A CQM-based approach to solving a combinatorial problem with applications in drug design

The use of D-Wave's Leap Hybrid solver is demonstrated here in solving a Knapsack optimization problem: finding meal combinations from a fixed menu that fit a diner's constraints. This is done by first formulating the optimization problem as a Constrained Quadratic Model (CQM) and then submitting it to a quantum annealer. We highlight here the steps needed, as well as the implemented code, and provide solutions from a Chicken and Waffle restaurant menu. Additionally, we discuss how this model may be generalized to find optimal drug molecules within a large search space with many complex, and often contradictory, structures and property constraints.Comment: 10 pages, 2 table

Mouse models of mastitis - how physiological are they?

CommentaryLactation mastitis is a common, but poorly understood, inflammatory breast disease that is a significant health burden. A better understanding of the aetiology of mastitis is urgently required, and will assist in the development of improved prevention and treatment strategies in both human and animal species. Studies in mice have the potential to greatly assist in identifying new drug candidates for clinical trials, and in developing a better understanding of the disease. Mouse models of mastitis involve administration of a mastitis-inducing agent to the mammary gland usually during lactation to examine the host immune response, and progression through to resolution of the disease. There are important variations in the protocols of these mouse models that critically affect the conclusions that can be drawn from the research. Some protocols involve weaning of offspring at the time of mastitis induction, and there are variations in the mastitis-inducing agent and its carrier. Induction of mammary gland involution through weaning of offspring limits the capacity to study the disease in the context of a lactating mammary gland. Administration of live bacteria in an aqueous carrier can cause sepsis, restricting the physiological relevance of the model. Mouse model research should employ appropriately designed controls and closely monitor the health of the mice. In this commentary, we discuss the advantages and study design limitations of each mouse model, and highlight the potential for further development of physiologically relevant mouse models of mastitis.Wendy V Ingman, Danielle J Glynn, and Mark R Hutchinso

Complete mitochondrial DNA sequences provide new insights into the Polynesian motif and the peopling of Madagascar

More than a decade of mitochondrial DNA (mtDNA) studies have given the 'Polynesian motif' renowned status as a marker for tracing the late-Holocene expansion of Austronesian speaking populations. Despite considerable research on the Polynesian motif in Oceania, there has been little equivalent work on the western edge of its expansion - leaving major issues unresolved regarding the motif's evolutionary history. This has also led to considerable uncertainty regarding the settlement of Madagascar. In this study, we assess mtDNA variation in 266 individuals from three Malagasy ethnic groups: the Mikea, Vezo, and Merina. Complete mtDNA genome sequencing reveals a new variant of the Polynesian motif in Madagascar; two coding region mutations define a Malagasy-specific sub-branch. This newly defined 'Malagasy motif' occurs at high frequency in all three ethnic groups (13-50%), and its phylogenetic position, geographic distribution, and estimated age all support a recent origin, but without conclusively identifying a specific source region. Nevertheless, the haplotype's limited diversity, similar to those of other mtDNA haplogroups found in our Malagasy groups, best supports a small number of initial settlers arriving to Madagascar through the same migratory process. Finally, the discovery of this lineage provides a set of new polymorphic positions to help localize the Austronesian ancestors of the Malagasy, as well as uncover the origin and evolution of the Polynesian motif itself

Complete Mitochondrial Genome Sequencing Reveals Novel Haplotypes in a Polynesian Population

The high risk of metabolic disease traits in Polynesians may be partly explained by elevated prevalence of genetic variants involved in energy metabolism. The genetics of Polynesian populations has been shaped by island hoping migration events which have possibly favoured thrifty genes. The aim of this study was to sequence the mitochondrial genome in a group of Maoris in an effort to characterise genome variation in this Polynesian population for use in future disease association studies. We sequenced the complete mitochondrial genomes of 20 non-admixed Maori subjects using Affymetrix technology. DNA diversity analyses showed the Maori group exhibited reduced mitochondrial genome diversity compared to other worldwide populations, which is consistent with historical bottleneck and founder effects. Global phylogenetic analysis positioned these Maori subjects specifically within mitochondrial haplogroup - B4a1a1. Interestingly, we identified several novel variants that collectively form new and unique Maori motifs – B4a1a1c, B4a1a1a3 and B4a1a1a5. Compared to ancestral populations we observed an increased frequency of non-synonymous coding variants of several mitochondrial genes in the Maori group, which may be a result of positive selection and/or genetic drift effects. In conclusion, this study reports the first complete mitochondrial genome sequence data for a Maori population. Overall, these new data reveal novel mitochondrial genome signatures in this Polynesian population and enhance the phylogenetic picture of maternal ancestry in Oceania. The increased frequency of several mitochondrial coding variants makes them good candidates for future studies aimed at assessment of metabolic disease risk in Polynesian populations

Immune Regulation of Mammary Fibroblasts and the Impact of Mammographic Density

Mammographic density is associated with a 4–6-fold increase in breast cancer risk independent of age and BMI. High mammographic density is characterized by breast tissue with high proportions of stroma comprised of fibroblasts, collagen, and immune cells. This study sought to investigate whether stromal fibroblasts from high mammographic density breast tissue contributes to increased extracellular matrix deposition and pro-tumorigenic signaling. Mammary fibroblasts were isolated from women with high and low mammographic density and exposed to immune factors myeloperoxidase (MPO), eosinophil peroxidase (EPO), transforming growth factor beta 1 (TGFB1) and tumour necrosis factor alpha (TNFA) for 72 h and profiled for expression of cancer-associated fibroblast and extracellular matrix regulation markers. No differences in gene expression profiles or collagen production were observed between fibroblasts with high or low mammographic density, and they did not have a differential response to immune mediators. MPO and EPO significantly increased the production of collagen 1. TGFB and TNFA induced variable changes in gene expression. Fibroblasts cultured in vitro from women with high mammographic density do not appear to be inherently different to those from women with low mammographic density. The function of fibroblasts in mammographic density-associated breast cancer risk is likely to be regulated by immune signals from surrounding cells in the microenvironment.Maddison Archer, Pallave Dasari, David Walsh, Kara L. Britt, Andreas Evdokiou, and Wendy V. Ingma

En färd i språket. Festskrift till Marketta Sundman på 60-årsdagen den 12 mars 2009

Marketta Sundman är en uppskattad forskare och en ansedd akademisk lärare. Till hennes forskningsintressen hör framför allt nusvenskansgrammatiska struktur, tvåspråkighet och inlärning av svenska som främmande språk. Det grammatiska studiet av svenskan representeras i hennes vetenskapliga produktion först och främst av den gedigna doktorsavhandlingen Subjektsval och diates i svenskan (1987). Problem kring tvåspråkighet har hon behandlat ingående t.ex. i monografierna Tvåspråkigheten i skolan: en undersökning av språkfärdigheten hos en- och tvåspråkiga grundskoleelever i Finland (1994) och Barnet, skolan och tvåspråkigheten (1998). Under de senaste åren har hon intresserat sig för inlärning av svenska som främmande språk och för närvarande leder hon ett av Svenska litteratursällskapet i Finland finansierat forskningsprojekt med titeln På väg mot kommunikativ kompetens: Tillägnandet av svenskans struktur hos finska inlärare Marketta Sundmans vetenskapliga verksamhet har uppmärksammats även i Sverige; år 2008 tilldelades hon av Svenska Akademien ett pris som årligen tillerkänns en person som ”genom sin verksamhet har gjort särskilt viktiga insatser för svenska språket.” Artiklarna i denna festskrift är skrivna av personer som har anknytning till olika tidsperioder under Markettas akademiska bana – hennes ”färd i språket”. En del av dem kan karakteriseras som akademiska mentorer, en del som kolleger – tidigare eller nuvarande – och en del som adepter till henne. Detta har också varit vårt mål; vi ville bjuda in både namnkunniga nordister och unga forskare från jubilarens närmaste bekantskapskrets. Vi riktar ett stort tack till artikelförfattarna som trots den kärva tidtabellen ville ställa upp! Festskriften publiceras endast i elektroniskt format. Vid Åbo universitet är den därmed den första av sitt slag. Vår förhoppning är att artiklarna tack vare det nya mediet kommer att få stor spridning och vara lättillgängliga för alla intresserade.Siirretty Doriast