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After nearly 11 years of follow-up, long-term administration of imatinib was shown to be associated with prolonged control of chronic myeloid leukemia and no cumulative or late toxic effects have emerged. Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that is characterized by the Philadelphia (Ph) chromosome and driven by its product, the BCR-ABL1 tyrosine kinase. 1 In 2001, imatinib was introduced as a BCR-ABL1 tyrosine kinase inhibitor and was approved for the treatment of CML on the basis of a high level of activity in phase 2 studies. 2 Early results from the phase 3 International Randomized Study of Interferon and STI571 (IRIS) showed that imatinib at a dose of 400 mg once daily was more active and was associated with fewer side effects than interferon alfa plus cytarabine in patients with . . .

Despite Late Bronze Age Aegean art containing a number of depictions of armed women, unacknowledged preconceptions about gender continue to divert thoughts away from past women exercising violent or coercive power, and thus affecting significantly our understanding of Late Bronze Age Aegean societies in general. This paper examines the depiction of armed women in the art of the Late Bronze Age Aegean and considers how previous generations of researchers have chosen to interpret it. The author then uses recent developments in gender theory and political theory to suggest that the connection of women to power needs to be reassessed.

Achieving a uniform extraction of soluble material from a porous matrix is a generic problem in various separation and filtration operations, with applications in the food processing, chemical and pharmaceutical industries. This paper describes models of fluid flow and transport of soluble material within a packed granular bed in the context of coffee extraction. Coffee extraction is described by diffusion of soluble material from particles of one or more representative sizes into fluid flowing through the packed bed. One-dimensional flow models are compared to computational fluid dynamics (CFD) models. A fine and a coarse coffee grind are considered. Model results are compared to experimental data for a packed cylindrical coffee bed and the influence of a change in geometry to a truncated cone is considered. Non-uniform flow in the truncated cone causes significant variation in the local extraction level. Coffee extraction levels during brewing are analysed using extraction maps and the degree of variation is represented on the industry standard coffee brewing control chart. A high variation in extraction yield can be expected to impart bitter flavours into the brew and thus is an important variable to quantify.

The white shark (Carcharodon carcharias; Chondrichthyes, Elasmobranchii) is one of the most publicly recognized marine animals. Here we report the genome sequence of the white shark and comparative evolutionary genomic analyses to the chondrichthyans, whale shark (Elasmobranchii) and elephant shark (Holocephali), as well as various vertebrates. The 4.63-Gbp white shark genome contains 24,520 predicted genes, and has a repeat content of 58.5%. We provide evidence for a history of positive selection and gene-content enrichments regarding important genome stability-related genes and functional categories, particularly so for the two elasmobranchs. We hypothesize that the molecular adaptive emphasis on genome stability in white and whale sharks may reflect the combined selective pressure of large genome sizes, high repeat content, high long-interspersed element retrotransposon representation, large body size, and long lifespans, represented across these two species. Molecular adaptation for wound healing was also evident, with positive selection in key genes involved in the wound-healing process, as well as Gene Ontology enrichments in fundamental wound-healing pathways. Sharks, particularly apex predators such as the white shark, are believed to have an acute sense of smell. However, we found very few olfactory receptor genes, very few trace amine-associated receptors, and extremely low numbers of G protein-coupled receptors. We did however, identify 13 copies of vomeronasal type 2 (V2R) genes in white shark and 10 in whale shark; this, combined with the over 30 V2Rs reported previously for elephant shark, suggests this gene family may underlie the keen odorant reception of chondrichthyans.

Morphological variation in natural populations is a genomic test bed for studying the interface between molecular evolution and population genetics, but some of the most interesting questions involve non-model organisms that lack well annotated reference genomes. Many felid species exhibit polymorphism for melanism but the relative roles played by genetic drift, natural selection, and interspecies hybridization remain uncertain. We identify mutations of Agouti signaling protein (ASIP) or the Melanocortin 1 receptor (MC1R) as independent causes of melanism in three closely related South American species: the pampas cat (Leopardus colocolo), the kodkod (Leopardus guigna), and Geoffroy's cat (Leopardus geoffroyi). To assess population level variation in the regions surrounding the causative mutations we apply genomic resources from the domestic cat to carry out clone-based capture and targeted resequencing of 299 kb and 251 kb segments that contain ASIP and MC1R, respectively, from 54 individuals (13-21 per species), achieving enrichment of ~500-2500-fold and ~150x coverage. Our analysis points to unique evolutionary histories for each of the three species, with a strong selective sweep in the pampas cat, a distinctive but short melanism-specific haplotype in the Geoffroy's cat, and reduced nucleotide diversity for both ancestral and melanism-bearing chromosomes in the kodkod. These results reveal an important role for natural selection in a trait of longstanding interest to ecologists, geneticists, and the lay community, and provide a platform for comparative studies of morphological variation in other natural populations.

Alterations to post-translational crosslinking modifications in the extracellular matrix (ECM) are known to drive the pathogenesis of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Thus, the methodology for measuring crosslinking dynamics is valuable for understanding disease progression. The existing crosslinking analysis sample preparation and liquid chromatography tandem mass spectrometry (LC-MS/MS) methods are typically labor-intensive and time-consuming which limits throughput. We, therefore, developed a rapid approach minimizing specialized equipment and hands-on time. The LC-MS/MS sample analysis time was reduced to two minutes per sample. We then improved the analytical integrity of the method by developing a novel surrogate matrix approach for the dihydroxylysinonorleucine (DHLNL) crosslink. By modifying sample preparation, we prepared a tissue-based surrogate matrix with undetectable levels of endogenous DHLNL, providing a strategy for quantifying this crosslink with a more relevant standard matrix. We then applied this rapid methodology to evaluating crosslinking in lung fibrosis. We showed an increase in DHLNL in human IPF lung relative to healthy donors, as well as in a fibrotic mouse model. Finally, we demonstrated that this increase in DHLNL could be mitigated with an anti-fibrotic compound, suggesting that this assay has potential for evaluating pharmaceutical compound efficacy.

The world's domestic cats carry patterns of sequence variation in their genome that reflect a history of domestication and breed development. A genetic assessment of 979 domestic cats and their wild progenitors--Felis silvestris silvestris (European wildcat), F. s. lybica (Near Eastern wildcat), F. s. ornata (central Asian wildcat), F. s. cafra (southern African wildcat), and F. s. bieti (Chinese desert cat)--indicated that each wild group represents a distinctive subspecies of Felis silvestris. Further analysis revealed that cats were domesticated in the Near East, probably coincident with agricultural village development in the Fertile Crescent. Domestic cats derive from at least five founders from across this region, whose descendants were transported across the world by human assistance.

Artificial selection is the selection of advantageous natural variation for human ends and is the mechanism by which most domestic species evolved. Most domesticates have their origin in one of a few historic centers of domestication as farm animals. Two notable exceptions are cats and dogs. Wolf domestication was initiated late in the Mesolithic when humans were nomadic hunter-gatherers. Those wolves less afraid of humans scavenged nomadic hunting camps and over time developed utility, initially as guards warning of approaching animals or other nomadic bands and soon thereafter as hunters, an attribute tuned by artificial selection. The first domestic cats had limited utility and initiated their domestication among the earliest agricultural Neolithic settlements in the Near East. Wildcat domestication occurred through a self-selective process in which behavioral reproductive isolation evolved as a correlated character of assortative mating coupled to habitat choice for urban environments. Eurasian wildcats initiated domestication and their evolution to companion animals was initially a process of natural, rather than artificial, selection over time driven during their sympatry with forbear wildcats.

Vibrational spectroscopy techniques are widely used in analytical chemistry, physics and biology. The most prominent techniques are Raman and Fourier-transform infrared spectroscopy (FTIR). Combining both techniques delivers complementary information of the test sample. We present the design, construction, and calibration of a novel bimodal spectroscopy system featuring both Raman and infrared measurements simultaneously on the same sample without mutual interference. The optomechanical design provides a modular flexible system for solid and liquid samples and different configurations for Raman. As a novel feature, the Raman module can be operated off-axis for optical sectioning. The calibrated system demonstrates high sensitivity, precision, and resolution for simultaneous operation of both techniques and shows excellent calibration curves with coefficients of determination greater than 0.96. We demonstrate the ability to simultaneously measure Raman and infrared spectra of complex biological material using bovine serum albumin. The performance competes with commercial systems; moreover, it presents the additional advantage of simultaneously operating Raman and infrared techniques. To the best of our knowledge, it is the first demonstration of a combined Raman-infrared system that can analyze the same sample volume and obtain optically sectioned Raman signals. Additionally, quantitative comparison of confocality of backscattering micro-Raman and off-axis Raman was performed for the first time.

The rediscovery of remnant Florida panthers (Puma concolor coryi) in southern Florida swamplands prompted a program to protect and stabilize the population. In 1995, conservation managers translocated eight female pumas (P. c. stanleyana) from Texas to increase depleted genetic diversity, improve population numbers, and reverse indications of inbreeding depression. We have assessed the demographic, population-genetic, and biomedical consequences of this restoration experiment and show that panther numbers increased threefold, genetic heterozygosity doubled, survival and fitness measures improved, and inbreeding correlates declined significantly. Although these results are encouraging, continued habitat loss, persistent inbreeding, infectious agents, and possible habitat saturation pose new dilemmas. This intensive management program illustrates the challenges of maintaining populations of large predators worldwide.