Independent Expansion Research Articles

Pembrolizumab in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Long-Term Efficacy from the Phase 1b Keynote-013 Study

Pembrolizumab in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Long-Term Efficacy from the Phase 1b Keynote-013 Study

Gene Ages, Nomenclatures, and Functional Diversification of the Methuselah/Methuselah-Like GPCR Family in Drosophila and Tribolium.

Affecting lifespan regulation and oxidative stress resistance, the G-protein coupled receptor (GPCR) gene methuselah (mth) plays important roles in the life history of Drosophila melanogaster. Substantial progress has been made in elucidating the molecular pathways by which mth affects these traits, yet conflicting ideas exist as to how old these genetic interactions are as well as how old the mth gene itself is. Root to these issues is the complex gene family history of the Mth/Mthl GPCR family, which experienced independent expansions in a variety of animal clades, leading to at least six subfamilies in insects. Within insects, drosophilid flies stand out by possessing up to three times more Mth/Mthl receptors due to the expansion of a single subfamily, the mth superclade subfamily, which contains an even younger subfamily introduced here as the melanogaster subgroup subfamily. As a result, most of the 16 Mth/Mthl receptors of D. melanogaster are characterized by n:1 orthology relationships to singleton mth superclade homologs in nondrosophilid species. This challenge is exacerbated by the inconsistent naming of Mth/Mthl orthologs across species. To consolidate this situation, we review established ortholog relationships among insect Mth/Mthl receptors, clarify the gene nomenclatures in two important satellite model species, the fruit fly relative D. virilis and the red flour beetle Tribolium castaneum, and discuss the genetic and functional evolution of the D. melanogaster Mth GPCR.

Global population divergence and admixture of the brown rat (Rattus norvegicus).

Native to China and Mongolia, the brown rat (Rattus norvegicus) now enjoys a worldwide distribution. While black rats and the house mouse tracked the regional development of human agricultural settlements, brown rats did not appear in Europe until the 1500s, suggesting their range expansion was a response to relatively recent increases in global trade. We inferred the global phylogeography of brown rats using 32 k SNPs, and detected 13 evolutionary clusters within five expansion routes. One cluster arose following a southward expansion into Southeast Asia. Three additional clusters arose from two independent eastward expansions: one expansion from Russia to the Aleutian Archipelago, and a second to western North America. Westward expansion resulted in the colonization of Europe from which subsequent rapid colonization of Africa, the Americas and Australasia occurred, and multiple evolutionary clusters were detected. An astonishing degree of fine-grained clustering between and within sampling sites underscored the extent to which urban heterogeneity shaped genetic structure of commensal rodents. Surprisingly, few individuals were recent migrants, suggesting that recruitment into established populations is limited. Understanding the global population structure of R. norvegicus offers novel perspectives on the forces driving the spread of zoonotic disease, and aids in development of rat eradication programmes.

DIMENSÕES DO EMPODERAMENTO FEMININO: AUTONOMIA OU DEPENDÊNCIA?

Este estudo objetiva compreender as manifestações das dimensões do empoderamento entre mulheres empreendedoras do município de Forquilhinha, SC. O empreendedorismo e o empoderamento feminino constituem os temas centrais contextualizados teoricamente neste trabalho. Para alcançar o objetivo proposto, esta pesquisa se caracteriza como descritiva, qualitativa e com amostragem não probabilística por acessibilidade. A técnica de coleta dos dados foi a entrevista qualitativa com roteiro semiestruturado elaborado com base nas dimensões do empoderamento alinhadas à iniciativa empreendedora para abrir o próprio negócio, aplicada a 15 mulheres lojistas. Os resultados evidenciaram que o empreendedorismo oportunizou às entrevistadas o empoderamento econômico, tendo em vista que as afirmações se concentraram na ampliação da renda, na independência financeira e autovalorização. Nas dimensões psicológica, educacional, política e familiar as entrevistadas demonstraram certo grau de dependência de outras pessoas, insegurança na tomada de decisão e direcionamento do próprio negócio.

Complete Chloroplast Genome Sequence of Corroborates Structural Heterogeneity of Inverted Repeats in Wild Progenitors of Cultivated Bananas and Plantains.

Complete genome sequencing of cytoplasmically inherited chloroplast DNA provides novel insights into the origins of clonally propagated crops such as banana and plantain ( spp.). This study describes the structural organization of the chloroplast genome of Colla and its phylogenetic relationship with other wild progenitors of the domesticated banana cultivars. The chloroplast genome was sequenced using Illumina HiSeq 2000 platform, followed by a combination of de novo short-read assembly and reference-guided mapping of contigs to generate complete plastome sequence. The chloroplast genome is 169,503 bp in length, exhibits a typical quadripartite structural organization with a large single-copy (LSC; 87,828 bp) region and a small single-copy (SSC; 11,547 bp) region interspersed between inverted repeat (IRa/b; 35,064 bp) regions. Overall, its gene content, size, and gene order were identical to that of Colla with extensive expansion of the inverted repeat-small single-copy (IR-SSC) junctions. Comparative analyses revealed the conserved IRa-SSC expansion in three wild species and members of the order Zingiberales. In contrast, IRb-SSC expansion was conspicuously absent in the sister taxon Nee and related species of Zingiberales. Interestingly, phylogenomic assessment based on whole-plastome and protein-coding gene sets have provided robust support for the association of and as a sister group, despite the variation in IRb-SSC expansion. Although the current study substantiates the infrageneric IRb-SSC fluctuations in Musaceae, extensive taxon sampling is necessary to confirm whether the accessions of section have undergone independent IRb-SSC expansion relative to section .

Evolution of the EGFR pathway in Metazoa and its diversification in the planarian Schmidtea mediterranea.

The EGFR pathway is an essential signaling system in animals, whose core components are the epidermal growth factors (EGF ligands) and their trans-membrane tyrosine kinase receptors (EGFRs). Despite extensive knowledge in classical model organisms, little is known of the composition and function of the EGFR pathway in most animal lineages. Here, we have performed an extensive search for the presence of EGFRs and EGF ligands in representative species of most major animal clades, with special focus on the planarian Schmidtea mediterranea. With the exception of placozoans and cnidarians, we found that the EGFR pathway is potentially present in all other analyzed animal groups, and has experienced frequent independent expansions. We further characterized the expression domains of the EGFR/EGF identified in S. mediterranea, revealing a wide variety of patterns and localization in almost all planarian tissues. Finally, functional experiments suggest an interaction between one of the previously described receptors, Smed-egfr-5, and the newly found ligand Smed-egf-6. Our findings provide the most comprehensive overview to date of the EGFR pathway, and indicate that the last common metazoan ancestor had an initial complement of one EGFR and one putative EGF ligand, which was often expanded or lost during animal evolution.

Regions’ Economic Autonomy in the New Reality

The paper discloses the understanding of new reality (normality) for Russia that consists in the strengthening of the role of a man-personality and in the expansion of the economic autonomy of the territories in their interaction with the federal center. The rationale is based on a hypothesis according to which in the conditions of new reality, the increase of the well-being of the population and the overcoming of economic inequality between the territories are provided by the expansion of their economic independence as it leads to the increase of their intellectual, engineering and manufacturing potential. In the research, the author used the basic concepts of the classical economic theory, the theory of behavioural economics, interdisciplinary approach and statistical grouping method. The dynamics of the economic independence of the territories, which is manifested in the decrease in a number of donor regions and the socio-economic dividing of the territories, is shown. The assumption is proved that the consequences of the territorial stratification are the restraining of the growth of their socio-economic development and possibility probable emergence of «regional peripheral economy» with the property of the dependence of the periphery on the center, the decrease in a local initiative, the inhibition of technological development. The need to use the social psychology of the population, the psychological sets of economic development, «the second invisible hand of the market» and soft power to overcome the «regional peripheral economy» is revealed. The result of the research is the proof that the expansion of the economic independence of the territories is not only the increase of the self-isolation of regions and municipalities, but also the need to save the considerable part of the income from the production of goods and services created by the local population under control of the regional and municipal authorities and direct it to the increase of the well-being of the population of the territory. The idea of creating the legal document to provide and strengthen the economic independence of territories is offered; the suggestions on the principles of its contents and structuring are stated.

Distinctive ultraviolet structure of extra-dimensional Yang-Mills theories by integration of heavy Kaluza-Klein modes

One-loop Standard Model observables produced by virtual heavy Kaluza-Klein fields play a prominent role in the minimal model of universal extra dimensions. Motivated by this aspect, we integrate out all the Kaluza-Klein heavy modes coming from the Yang-Mills theory set on a spacetime with an arbitrary number, $n$, of compact extra dimensions. After fixing the gauge with respect to the Kaluza-Klein heavy gauge modes in a covariant manner, we calculate a gauge independent effective Lagrangian expansion containing multiple Kaluza-Klein sums that entail a bad divergent behavior. We use the Epstein-zeta function to regularize and characterize discrete divergences within such multiple sums, and then we discuss the interplay between the number of extra dimensions and the degree of accuracy of effective Lagrangians to generate or not divergent terms of discrete origin. We find that nonrenormalizable terms with mass dimension $k$ are finite as long as $k>4+n$. Multiple Kaluza-Klein sums of nondecoupling logarithmic terms, not treatable by Epstein-zeta regularization, are produced by four-dimensional momentum integration. On the grounds of standard renormalization, we argue that such effects are unobservable.

Helitrons in Drosophila: Chromatin modulation and tandem insertions.

Although Helitrons were discovered 15y ago, they still represent an elusive group of transposable elements (TEs). They are thought to transpose via a rolling-circle mechanism, but no transposition assay has yet been conducted. We have recently characterized a group of Helitrons in Drosophila, named DINE-TR1, that display interesting features, including pronounced enrichment at β-heterochromatin, multiple tandem insertions (TIs) of the entire TE, and that experienced at least 2 independent expansion events of its internal tandem repeats (TRs) in distant Drosophila lineages. Here we discuss 2 aspects of TE dynamics displayed by the DINE-TR1 Helitrons: (i) the general evolutionary impact of piRNA-guided heterochromatin formation via TE-derived TR expansion and (ii) the possible mechanisms that could account for the recurrent TIs of Helitrons.

Ordynacja i preskrypcja pielęgniarska w Polsce

Introduction. Expansion of professional independence of nurses and midwives resulted in the creation and introduction into practice of several new professional responsibilities. The new responsibilities include dispensing drugs, writing prescriptions, and ordering diagnostic tests. Introduction of such changes undoubtedly strengthens the position of professional nurses. Therefore the current situation should be assessed as extremely momentous for nurses and midwifes not only in regards to the development of both professions but also in regards to the functioning of the entire health care system. Aim of the study. The paper is a review and analysis of legal regulations while formulating conclusions based on the current international research. Conclusions. International experiences in expanding the responsibilities of nurses and midwives in ordination of drugs and writing prescriptions already have a decades-long history and are positive. Therefore, we should hope that in Poland, these changes will benefit patients, health system, and the professional environment of medical staff. Problemy Pielegniarstwa 2015; 23 (4): 551–556

The diversification of the basic leucine zipper family in eukaryotes correlates with the evolution of multicellularity.

BackgroundMulticellularity evolved multiple times in eukaryotes. In all cases, this required an elaboration of the regulatory mechanisms controlling gene expression. Amongst the conserved eukaryotic transcription factor families, the basic leucine zipper (bZIP) superfamily is one of the most ancient and best characterised. This gene family plays a diversity of roles in the specification, differentiation and maintenance of cell types in plants and animals. bZIPs are also involved in stress responses and the regulation of cell proliferation in fungi, amoebozoans and heterokonts.ResultsUsing 49 sequenced genomes from across the Eukaryota, we demonstrate that the bZIP superfamily has evolved from a single ancestral eukaryotic gene and undergone multiple independent expansions. bZIP family diversification is largely restricted to multicellular lineages, consistent with bZIPs contributing to the complex regulatory networks underlying differential and cell type-specific gene expression in these lineages. Analyses focused on the Metazoa suggest an elaborate bZIP network was in place in the most recent shared ancestor of all extant animals that was comprised of 11 of the 12 previously recognized families present in modern taxa. In addition this analysis identifies three bZIP families that appear to have been lost in mammals. Thus the ancestral metazoan and eumetazoan bZIP repertoire consists of 12 and 16 bZIPs, respectively. These diversified from 7 founder genes present in the holozoan ancestor.ConclusionsOur results reveal the ancestral opisthokont, holozoan and metazoan bZIP repertoire and provide insights into the progressive expansion and divergence of bZIPs in the five main eukaryotic kingdoms, suggesting that the early diversification of bZIPs in multiple eukaryotic lineages was a prerequisite for the evolution of complex multicellular organisms.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-016-0598-z) contains supplementary material, which is available to authorized users.

Evolution of brain elaboration.

Large, complex brains have evolved independently in several lineages of protostomes and deuterostomes. Sensory centres in the brain increase in size and complexity in proportion to the importance of a particular sensory modality, yet often share circuit architecture because of constraints in processing sensory inputs. The selective pressures driving enlargement of higher, integrative brain centres has been more difficult to determine, and may differ across taxa. The capacity for flexible, innovative behaviours, including learning and memory and other cognitive abilities, is commonly observed in animals with large higher brain centres. Other factors, such as social grouping and interaction, appear to be important in a more limited range of taxa, while the importance of spatial learning may be a common feature in insects with large higher brain centres. Despite differences in the exact behaviours under selection, evolutionary increases in brain size tend to derive from common modifications in development and generate common architectural features, even when comparing widely divergent groups such as vertebrates and insects. These similarities may in part be influenced by the deep homology of the brains of all Bilateria, in which shared patterns of developmental gene expression give rise to positionally, and perhaps functionally, homologous domains. Other shared modifications of development appear to be the result of homoplasy, such as the repeated, independent expansion of neuroblast numbers through changes in genes regulating cell division. The common features of large brains in so many groups of animals suggest that given their common ancestry, a limited set of mechanisms exist for increasing structural and functional diversity, resulting in many instances of homoplasy in bilaterian nervous systems.

Phylogeographic pattern of range expansion provides evidence for cryptic species lineages in Silene nutans in Western Europe.

As a result of recent or past evolutionary processes, a single species might consist of distinct Evolutionary Significant Units (ESUs), even corresponding to cryptic species. Determining the underlying mechanisms of range shifts and the processes at work in the build-up of divergent ESUs requires elucidating the factors that contribute to population genetic divergence across a species' range. We investigated the large-scale patterns of genetic structure in the perennial herbaceous plant species Silene nutans (Caryophyllaceae) in Western Europe. We sampled and genotyped 111 populations using 13 nuclear microsatellite loci and 6 plastid single-nucleotide polymorphisms. Broad-scale spatial population genetic structure was examined using Bayesian clustering, spatial multivariate analyses and measures of hierarchical genetic differentiation. The genotypic structure of S. nutans was typical of a predominantly allogamous mating system. We also identified plastid lineages with no intra-population polymorphism, mirroring two genetically differentiated nuclear lineages. No evidence of admixture was found. Spatial trends in genetic diversity further suggested independent leading-edge expansion associated with founding events and subsequent genetic erosion. Overall, our findings suggested speciation processes in S. nutans and highlighted striking patterns of distinct stepwise recolonisation of Western Europe shaped by Quaternary climate oscillations. Two main potential ESUs can be defined in Western Europe, corresponding to Eastern and Western nuclear-plastid lineages. In situ preservation of populations and genetic rescue implying ex situ conservation techniques should take the lineage identity into account. This is particularly true in Great Britain, northern France and Belgium, where S. nutans is rare and where distinct lineages co-occur in close contact.

PD-1 Blockade with Pembrolizumab in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Safety, Efficacy, and Biomarker Assessment

PD-1 Blockade with Pembrolizumab in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Safety, Efficacy, and Biomarker Assessment

Neutral and adaptive genomic signatures of rapid poleward range expansion.

Many species are expanding their range polewards, and this has been associated with rapid phenotypic change. Yet, it is unclear to what extent this reflects rapid genetic adaptation or neutral processes associated with range expansion, or selection linked to the new thermal conditions encountered. To disentangle these alternatives, we studied the genomic signature of range expansion in the damselfly Coenagrion scitulum using 4950 newly developed genomic SNPs and linked this to the rapidly evolved phenotypic differences between core and (newly established) edge populations. Most edge populations were genetically clearly differentiated from the core populations and all were differentiated from each other indicating independent range expansion events. In addition, evidence for genetic drift in the edge populations, and strong evidence for adaptive genetic variation in association with the range expansion was detected. We identified one SNP under consistent selection in four of the five edge populations and showed that the allele increasing in frequency is associated with increased flight performance. This indicates collateral, non-neutral evolutionary changes in independent edge populations driven by the range expansion process. We also detected a genomic signature of adaptation to the newly encountered thermal regimes, reflecting a pattern of countergradient variation. The latter signature was identified at a single SNP as well as in a set of covarying SNPs using a polygenic multilocus approach to detect selection. Overall, this study highlights how a strategic geographic sampling design and the integration of genomic, phenotypic and environmental data can identify and disentangle the neutral and adaptive processes that are simultaneously operating during range expansions.

Deep divergence and structure in the Tropical Oceanic Pacific: a multilocus phylogeography of a widespread gekkonid lizard (Squamata: Gekkonidae:Gehyra oceanica)

AbstractAimThe islands of the Tropical Oceanic Pacific (TOP) host both local radiations and widespread, colonizing species. The few phylogeographical analyses of widespread species often point to recent human‐aided expansions through the Pacific, suggesting that the communities are recently assembled. Here we apply multilocus data to infer biogeographical history of the gekkonid lizard,Gehyra oceanica,which is widespread, but for which prior analyses suggested a pre‐human history andin situdiversification.LocationTropical Oceanic Pacific.MethodsWe generated a data set including mtDNAand diagnosticSNPs for 173 individuals ofG. oceanicaspanning Micronesia, Melanesia, and Polynesia. For a subset of these individuals, we also sequenced nuclear loci. From these data, we performed maximum likelihood and Bayesian inference to reveal major clades. We also performed Bayesian clustering analyses and coalescence–based species delimitation tests to infer the number of species in this area.ResultsWe found evidence for six independent evolutionary lineages (candidate species) withinG. oceanicathat diverged between the Pliocene and the early Pleistocene, with high diversity through northern Melanesia, and pairing of northern Melanesian endemic taxa with widespread lineages across Micronesia and Polynesia.Main conclusionsThe islands of northern Melanesia not only have unrecognized diversity, but also were the source of independent expansions of lineages through the more remote northern and eastern Pacific. These results highlight the very different evolutionary histories of island faunas on remote archipelagos versus those across Melanesia and point to the need for more intensive studies of fauna within Melanesia if we are to understand the evolution of diversity across the tropical Pacific.

The visible foreign matter visual detecting algorithm research in oral liquid

Aiming at poor precision of the visible foreign body visual inspection in oral liquid, This paper adopt improved image processing algorithm to achieve the accurate detection of foreign body. Using joint difference way to separate the background at the same time improve the energy value of target. Using slope correlation determine whether filling possible fracture and hole in the target. Using self-adaption search algorithm independent choice expansion direction to realize the virtual Foreign body target accurate search. Through the change of form and movement direction difference to eliminate the interference of bubbles, eventually identify the real foreign body target. Experimental results show that the improved foreign body target visual detection steps enhance the detection accuracy of tiny hair and fiber target, the average error rate is less than 2%. It has important guiding significance for foreign body in oral liquid monitoring on the actual production and ensure the safety use of related products.

Phylogenetic analysis of the endangered takin in the confluent zone of the Qinling and Minshan Mountains using mtDNA control region

The takin (Budorcas taxicolor) is an Endangered ungulate. We analyzed the variation within mtDNA control region sequences of takin populations in the Qinling Mountains, the Minshan Mountains and the confluence of these two mountain ranges. We did not find any shared haplotypes among the populations. We observed apparent variation in the control region length among the three populations, and independent population expansions in the late of Pleistocene, which suggests these populations may have independent evolutionary histories. We found only one haplotype, and the lowest measures of genetic diversity (h = 0; π = 0) in the population from the confluent zone, which suggests populations in the confluent zone may have grown from small founder populations and gene flow with other populations has ceased. Based on their phylogenetic relationships, we concluded that the takin population in the confluent zone was in the same clade as the Tangjiahe population, which suggests that these takin populations are Sichuan takin (Budorcas taxicolor tibetana).

Role of CD47 in CD4+ T cell Proliferation after TCR Stimulation

CD47 is involved in adaptive immune responses and leukocyte homeostasis. Han and colleagues (JEM 209:1325, 2012) have reported that CD47‐/‐ mice are protected from (MOG)35‐55 peptide induced experimental autoimmune encephalomyelitis (EAE), but not from passive EAE, suggesting a defect in the immune cell compartment. They concluded a defect in T cell proliferation due to failed T cell activation. We also observed CD47‐/‐ are not susceptible to MOG‐induced EAE, and have reduced CD4 T cell proliferation after MOG immunization in vivo and MOG‐dependent recall proliferation assay in vitro. However, in our hands CD47‐/‐ T cells from MOG‐immunized mice express identical levels of surface activation markers (CD69, CD44, IL2R, PD‐1) vs WT cells, and similar levels of intracellular cytokine production. CD47‐/‐ T cells also have defective Ag independent expansion after TCR stimulation, even though proximal signaling events (p‐Lck, p‐ZAP‐70, p‐ERK1/2) are identical to WT cells using FACS and CyTOF mass spectrometry. Intriguingly, kinetics of CD47‐/‐ T cell proliferation and cell cycle analyzed by CSFE dye dilution and by DNA staining respectively, show a comparable proliferative response to WT cells in the first 48h, but fail to proliferate beyond day 3. Accordingly, CD47‐/‐ CD4 T cells show a 2.3 fold increase in Annexin‐V staining and a 40% reduced [H3]thymidine incorporation vs WT. In summary, CD47‐/‐ CD4 T cells become activated by MOG or TCR stimulation, but fail to maintain clonal expansion. We suggest this is due to defects in cell cycle machinery and/or increased cell apoptosis. This work was supported by NIH P01HL03628 and AHA 11POST7730055.

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Whole genome DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of on-going abnormal mutational processes, consistent with field-effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissue or between different ERG-lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.