drug apparently meant to strengthen children at a young age (as the child in the news report looked not even six months old), but Freak Green also turns their skin green.

While visiting an area of The City known as the Reservations where humans choose to live in different time periods throughout history in order to preserve the culture of past civilizations, Spider Jerusalem is invited to also experience a portion of the Reservations called the Farsight Community. This wasnt a living monument to the past, but rather a corner of a potential future, one of advanced cybernetic enhancements (more so than the average amount found in The City), and where drugs that were banned in The City can be experienced freely - including and especially Infopollen.

Jerusalem was sprayed in the face with Infopollen the moment he walked into the Farsight Community, and he experienced trippy visions of an abstract future, an experience he described as being akin to washing down a bucket of peyote with a vatful of absinthe.

In the very first issue of the series, when Spider Jerusalem goes back into The City to start writing for The Word once again, hes more than a little rusty after living in the mountains for five years in complete solitude. So, in an effort to hit the ground running, he approaches a local drug pusher and tells him he needs the best Intelligence Enhancers on the market.

It seems Intelligence Enhancers is more of a narcotic classification than the actual name of a specific drug, though the effects of it speak for itself.

When Spider Jerusalem went to a Religions Convention to cover the vast number of new religions that have been popping-up recently, he saw people doing some decidedly odd practices in the name of their religious beliefs. However, one of the weirdest sights had to be the person who was using Liquid Holy Thoughts in an effort to wash away any impure thoughts by way of mind-altering fluid.

If the idea of what this drug does to the human mind isnt horrific enough, the application of said drug certainly is, as its a tube of green liquid thats pumped directly into the brain through a surgically-made hole in the forehead.

During a column thats dedicated to the citizens of The City themselves, Spider Jerusalem takes a deep dive into the lives of the New Scum (a phrase coined by the Smiler to illustrate his disdain for the people hes supposed to represent). One such person is someone who is on his way to becoming addicted to a drug called Mechanics. This drug temporarily merges ones mind with their personal AI, and during the duration of the drugs effects, the AI makes changes to the persons DNA. Once the high wears off, a formerly regular human now has a piece of their flesh replaced with techno-organic matter.

With each dose, a person literally loses a little bit of their own humanity at a time, slowly becoming a drug-addicted robot that only lives for the promise of the next fix.

The only drug in Transmetropolitan to make Spider Jerusalem want to swear off all narcotics completely. RPG Drugs are as they sound: they transport users to a fantasy world where they literally roleplay as a fictional character. When Spider took it, he became a parody of Superman, complete with the life the original Superman led as his alter ego, Clark Kent.

Spider hated being a mild-mannered journalist and goody-two-shoes superhero so much that he wanted to give up taking drugs completely - thats how off-put he was by his RPG-induced hallucination.

Transmetropolitan #52 opens with a woman who the Smiler is trying to have murdered due to the fact that she used to be a sex worker who serviced him, and hes trying to eliminate any and all skeletons in his closet. These days, shes a drug dealer who sells Space and Space Dust (which is a heightened version of Space seemingly the same way crack is to cocaine). The drug is primarily smoked, giving the user a euphoric high that slows down their perception of time, and is also one of the primary social drugs of the era.

However, thats not Spider Jerusalems take on the drug, as his description of the slowed-down time effect is hellish and void. Spider describes it as something that traps you in an airport waiting lounge of the mind and doesnt let you go for approximately two hundred years. It seems this particular drug was too much for even Spider Jerusalem, meaning an average person within Vertigo Comics Transmetropolitan would be wise to avoid it.

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Sam Altman’s Second Coming Sparks New Fears of the AI Apocalypse – WIRED

Posted: at 12:39 pm

Open AIs new boss is the same as the old boss. But the companyand the artificial intelligence industrymay have been profoundly changed by the past five days of high-stakes soap opera. Sam Altman, OpenAIs CEO, cofounder, and figurehead, was removed by the board of directors on Friday. By Tuesday night, after a mass protest by the majority of the startups staff, Altman was on his way back, and most of the existing board was gone. But that board, mostly independent of OpenAIs operations, bound to a for the good of humanity mission statement, was critical to the companys uniqueness.

As Altman toured the world in 2023, warning the media and governments about the existential dangers of the technology that he himself was building, he portrayed OpenAIs unusual for-profit-within-a-nonprofit structure as a firebreak against the irresponsible development of powerful AI. Whatever Altman did with Microsofts billions, the board could keep him and other company leaders in check. If he started acting dangerously or against the interests of humanity, in the boards view, the group could eject him. The board can fire me, I think thats important, Altman told Bloomberg in June.

It turns out that they couldnt fire him, and that was bad, says Toby Ord, senior research fellow in philosophy at Oxford University, and a prominent voice among people who warn AI could pose an existential risk to humanity.

The chaotic leadership reset at OpenAI ended with the board being reshuffled to consist of establishment figures in tech and former US secretary of the treasury Larry Summers. Two directors associated with the effective altruism movement, the only women, were removed from the board. It has crystallized existing divides over how the future of AI should be governed. The outcome is seen very differently by doomers who worry that AI is going to destroy humanity; transhumanists who think the tech will hasten a utopian future; those who believe in freewheeling market capitalism; and advocates of tight regulation to contain tech giants that cannot be trusted to balance the potential harms of powerfully disruptive technology with a desire to make money.

To some extent, this was a collision course that had been set for a long time, says Ord, who is also credited with cofounding the effective altruism movement, parts of which have become obsessed with the doomier end of the AI risk spectrum. If its the case that the nonprofit governance board of OpenAI was fundamentally powerless to actually affect its behavior, then I think that exposing that it was powerless was probably a good thing.

Governance Gap

The reason that OpenAIs board decided to move against Altman remains a mystery. Its announcement that Altman was out of the CEO seat said he was not consistently candid in his communications with the board, hindering its ability to exercise its responsibilities. An internal OpenAI memo later clarified that Altmans ejection was not made in response to malfeasance. Emmett Shear, the second of two interim CEOs to run the company between Friday night and Wednesday morning, wrote after accepting the role that hed asked why Altman was removed. The board did not remove Sam over any specific disagreement on safety, he wrote. Their reasoning was completely different from that. He pledged to launch an investigation into the reasons for Altmans dismissal.

The vacuum has left space for rumors, including that Altman was devoting too much time to side projects or was too deferential to Microsoft. It has also nurtured conspiracy theories, like the idea that OpenAI had created artificial general intelligence (AGI), and the board had flipped the kill switch on the advice of chief scientist, cofounder, and board member Ilya Sutskever.

What I know with certainty is we don't have AGI, says David Shrier, professor of practice, AI, and innovation, at Imperial College Business School in London. I know with certainty there was a colossal failure of governance.

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The New Progressive Nihilism – Compact Mag

Posted: at 12:39 pm

Since the dawn of the modern age, the conquest of disease and death has been a central dimension of progressive optimism. Modern thought has long dreamed of a day when the human lifespan would know no upper limitwhen, as Condorcet put it, nature has fixed no limits to our hopes. Declining infant mortality, increasing life expectancy, and a growing arsenal of cures for once deadly illnesses have encouraged these hopes. To be sure, the dream of life extension sometimes mutates into a hubristic denial that death and dying are a part of life, as with the transhumanist fantasies that captivate many of Silicon Valleys techno-optimists. Nonetheless, as the philosopher Martin Hgglund has argued, the conviction that no life can ever be complete is closely linked to the broader modern conception of progress.

Recently, however, a retreat from this core conviction has been underway across the West, especially among self-declared progressives. This is one way to understand the jubilation with which many on the Western left responded to Hamass Oct. 7 attack on Israel. It takes a profound pessimism about the world to see mass slaughtercarried out by a group animated by overtly anti-modern politicsas an exhilarating act, as apparently did many of those who took to the streets to express solidarity with the attackers and turned the paragliders Hamas fighters used to descend murderously on a music festival into a positive symbol. How did we arrive at this point?

As progressive optimism declined, so did the notion that politics could reach for something beyond itself. In its place has been substituted a progressive nihilism. In the late 20th century, the vanishing of a utopian horizon left only a politics of subversion, in which disruption became an end in itself. Think of the carnivals against capitalism of the late 1990s and early aughts.

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Is Laughter All Weve Got? On David Baddiels The God Desire – lareviewofbooks

Posted: at 12:39 pm

THE LESSON OF The God Desire: On Being a Reluctant Atheist (2023), its author concludes, is bleak. Despite, or (as he holds) because of, this desire, there is no God and hence no comfort and hope in the face of death. But as we know from, say, Jonathan Swift or Isaac Bashevis Singer, the bleakness of its lesson does not exclude the books enjoyability. Much of the enjoyment of this book comes from the one thing that David Baddiel thinks he can offer to lighten his messagelaughter. For example, he quotes a line from Maurice MaeterlinckThe living are just the dead on holidaythat, he says, sends bad shivers down his spine, but it is also very funny.

The humor in this short and serious book will not surprise readers who know its author as a successful British performer and writer of comedy. Its seriousness will not surprise those familiar with his well-received book on antisemitism, Jews Dont Count (2021), and a play, Gods Dice (2019), that, like Michael Frayns Copenhagen (1998), finds drama in the history of quantum physics. Baddiel also writes novels and books for children and is a keen observer and analyst of the game of soccer.

Baddiels life is clearly one of considerable achievement, but it is compromised, he explains, by his fear of death and a related, unsatisfied desire for God to exist. He loves God in the way he does Santa Claus: in neither case, sadly, is the object of his love real. He finds himself, therefore, a reluctant but also fundamentalist atheist. This means, first, that he knows, rather than merely believes, that there is no God. It means, too, that he rejects various ersatz Gods to which people have turned for spiritual solacenature, wonder, love. None of these, he insists, do anything to allay our fear of death.

This fundamentalist atheism might seem to align Baddiel with the newor, less politely, undergraduateatheism of such figures as Richard Dawkins and Christopher Hitchens. He dislikes, however, their dismissal of great religious traditions as mere fairy stories. The tradition in which he was brought up, Judaism, is a repository of rituals, acts, and customs that have enabled a people to survive persecution and worse. Moreover, the New Atheists are guilty of a macho pretense that people require no spiritual solace when confronted with anxiety about the prospect of death.

God, asserts Baddiel, is all about death. It is the horror of oblivion and nothingness that has been the main driver of religious belief. God has served other functionsfor instance, to provide meaning and narrative structure to peoples livesbut Baddiel would agree with Tolstoy, in his Confession (1882), that these are spin-offs from the main role. Whatever meaning I am tempted to assign to my life leaches out with my death. There is, for Baddiel, nothing self-obsessed in this lust to survive after death. He endorses John Updikes suggestion that it is because of our love and praise of the world that we cant bear to think of [the] shutting of our window onto it.

Many historians of religion will challenge the claim that God is all about death, emphasizing instead a felt need for a God who maintains order and harmony, say, or who sanctions the moral law. But Baddiel might be willing to soften his claim and simply point out that many people, himself included, desire the existence of a God who guarantees survival after death, and that its for them that his book is written. Moreover, his argument for atheism doesnt turn on any particular form of the God desire but on its strength. It is not like traditional arguments against the existence of God, such as that deriving from the problem of evil. Indeed, Baddiel wants to bat away nearly all familiar arguments on the subject, pro or con. Even when one is unable to detect flaws in their reasoning, he indicates, these arguments have no power to persuade.

Baddiels own argumentwith its Nietzschean and Freudian tracesis that the very intensity of the God desire shows belief in the divine to be delusional. To the obvious objection that, in general, strongly wishing for something does not exclude its existence, Baddiel replies that it does so in cases where the something is invisible. When, that is, something cannot be, in concrete terms, experienced, an intense desire for it shows it to be a fantasy. There is surely some confusion here. Visible or invisible, a things existence or nonexistence cannot be settled by what people wish to be real. Wishes cannot dictate what is out there.

That said, Baddiel is driving at two important points. The first is the fact that when you desperately want a belief to be true, you should be especially careful in your judgment. Perhaps youve paid insufficient attention to reasons against the belief, or have surrounded yourself only with people who reinforce it. Second, as Baddiel notes, projection of features onto the world in accordance with our desires is a familiar phenomenon. The lover, desperate for the beloved to return his love, reads into simple gestures and words emotions that may not be there. For Baddiel, the believers alleged experience of Gods love is similarlyand economicallyexplained in terms of a wish-fulfilling projection onto reality. But while these considerations should be taken seriously, they do not warrant the claim, by fundamentalist atheists, to know that God is a delusion. Moreover, this is a claim to which religious believers have a reply. The experience of Gods love during prayer, meditation, or moments of personal crisis, they insist, is a palpable, concrete one, quite different in kind from the young lovers wishful projection of love reciprocated.

William James long ago noted that an impasse is soon reached between competing interpretations of putative religious experience. For those who have it, its veridicality cannot be in doubt, while for those, like Dawkins, who are religiously tone-deaf, testimonies to religious experience are ones whose truth they are no more obliged to recognize than that of reports of encounters with gremlins or angels. Baddiels claim to know that God does not exist may be unwarranted, but nonetheless, like others to whom religious experience is foreign, he has no reason to believe in God and to look to God, therefore, for comfort and hope in the face of death.

But might he look elsewhere for this? He doesnt consider any nontheistic proposals for a sort of survival of personhood after death, such as the Buddhist teaching of rebirth. Nor does he discuss transhumanist scenarios in which, say, electronic copies of ones brain are supposed to ensure a sort of survival. What would worry Baddiel, Im sure, about such speculations is that they at best promise only a sort of survival. The coming into existence after my death of somebody or something that has some kind of continuity with myself is small comfort. Despair at the shutting of my particular window onto the world is hardly alleviated by the prospect of a related, but nevertheless different, window opening.

So, are Baddiel and fellow atheists who share his anxieties left with nothing except some laughter to lighten their lives? Perhaps the following thought might give a little more light. Baddiels claim that [d]eath is shit simply because of the prospect of oblivion strikes me as too simple. In my own case, certainly, I find anxiety about my death to be a mlange of largely inchoate fears and feelings. They include, in addition to the image of the closing window, a concern about dying well, a nagging fear of having significantly wasted my life, a sympathy for those who might miss me, a hope that my death might benefit some people or creatures, and an unpleasant sense of objects that matter to me falling into the hands of people to whom they mean nothing.

None of these are happy thoughts, but unlike the blank horror of oblivion, they are ones that, however modestly, a person can do something about. I can leave money to a good charity and bequeath my paintings to someone who will care for them. I can try to cultivate a certain calm and dignity that will serve me, and those around me, during the final days. I might even try to finish writing the big book that Ive been too lazy or lacking in confidence to complete.

I would like to think that David Baddiel might find in these and other strategies not a reconciliation with death but rather an accommodation with it that goes a bit beyond the laughter that, at present, is all I got.

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Luxury industry set to reach $1.6 trillion in sales this year – Glossy

Posted: at 12:39 pm

According to a November study by the management consultancy Bain and the Italian luxury association Altagamma, the global luxury market is projected to reach $1.6 trillion in 2023 sales, marking an 8-10% increase from 2022. Growth is set to outpace that of the last few years, with sales surpassing pre-pandemic levels.

There is a question mark regarding the profitability of brands, both this year and next year, said Federica Levato, senior partner and EMEA leader of fashion and luxury at Bain, and co-author of the annual Luxury Goods Worldwide Market Study. Theres increased attention being placed on scenario-based budgeting for next year. So far, brands have been very good at absorbing the delta costs of economic impacts in their prices and gross margins. But with the consolidating growth rates, the cost base is increasing.

The report, which came out on November 14, is based on macroeconomic data like GDP and the consumer confidence index, as well as Bains and Altagammas latest luxury industry forecasts. It also factors luxury industry players trading performance, annual reports, quarterly results and analyst reports, as well as findings from 100 expert interviews.

The European luxury market is expected to grow 7% to $111 billion in 2023, as a rebound in tourism offsets weakening in local consumer spending, the report found. Local tourist spending has surpassed pre-pandemic levels, driven by the sales of full-price products. In the U.K., the luxury market faces setbacks due to the removal of tax-free shopping in 2020, as well as a lack of tourism. According to a study from March by the Association of Leading Visitor Attractions, visits to British attractions in 2022 increased 69% compared to 2021, but the attractions saw 37.8 million fewer visits compared to 2019. For 2024, the report predicts GDP growth of 1.4% in the U.K.

The U.S. luxury market continues to slow down due to a number of macroeconomic factors, including inflation, student loan repayments, a weaker luxury ecosystem in the U.S., a declining consumer demand for department stores and a lack of post-lockdown savings. GDP growth is forecasted to grow 1.5% in 2024. The U.S. has gained traction as a luxury market, going from $88 billion in sales in 2019 to $110 billion this year. As a result, many brands are focusing on their top-spending customers.

Brands are focusing on top-customer strategies and developing dedicated value propositions, products and experiences for that audience, said Levato. Meanwhile, the entry-level or core customer can feel a bit left behind. [Retailers] dont have a dedicated customer experience for that customer.

And while Gen Z isnt driving significant sales, the demo is bringing influence. In an economic downturn, Gen Z doesnt have big purchasing power, but millennials and Gen X do, said Levato. But Gen Z is by far the generation that is influencing the other generations the most, in terms of tastes, value systems and cultural change. Brands who engage in that dialogue will win out.

Top-selling luxury categories are shifting, from small leather goods to others. Jewelry is set to reach $32.7 billion in market value in 2023. A big driver is the fine jewelry category, which is proving to be an investment proposition for high-net-worth customers, along with ready-to-wear investment pieces. For its part, Tiffany & Co. re-opened its flagship on NYCs Fifth Avenue in May after a reported $70 million renovation. The goal was to attract more high-net-worth customers and reintroduce customers to Tiffany & Co.s retail proposition, according to the company.

The premium beauty market is also seeing growth, which is being driven by the lipstick effect among aspirational customers in the Americas and Europe. Prada, for one, re-launched its beauty collection in July to focus on design-led palettes and logoed lip products.

Overall, brands are focusing on their own channels to reach customers, as multi-brand retailers struggle to define their value proposition and customers increasingly seek out branded physical experiences. Multi-brand retailer Showfields, for one, filed for bankruptcy in October after closing its Manhattan store. As time goes on, DTC is becoming less about e-commerce and more about a combination of physical and digital touchpoints.

We talk about trans-human retail a mixture of physical retail enabled by technologies and digital touchpoints that enhance the customer experience as a whole, said Levato. Finding a new and relevant role for the multi-brand channel needs to start from the brands themselves, because its also helpful for the brand to enhance the value proposition there for the customer.

According to the report, online and mono-brand channels are expected to account for two-thirds of the entire luxury market by 2030. The brands that are poised to win in the long term are leading on sustainability and embracing technology, said Levato.

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SKILLET’s JOHN COOPER Explains Why He Believes ‘Queer … – BLABBERMOUTH.NET

Posted: at 12:39 pm

During a recent appearance on the "Conversations That Matter" podcast, John Cooper, the frontman and bassist for the Grammy-nominated Christian rock band SKILLET, weighed in on "queer theory", a field of study that challenges existing traditional ideas about identity, sexuality, and gender particularly that of heteronormativity, or the belief that heterosexuality is the natural, moral, or "normal" expression of sexuality. The 48-year-old musician, who is promoting his recently released second book, "Wimpy, Weak And Woke", said in part: "I believe that queer theory is literally the end of all things. There will be no meaningful conversations even able to have in the world if queer theory actually becomes as ubiquitous as it seems like it is already becoming. There will be no distinctions between anything. If you embrace queer theory, and you embrace the idea that men can be women and women can be men, or you can be both, or neither, blah, blah, blah, then you will end up having to accept that there really is no difference between mankind and beast. It just follows. And in fact, the queer theorists would probably be, like, 'Yeah, that's right.'"

He continued: "Sexuality, to me, that's the key. If the church does not stand our ground on sexuality, we lose everything. We absolutely lose everything.

"This is just so upsetting to me. A lot of Christians just do not believe that it's as bad as it is They just refuse to believe it. And they keep saying, 'Guys, there's nothing new under the sun. It's always been this bad. You're making it seem like it's worse.' That's just not true. It hasn't always been this bad.

"Transgenderism is the most civilizational-shifting thing that has happened in I don't even know how long. You're talking about something that could change the trajectory of human nature forever. And, of course, if anybody's done the reading, I'm not gonna get into this, and I don't write about this in the book, but if anybody knows what transhumanism is, we're one step away from transhumanism, which we won't even get into," he added, referencing the position that human beings should be permitted to use technology to modify and enhance human cognition and bodily function, expanding abilities and capacities beyond current biological constraints. "And transgenderism sort of makes that possible. It's a sort of Gnosticism that really will bring us into a man-and-machine kind of thing coming in together. It's absolutely horrifying."

Cooper previously warned against transgender ideology earlier this year in an interview with The Daily Signal.

"We don't even believe in objective reality now," he lamented, referring to American society. "We are saying you can be a Christian as you want to, as long as you privatize it. You can be a Christian at your home. Just don't go around telling people. But in the public sphere, [where] we used to be able to talk about religion and objective reality In the public sphere, we are going to make peoples personal subjective feelings be public truth.

"So if you say, 'I'm a boy, but I know I'm actually a girl, and I believe it in my heart,' the public has to say your inner feelings are true," he added. "But if somebody says, 'No. I can see objective reality. You are a boy,' that's not publicly true, though it can be a privately held belief if you want.

"That's the way to end all things," Cooper said. "That is the destruction of objective reality."

In various interviews over the years, Cooper has said that he "always had faith in God" and that his mother was a "Jesus fanatic." He also claimed that he was willing to put his career on the line to take a stand for Christ.

In 2021, Cooper was asked by the "Undaunted.Life: A Man's Podcast" what he would say to someone who says that Satan works through rock music, and thus Christians shouldn't play rock music. He responded: "I would say Satan can work through just about anything. I would say that music is created not by the Devil; [it is] created by the Lord. All things were created by God. So instead of thinking that the Devil owns a genre of music, I would say capture that music and bring it back into subjection under the lordship of Christ."

As for what he would say to someone who says it is sinful for Christians to have tattoos, Cooper said: "I understand why Christians think that, because of the Old Testament. I would say it probably takes a little bit of a longer explanation of Old Testament law and what it meant. But a short version would be there are some things in the Old Testament that were a picture of something in the New Testament. There are some things that are not pictures, like murder we don't murder, we don't steal, so and so forth. Dietary restrictions, things like that, were a picture of something.

"Here's what God wanted: God wants to make his people set apart and holy unto his name," he continued. "And I don't think that God does that any longer from the way that we look; he does that now because of Christ's work on the cross, his resurrection, and he sanctifies us, which sets us apart from the sinner and the pagan."

SKILLET's latest album, "Dominion", was released in January 2022 via Atlantic.

"Wimpy, Weak And Woke" was released on November 14.

John's debut book, "Awake & Alive To Truth", has had over 10 printings and won the Book Impact Award at the 2021 K-Love Fan Awards. His podcast, "Cooper Stuff", continues to grow rapidly as well with over four million downloads and more than two million YouTube views.

John Cooper press photo courtesy of The Media Collective

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DC This Week Roundup – Superheroes Across Space and Time – GeekDad

Posted: at 12:39 pm

Steelworks #6 cover, via DC Comics. Steelworks #6 Michael Dorn, Writer; Sami Basri/Vicente Cifuentes, Artists; Andrew Dalhouse, Colorist Ray 8.5/10

Ray: The final issue of this miniseries has the biggest threat yet for our heroesa giant robot Steel armor, remotely controlled by deranged weapons manufacturer Charles Walker II. Hes a rather cartoony villain, but secondary villain Silver Mist has a slightly more sympathetic backstoryone that plays a key role when he decides to switch sides at the last minute and assist the floundering super-family against an enemy that seems to have their number in every way. Theres a clever reveal about why some members of the heroes feel so much more affected by the Kryptonian energy than others, and the issue ends on an ambiguous but hopeful note as Steel reviews his plans to transform Metropolis and rededicates Steelworks to his larger goals. This issue also has a surprisingly big focus on Lana Lang, who has her powers yet and is set to marry John, so itll be interesting to see where thats followed up on.

Ray: This continues to be the most bizarre Harley run weve had yetwhere else can you see Bud and Lou possessed by cosmic entities? As Harley kicks the hijackers out of her beloved hyenas, they return to Lady Quark, who creates another new attempt to bring Harley under controla powerful Harley AI that travels the multiverse targeting her counterparts. Harley is forced to align with another bizarre allyrobot detective Lux Kirby, who takes her on a trip through the multiverse to find other Harleys who have been targeted. Despite the truly bizarre plot in this issue, I did enjoy a lot of the quieter moments, including the reunion between Harley and Ivy even if the crisis is far from over.

The backup was bizarre in a very different way, as Grace Ellis and Steve Lieber take Harley into the comicsliterally. She explores a comic about herself, going from ad pages to script pages before finally bursting out of the page itself to confront the source of her problems. It might just be the most meta comic around.

Ray: After two issues setting up the threat of Blue Earth, Amalak, and a mysterious Kryptonian plague, this issue nicely dials things back for a fairly emotional issue as Paige holes up in the Fortress of Solitude seeking answers. While Omen deals with Blue Earth rioters back in Metropolis, Paige bonds with an elderly Kryptonian lion named Hamlet who is nearing the natural end of his lifeand the inevitable extinction of his species. As the animal isolates itself before the end comes, Paige tries to offer it comfort and find some herself. But this is the DCU, and its never long before the outside world comes calling. The dark moments in this issue are nicely balanced by some positive concepts about the way we all play a role in the world, but I do think the creative team is still struggling to figure out where Paige fits in the DCU and in the Super-familywhich is, of course, the meta point of the series.

Ray: As Terry and Kyle reach the core of the Garden and are confronted by a trio of DCs most iconic plant-based superheroes and villains, it becomes clear that this situation is far more than it first appeared to be. Its not a simple case of missing children but rather a cosmic-level threat led by a surprising face. As the truth of John Constantines involvement in the world under Gotham is revealed, Kyle comes into his own as a hero. The cat-human boy hybrid has been the most interesting part of the story, as he might become Terrys first real partner in the fieldassuming that both of them survive a cosmic battle for Gotham. On the surface, Donovan Lumos, the corrupt metahuman corporate titan, puts his plan into actionand accidentally potentially unleashes an apocalypse just in time for the final issue. This series may be a bit too chaotic at times, but its definitely an interesting ride.

Ray: The last of the three Asian-American heroes introduced as part of a new initiative for DC, City Boy has flown a little under-the-radar but has a fascinating set of powers and a compelling backstory. While the main villainwhose name calls back to his true origins or identitywas a hateable figure, Cameron is both the hero of the story and its biggest threat, as his grief over his abusive mother passing away without giving him closure spirals out of control and threatens to envelop the world. As all the cast of the cities he visitedBatman, Superman, Nightwing, and Swamp Thingunite to save their cities and guide Cameron out of the void, the Intergang plot almost feels forgotten, with the villains beating a hasty retreat. However, the final moments of the issue pack a real emotional punch as Cameron is finally able to find some peace with the help of his new allies.

Ray: This series has been doing some very interesting things with the concepts of transhumanism and AI, as Cyborg finds himself up against a villain who comes from the brain patterns of his fathers rival Markusall the while Markus is still alive and being hunted by himself. While the new entity Solace makes a powerful villain, its also hard to disagree with himthe concept of a being being created as a mental double, but confined to a robot body and forced to serve the real person is rather horrifying and just asking for a robot rebellion. And thats exactly what Markus getscausing Cyborg to call in backup from the Titans. The Fearsome Five, now with some reinforcements, provide the main threat this issue, but the larger plot involving Markus and Solace are in full swing by the end of the issueleading to whats sure to be a tense finale.

Ray: Nikolas Draper-Ivey brings down the curtain on his second Static miniseries with an issue that reveals the mastermind behind the Bang Baby hunters who have been torturing Rubber-Band Man and killed Statics young friend Quincyand its a surprising twist that casts a dark pall on the earlier issues of the series. As Static and Ebon confront the villains behind the entire plot, the two former enemies find an uneasy understandingone that continues even after the immediate threat is vanquished. These two characters, on opposite sites of the law but driven by the same central goal to protect the innocent, have been the heart of this series and Im hoping to see more of their dynamic in the future. The final scene, set at Quincys funeral, feels like its commenting on some very real and hard-to-talk-about things. Im not sure whats next for Static, but Im hoping that Draper-Ivey is involved.

To find reviews of all the DC issues, visit DC This Week.

GeekDad received this comic for review purposes.

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DC This Week Roundup - Superheroes Across Space and Time - GeekDad

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