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Tetraallylsilane can undergo either a mono or double rearrangement when treated with iodine (I2). The extent of rearrangement depends on the equivalents of I2 used, where 1 equivalent gives high yields of mono-rearranged products and excess (e.g., 3 equivalents) causes double rearrangement to occur. This transformation can be applied to the synthesis of potentially valuable silicon-stereogenic organosilanes.

In cancer biology, a tumor begins from a single cell within a group of precancerous cells that share genetic mutations. Kaufman et al. used a zebrafish melanoma model to visualize cancer initiation (see the Perspective by Boumahdi and Blanpain). They used a fluorescent reporter that specifically lit up neural crest progenitors that are only present during embryogenesis or during adult melanoma tumor formation. The appearance of this tumor correlated with a set of gene regulatory elements, called super-enhancers, whose identification and manipulation may prove beneficial in detecting and preventing melanoma initiation. Science , this issue p. 10.1126/science.aad2197 ; see also p. 453 Melanocytes with oncogenic or tumor suppressor mutations revert to expressing the crestin gene early in melanoma formation. [Also see Perspective by Boumahdi and Blanpain ] The “cancerized field” concept posits that cancer-prone cells in a given tissue share an oncogenic mutation, but only discreet clones within the field initiate tumors. Most benign nevi carry oncogenic BRAF V600E mutations but rarely become melanoma. The zebrafish crestin gene is expressed embryonically in neural crest progenitors (NCPs) and specifically reexpressed in melanoma. Live imaging of transgenic zebrafish crestin reporters shows that within a cancerized field ( BRAF V600E - mutant; p53- deficient), a single melanocyte reactivates the NCP state, revealing a fate change at melanoma initiation in this model. NCP transcription factors, including sox10 , regulate crestin expression. Forced sox10 overexpression in melanocytes accelerated melanoma formation, which is consistent with activation of NCP genes and super-enhancers leading to melanoma. Our work highlights NCP state reemergence as a key event in melanoma initiation.

Antimicrobial resistance threatens the viability of modern medicine, which is largely dependent on the successful prevention and treatment of bacterial infections. Unfortunately, there are few new therapeutics in the clinical pipeline, particularly for Gram-negative bacteria. We now present a detailed evaluation of the antimicrobial activity of cannabidiol, the main non-psychoactive component of cannabis. We confirm previous reports of Gram-positive activity and expand the breadth of pathogens tested, including highly resistant Staphylococcus aureus, Streptococcus pneumoniae, and Clostridioides difficile. Our results demonstrate that cannabidiol has excellent activity against biofilms, little propensity to induce resistance, and topical in vivo efficacy. Multiple mode-of-action studies point to membrane disruption as cannabidiol’s primary mechanism. More importantly, we now report for the first time that cannabidiol can selectively kill a subset of Gram-negative bacteria that includes the ‘urgent threat’ pathogen Neisseria gonorrhoeae. Structure-activity relationship studies demonstrate the potential to advance cannabidiol analogs as a much-needed new class of antibiotics.Blaskovich et al. demonstrate the antimicrobial applications of cannabidiol and cannabidiol analogs against a range of pathogenic bacteria, including the capacity to kill MRSA and the Gram-negative bacteria Neisseria gonorrhoeae. This article highlights the potential for cannabidiol in the age of antimicrobial resistance.

Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a nutrient-rich replicative niche. Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with terpenyl nucleoside-producing M. tuberculosis, caused intralysosomal and peribacillary lipid storage patterns that matched both the molecules and subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters and that 1-TbAd increased M. tuberculosis growth under conditions of restricted lipid access in macrophages. Furthermore, lipidomics identified 1-TbAd-induced lipid substrates that define Gaucher's disease, Wolman's disease, and other inborn lysosomal storage diseases. These data identify genetic and molecular causes of M. tuberculosis-induced lysosomal failure, leading to successful testing of an agonist of TRPML1 calcium channels that reverses lipid storage in cells. These data establish the host-directed cellular functions of an orphan effector molecule that promotes survival in macrophages, providing both an upstream cause and detailed picture of lysosome failure in foamy macrophages.

The APOBEC3 family of RNA and single stranded DNA cytidine deaminases contribute prominently to the mutagenesis of certain cancers including urothelial carcinoma of the bladder (UC). Remarkably, up to 70% of mutations in UC are attributable to the mutagenic activity of the APOBEC3 deaminases. Despite this strong association, few functional studies have investigated APOBEC3’s role in bladder cancer. We report a genetically engineered murine model with conditional knock out of Pten and Trp53 in addition to overexpression of mouse Apobec3 (UPPA). Analysis of bladder tumors from UPPA mice demonstrates that mA3 promotes tumor progression and squamous trans-differentiation. We establish that APOBEC3 promotes squamous differentiation through IL-1α and downstream activation of the AP-1 transcription factor. Bulk RNA-sequencing from human UC shows APOBEC3A as the only human APOBEC3 family member to correlate with squamous differentiation. Furthermore, single cell and spatial transcriptomics reinforces the role of APOBEC3A in fostering squamous trans-differentiation and promoting the emergence of a subpopulation of highly squamous epithelial cells. Our results demonstrate that mouse Apobec3 and human APOBEC3A promote squamous differentiation in urothelial carcinoma and that this trans-differentiation phenotype is mediated through IL-1α signaling, a target of FDA approved therapies for rheumatologic disease. Deaminases of the APOBEC3 family contribute to the mutagenesis of various cancers, including urothelial carcinoma (UC) of the bladder. Here, the authors use functional studies and transcriptomics to demonstrate that APOBEC3 promotes tumour progression and squamous trans-differentiation in UC through IL-1α and downstream activation of the AP-1 transcription factor.

A receptor that mediates osteoprotegerin ligand (OPGL)-induced osteoclast differentiation and activation has been identified via genomic analysis of a primary osteoclast precursor cell cDNA library and is identical to the tumor necrosis factor receptor (TNFR) family member RANK. The RANK mRNA was highly expressed by isolated bone marrow-derived osteoclast progenitors and by mature osteoclasts in vivo. Recombinant OPGL binds specifically to RANK expressed by transfected cell lines and purified osteoclast progenitors. Transgenic mice expressing a soluble RANK-Fc fusion protein have severe osteopetrosis because of a reduction in osteoclasts, similar to OPG transgenic mice. Recombinant RANK-Fc binds with high affinity to OPGL in vitro and blocks osteoclast differentiation and activation in vitro and in vivo. Furthermore, polyclonal Ab against the RANK extracellular domain promotes osteoclastogenesis in bone marrow cultures suggesting that RANK activation mediates the effects of OPGL on the osteoclast pathway. These data indicate that OPGL-induced osteoclastogenesis is directly mediated through RANK on osteoclast precursor cells.

DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P < 1 × 10-7). We connect obesity-associated methylation variations to transcriptomic changes at >500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions. DNA methylation variation is associated with human obesity but a whether it plays a causal role in disease pathogenesis is unclear. Here, the authors perfom an integrative genomic study in human adipocytes to show that DNA methylation variations contribute to obesity and type 2 diabetes susceptibility, revealing underlying genomic and molecular mechanisms.

Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population. Clinically significant genetic variation in Asian populations is under-characterized. Here, the authors show the diversity in prevalence and spectrum of human disease and pharmacogenetic variants in a multi-ethnic Asian population.

We have generated RANK (receptor activator of NF-κ B nullizygous mice to determine the molecular genetic interactions between osteoprotegerin, osteoprotegerin ligand, and RANK during bone resorption and remodeling processes. RANK-/-mice lack osteoclasts and have a profound defect in bone resorption and remodeling and in the development of the cartilaginous growth plates of endochondral bone. The osteopetrosis observed in these mice can be reversed by transplantation of bone marrow from rag1-/-(recombinase activating gene 1) mice, indicating that RANK-/-mice have an intrinsic defect in osteoclast function. Calciotropic hormones and proresorptive cytokines that are known to induce bone resorption in mice and human were administered to RANK-/-mice without inducing hypercalcemia, although tumor necrosis factor α treatment leads to the rare appearance of osteoclast-like cells near the site of injection. Osteoclastogenesis can be initiated in RANK-/-mice by transfer of the RANK cDNA back into hematopoietic precursors, suggesting a means to critically evaluate RANK structural features required for bone resorption. Together these data indicate that RANK is the intrinsic cell surface determinant that mediates osteoprotegerin ligand effects on bone resorption and remodeling as well as the physiological and pathological effects of calciotropic hormones and proresorptive cytokines.

Charge density waves (CDWs) in kagome metals have been tied to many exotic phenomena. Here, using spectroscopic-imaging scanning tunneling microscopy and angle-resolved photoemission spectroscopy, we study the charge order in kagome metal ScV6Sn6. The similarity of electronic band structures of ScV6Sn6 and TbV6Sn6 (where charge ordering is absent) suggests that charge ordering in ScV6Sn6 is unlikely to be primarily driven by Fermi surface nesting of the Van Hove singularities. In contrast to the CDW state of cousin kagome metals, we find no evidence supporting rotation symmetry breaking. Differential conductance dI/dV spectra show a partial gap Δ1CO ≈ 20 meV at the Fermi level. Interestingly, dI/dV maps reveal that charge modulations exhibit an abrupt phase shift as a function of energy at energy much higher than Δ1CO, which we attribute to another spectral gap. Our experiments reveal a distinctive nature of the charge order in ScV6Sn6 with fundamental differences compared to other kagome metals.