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Fulltext Intensification of IDegAsp Twice Daily (Adding Insulin Aspart vs. Switching To Basal-Bolus): Exploratory Randomized Trial in Type 2 Diabetes

Bebakar WM, Chaykin L, Hersløv ML, Rasmussen S

Diabetes Ther, 2017 Feb;8(1):197-205.
PMID: 27853981 DOI: 10.1007/s13300-016-0213-8

INTRODUCTION: In a preceding trial comparing two different titration schemes, insulin degludec/insulin aspart (IDegAsp) showed good efficacy for achieving HbA1c <7% when administered twice daily (BID) in patients with uncontrolled type 2 diabetes (T2D). However, poor glycemic control persisted in a minority of patients. The current exploratory trial investigated the efficacy and safety of intensifying IDegAsp BID treatment in these patients by either adding a once-daily (OD) bolus injection of insulin aspart (IAsp) or by switching to a basal-bolus regimen of insulin degludec (IDeg) plus IAsp taken three times a day (TID).
METHOD: A 26-week, randomized, open-label, phase 3b, treat-to-target trial in which 40 patients with T2D who had not reached target HbA1c ≤7.0% following previous 26-week treatment intensification with IDegAsp BID ±3 oral antidiabetic agents (OADs) were randomized (1:1) to receive IDegAsp BID + IAsp OD (n = 20) or IDeg OD + IAsp TID (n = 20).
RESULTS: Mean baseline HbA1c was 7.9% in the IDegAsp BID + IAsp OD group and 7.7% in the IDeg OD + IAsp TID group. After 26 weeks, the estimated mean change in HbA1c from baseline was 0.05% points in the IDegAsp BID + IAsp OD group and -0.49% points for IDeg OD + IAsp TID: estimated treatment difference (ETD) [95% confidence interval] 0.54% [0.09; 0.99], p = 0.021. Few achieved HbA1c <7% in IDegAsp BID + IAsp OD (four patients) and IDeg OD + IAsp TID groups (five patients). Fasting plasma glucose, hypoglycemia, and adverse events were similar between groups.
CONCLUSION: When used as intensification regimens in patients who failed to achieve target HbA1c during 26-week IDegAsp BID treatment, HbA1c improvements were numerically greater with IDeg OD + IAsp TID compared with IDegAsp BID + IAsp OD. No new safety issues were identified. However, the small, selective sample means clinical generalizations should be made with caution.
FUNDING: Novo Nordisk. CLINICALTRIALS.
GOV IDENTIFIER: NCT01814137.
Fulltext Biosynthesis of bioactive diterpenoids in the medicinal plant Vitex agnus-castus

Heskes AM, Sundram TCM, Boughton BA, Jensen NB, Hansen NL, Crocoll C, et al.

Plant J, 2018 03;93(5):943-958.
PMID: 29315936 DOI: 10.1111/tpj.13822

Vitex agnus-castus L. (Lamiaceae) is a medicinal plant historically used throughout the Mediterranean region to treat menstrual cycle disorders, and is still used today as a clinically effective treatment for premenstrual syndrome. The pharmaceutical activity of the plant extract is linked to its ability to lower prolactin levels. This feature has been attributed to the presence of dopaminergic diterpenoids that can bind to dopamine receptors in the pituitary gland. Phytochemical analyses of V. agnus-castus show that it contains an enormous array of structurally related diterpenoids and, as such, holds potential as a rich source of new dopaminergic drugs. The present work investigated the localisation and biosynthesis of diterpenoids in V. agnus-castus. With the assistance of matrix-assisted laser desorption ionisation-mass spectrometry imaging (MALDI-MSI), diterpenoids were localised to trichomes on the surface of fruit and leaves. Analysis of a trichome-specific transcriptome database, coupled with expression studies, identified seven candidate genes involved in diterpenoid biosynthesis: three class II diterpene synthases (diTPSs); three class I diTPSs; and a cytochrome P450 (CYP). Combinatorial assays of the diTPSs resulted in the formation of a range of different diterpenes that can account for several of the backbones of bioactive diterpenoids observed in V. agnus-castus. The identified CYP, VacCYP76BK1, was found to catalyse 16-hydroxylation of the diol-diterpene, peregrinol, to labd-13Z-ene-9,15,16-triol when expressed in Saccharomyces cerevisiae. Notably, this product is a potential intermediate in the biosynthetic pathway towards bioactive furan- and lactone-containing diterpenoids that are present in this species.
Fulltext Global monitoring of antimicrobial resistance based on metagenomics analyses of urban sewage

Hendriksen RS, Munk P, Njage P, van Bunnik B, McNally L, Lukjancenko O, et al.

Nat Commun, 2019 03 08;10(1):1124.
PMID: 30850636 DOI: 10.1038/s41467-019-08853-3

Antimicrobial resistance (AMR) is a serious threat to global public health, but obtaining representative data on AMR for healthy human populations is difficult. Here, we use metagenomic analysis of untreated sewage to characterize the bacterial resistome from 79 sites in 60 countries. We find systematic differences in abundance and diversity of AMR genes between Europe/North-America/Oceania and Africa/Asia/South-America. Antimicrobial use data and bacterial taxonomy only explains a minor part of the AMR variation that we observe. We find no evidence for cross-selection between antimicrobial classes, or for effect of air travel between sites. However, AMR gene abundance strongly correlates with socio-economic, health and environmental factors, which we use to predict AMR gene abundances in all countries in the world. Our findings suggest that global AMR gene diversity and abundance vary by region, and that improving sanitation and health could potentially limit the global burden of AMR. We propose metagenomic analysis of sewage as an ethically acceptable and economically feasible approach for continuous global surveillance and prediction of AMR.
Fulltext A draft genome sequence of the elusive giant squid, Architeuthis dux

da Fonseca RR, Couto A, Machado AM, Brejova B, Albertin CB, Silva F, et al.

Gigascience, 2020 Jan 01;9(1).
PMID: 31942620 DOI: 10.1093/gigascience/giz152

BACKGROUND: The giant squid (Architeuthis dux; Steenstrup, 1857) is an enigmatic giant mollusc with a circumglobal distribution in the deep ocean, except in the high Arctic and Antarctic waters. The elusiveness of the species makes it difficult to study. Thus, having a genome assembled for this deep-sea-dwelling species will allow several pending evolutionary questions to be unlocked.
FINDINGS: We present a draft genome assembly that includes 200 Gb of Illumina reads, 4 Gb of Moleculo synthetic long reads, and 108 Gb of Chicago libraries, with a final size matching the estimated genome size of 2.7 Gb, and a scaffold N50 of 4.8 Mb. We also present an alternative assembly including 27 Gb raw reads generated using the Pacific Biosciences platform. In addition, we sequenced the proteome of the same individual and RNA from 3 different tissue types from 3 other species of squid (Onychoteuthis banksii, Dosidicus gigas, and Sthenoteuthis oualaniensis) to assist genome annotation. We annotated 33,406 protein-coding genes supported by evidence, and the genome completeness estimated by BUSCO reached 92%. Repetitive regions cover 49.17% of the genome.
CONCLUSIONS: This annotated draft genome of A. dux provides a critical resource to investigate the unique traits of this species, including its gigantism and key adaptations to deep-sea environments.
A genomic history of Aboriginal Australia

Malaspinas AS, Westaway MC, Muller C, Sousa VC, Lao O, Alves I, et al.

Nature, 2016 Oct 13;538(7624):207-214.
PMID: 27654914 DOI: 10.1038/nature18299

The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of Pama-Nyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 25-40 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated ~10-32 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the Pama-Nyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 51-72 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert.
The prehistoric peopling of Southeast Asia

McColl H, Racimo F, Vinner L, Demeter F, Gakuhari T, Moreno-Mayar JV, et al.

Science, 2018 07 06;361(6397):88-92.
PMID: 29976827 DOI: 10.1126/science.aat3628

The human occupation history of Southeast Asia (SEA) remains heavily debated. Current evidence suggests that SEA was occupied by Hòabìnhian hunter-gatherers until ~4000 years ago, when farming economies developed and expanded, restricting foraging groups to remote habitats. Some argue that agricultural development was indigenous; others favor the "two-layer" hypothesis that posits a southward expansion of farmers giving rise to present-day Southeast Asian genetic diversity. By sequencing 26 ancient human genomes (25 from SEA, 1 Japanese Jōmon), we show that neither interpretation fits the complexity of Southeast Asian history: Both Hòabìnhian hunter-gatherers and East Asian farmers contributed to current Southeast Asian diversity, with further migrations affecting island SEA and Vietnam. Our results help resolve one of the long-standing controversies in Southeast Asian prehistory.
Fulltext The population genomic legacy of the second plague pandemic

Gopalakrishnan S, Ebenesersdóttir SS, Lundstrøm IKC, Turner-Walker G, Moore KHS, Luisi P, et al.

Curr Biol, 2022 Nov 07;32(21):4743-4751.e6.
PMID: 36182700 DOI: 10.1016/j.cub.2022.09.023

Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%-40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th-19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics.