Total synthesis of the cyclic dodecapeptides wewakazole and wewakazole B

The cyclic dodecapeptides wewakazole and wewakazole B have been synthesized by a divergent strategy via a common tris-proline containing oxazole octapeptide and two separate bisoxazole containing tetrapeptide units, followed by peptide coupling and macrocyclization. The three oxazole amino acid fragments are readily accessible by rhodium(II)-catalysed amide N–H insertion of diazocarbonyl compounds, or by the cycloaddition of rhodium carbenoids with nitriles

Bypass of mutagenic O 6 -Carboxymethylguanine DNA Adducts by Human Y- and B-Family Polymerases

The generation of chemical alkylating agents from nitrosation of glycine and bile acid conjugates in the gastrointestinal tract is hypothesized to initiate carcinogenesis. O6-carboxymethylguanine (O6-CMG) is a product of DNA alkylation derived from nitrosated glycine. Although the tendency of the structurally related adduct O6-methylguanine to code for the misincoporation of TTP during DNA replication is well-established, the impact of the presence of the O6-CMG adduct in a DNA template on the efficiency and fidelity of translesion DNA synthesis (TLS) by human DNA polymerases (Pols) has hitherto not been described. Herein, we characterize the ability of the four human TLS Pols η, ι, κ, and ζ and the replicative Pol δ to bypass O6-CMG in a prevalent mutational hot-spot for colon cancer. The results indicate that Pol η replicates past O6-CMG, incorporating dCMP or dAMP, whereas Pol κ incorporates dCMP only, and Pol ι incorporates primarily dTMP. Additionally, the subsequent extension step was carried out with high efficiency by TLS Pols η, κ, and ζ, while Pol ι was unable to extend from a terminal mismatch. These results provide a first basis of O6-CMG-promoted base misincorporation by Y- and B-family polymerases potentially leading to mutational signatures associated with colon cancer

Post translational changes to α-synuclein control iron and dopamine trafficking : a concept for neuron vulnerability in Parkinson's disease

Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease

A global phylogeny of butterflies reveals their evolutionary history, ancestral hosts and biogeographic origins

Butterflies are a diverse and charismatic insect group that are thought to have evolved with plants and dispersed throughout the world in response to key geological events. However, these hypotheses have not been extensively tested because a comprehensive phylogenetic framework and datasets for butterfly larval hosts and global distributions are lacking. We sequenced 391 genes from nearly 2,300 butterfly species, sampled from 90 countries and 28 specimen collections, to reconstruct a new phylogenomic tree of butterflies representing 92% of all genera. Our phylogeny has strong support for nearly all nodes and demonstrates that at least 36 butterfly tribes require reclassification. Divergence time analyses imply an origin similar to 100 million years ago for butterflies and indicate that all but one family were present before the K/Pg extinction event. We aggregated larval host datasets and global distribution records and found that butterflies are likely to have first fed on Fabaceae and originated in what is now the Americas. Soon after the Cretaceous Thermal Maximum, butterflies crossed Beringia and diversified in the Palaeotropics. Our results also reveal that most butterfly species are specialists that feed on only one larval host plant family. However, generalist butterflies that consume two or more plant families usually feed on closely related plants

Comprehensive phylogeny of Pieridae butterflies reveals strong correlation between diversification and temperature

Summary: Temperature is thought to be a key factor influencing global species richness patterns. We investigate the link between temperature and diversification in the butterfly family Pieridae by combining next generation DNA sequences and published molecular data with fine-grained distribution data. We sampled nearly 600 pierid butterfly species to infer the most comprehensive molecular phylogeny of the family and curated a distribution dataset of more than 800,000 occurrences. We found strong evidence that species in environments with more stable daily temperatures or cooler maximum temperatures in the warm seasons have higher speciation rates. Furthermore, speciation and extinction rates decreased in tandem with global temperatures through geological time, resulting in a constant net diversification

Fig. 1 in A global phylogeny of butterflies reveals their evolutionary history, ancestral hosts and biogeographic origins

Fig. 1 | Evolutionaryrelationshipsanddiversificationpatternsofbutterflies. Time-calibratedtreeof 2,244 butterflyspeciesbasedon 391 loci and 150 amino acidpartitions.Branchesshowdistinctchangesindiversification (circles) asestimatedbyclade-specificmodels.Lettersatnodesrefertocladeswith significantrateshifts (seesection 6 of Supplementary Results).Colouredlines intheouterringbesidetipsindicateassociationwithoneof the 13 hostmodules (seesection 17 of Extended Online Methods).Blacklinesinthehostassociation ringindicatespecieswithoutdata,andasterisksdenotenon-monophyletic subfamilies.Supplementary Fig. 1 showsthistreewithvisiblespeciesnamesand agesforallnodes.Published as part of <i>Kawahara, Akito Y., Storer, Caroline, Carvalho, Ana Paula S., Plotkin, David M., Condamine, Fabien L., Braga, Mariana P., Ellis, Emily A., St Laurent, Ryan A., Li, Xuankun, Barve, Vijay, Cai, Liming, Earl, Chandra, Frandsen, Paul B., Owens, Hannah L., Valencia-Montoya, Wendy A., Aduse-Poku, Kwaku, Toussaint, Emmanuel F. A., Dexter, Kelly M., Doleck, Tenzing, Markee, Amanda, Messcher, Rebeccah, Nguyen, Y-Lan, Badon, Jade Aster T., Benítez, Hugo A., Braby, Michael F., Buenavente, Perry A. C., Chan, Wei-Ping, Collins, Steve C., Rabideau Childers, Richard A., Dankowicz, Even, Eastwood, Rod, Fric, Zdenek F., Gott, Riley J., Hall, Jason P. W., Hallwachs, Winnie, Hardy, Nate B., Sipe, Rachel L. Hawkins, Heath, Alan, Hinolan, Jomar D., Homziak, Nicholas T., Hsu, Yu-Feng, Inayoshi, Yutaka, Itliong, Micael G. A., Janzen, Daniel H., Kitching, Ian J., Kunte, Krushnamegh, Lamas, Gerardo, Landis, Michael J., Larsen, Elise A., Larsen, Torben B., Leong, Jing V., Lukhtanov, Vladimir, Maier, Crystal A., Martinez, Jose I., Martins, Dino J., Maruyama, Kiyoshi, Maunsell, Sarah C., Mega, Nicolás Oliveira, Monastyrskii, Alexander, Morais, Ana B. B., Müller, Chris J., Naive, Mark Arcebal K., Nielsen, Gregory, Padrón, Pablo Sebastián, Peggie, Djunijanti, Romanowski, Helena Piccoli, Sáfián, Szabolcs, Saito, Motoki, Schröder, Stefan, Shirey, Vaughn, Soltis, Doug, Soltis, Pamela, Sourakov, Andrei, Talavera, Gerard, Vila, Roger, Vlasanek, Petr, Wang, Houshuai, Warren, Andrew D., Willmott, Keith R., Yago, Masaya, Jetz, Walter, Jarzyna, Marta A., Breinholt, Jesse W., Espeland, Marianne, Ries, Leslie, Guralnick, Robert P., Pierce, Naomi E. & Lohman, David J., 2023, A global phylogeny of butterflies reveals their evolutionary history, ancestral hosts and biogeographic origins, pp. 903-913 in Nature Ecology & Evolution 7 (6)</i> on page 904, DOI: 10.1038/s41559-023-02041-9, <a href="http://zenodo.org/record/7963518">http://zenodo.org/record/7963518</a&gt

Refinements in husbandry, care and common procedures for non-human primates: Ninth report of the BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement

This report produced by the British Veterinary Association Animal Welfare Foundation (BVAAWF)/Fund for the Replacement of Animals in Medical Experiments (FRAME)/Royal Society for the Prevention of Cruelty to Animals (RSPCA)/Universities Federation for Animal Welfare (UFAW) Joint Working Group on Refinement (JWGR) sets out practical guidance on refining the husbandry and care of non-human primates (hereinafter primates) and on minimizing the adverse effects of some common procedures. It provides a valuable resource to help understand the physical, social and behavioural characteristics and needs of individual primates, and is intended to develop and complement the existing literature and legislative guidelines. Topics covered include refinements in housing, husbandry and common procedures such as restraint, identification and sampling, with comprehensive advice on issues such as primate communication, assessing and facilitating primate wellbeing, establishing and maintaining social groups, environmental and nutritional enrichment and animal passports. The most commonly used species are the key focus of this resource, but its information and recommendations are generally applicable to other species, provided that relevant individual species characteristics are taken into account

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease