Publications by authors named "Vladimir Lebedev"

29 Publications

  • Page 1 of 1

Karyotypic and molecular evidence supports the endemic Tibetan hamsters as a separate divergent lineage of Cricetinae.

Sci Rep 2021 May 18;11(1):10557. Epub 2021 May 18.

Institute of Molecular and Cellular Biology (IMCB), Siberian Branch of Russian Academy of Sciences (SB RAS), 8/2 Lavrentjev Ave., 630090, Novosibirsk, Russia.

The genus status of Urocricetus was defined recently based on morphological and molecular data. Even though the amount of evidence for a separate phylogenetic position of this genus among Cricetinae continues to increase, there is still no consensus on its relationship to other groups. Here we give the first comprehensive description of the U. kamensis karyotype (2n = 30, NFa = 50) including results of comparative cytogenetic analysis and detailed examination of its phylogenetic position by means of numerous molecular markers. The molecular data strongly indicated that Urocricetus is a distant sister group to Phodopus. Comparative cytogenetic data showed significant reorganization of the U. kamensis karyotype compared to karyotypes of all other hamsters investigated earlier. The totality of findings undoubtedly means that Urocricetus belongs to a separate divergent lineage of Cricetinae.
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http://dx.doi.org/10.1038/s41598-021-89890-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131748PMC
May 2021

Optimality in Self-Organized Molecular Sorting.

Phys Rev Lett 2021 Feb;126(8):088101

Institute of Condensed Matter Physics and Complex Systems, Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy.

We introduce a simple physical picture to explain the process of molecular sorting, whereby specific proteins are concentrated and distilled into submicrometric lipid vesicles in eukaryotic cells. To this purpose, we formulate a model based on the coupling of spontaneous molecular aggregation with vesicle nucleation. Its implications are studied by means of a phenomenological theory describing the diffusion of molecules toward multiple sorting centers that grow due to molecule absorption and are extracted when they reach a sufficiently large size. The predictions of the theory are compared with numerical simulations of a lattice-gas realization of the model and with experimental observations. The efficiency of the distillation process is found to be optimal for intermediate aggregation rates, where the density of sorted molecules is minimal and the process obeys simple scaling laws. Quantitative measures of endocytic sorting performed in primary endothelial cells are compatible with the hypothesis that these optimal conditions are realized in living cells.
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http://dx.doi.org/10.1103/PhysRevLett.126.088101DOI Listing
February 2021

Molecular systematics of the species complex: a contribution from historical DNA analysis.

PeerJ 2021 12;9:e10759. Epub 2021 Jan 12.

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.

The Tianshan birch mouse is an endemic of the Central Asian mountains and has previously been shown to include several karyomorphs ("Terskey", "Talgar", "Dzungar"); however, the taxonomic status of these forms has remained uncertain. We examined the genetic variation in based on historical DNA samples from museum collections, including the type series. Mitochondrial and nuclear data indicated that the species complex includes two major clades: Northern (N) and Southern (S) ( distance 13%). The N clade corresponds to the "Dzungar" karyomorph (Dzungar Alatau, Tarbagatay). The S clade is comprised of four lineages (S1-S4) divergent at 6-8%; the relationships among which are resolved incompletely. The S1 lineage is found in eastern Tianshan and corresponds to the nominal taxon. The S2 is distributed in central and northern Tianshan and corresponds to the "Terskey" karyomorph. The S3 is restricted to Trans-Ili Alatau and belongs to the "Talgar" karyomorph. The S4 is represented by a single specimen from southeastern Dzungar Alatau with "Talgar" karyotype. No interlineage gene flow was revealed. The validity of (equivalent to the N clade) is supported. Based on genetic and karyotypic evidence, lineages S2 and S3 are described as distinct species. The status of the S4 requires further investigation.
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http://dx.doi.org/10.7717/peerj.10759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810041PMC
January 2021

Field-induced SIM behaviour of a Co(II) complex with a 1,1'-diacetylferrocene-derived ligand.

Dalton Trans 2020 Nov;49(44):15592-15596

Institute of Problems of Chemical Physics of the Russian Academy of Sciences, Chernogolovka, Moscow Region, Russia.

Herein, we report the synthesis and magnetic properties of the Co(ii) coordination compound with the 1,1'-bis(1-((pyrid-2-ylmethylene)hydrazono)ethyl)ferrocene (L) ligand, having the general formula [CoLCl2]. The static magnetic data analysis supported by the CASSCF/NEVPT2 calculations revealed the presence of the triaxial magnetic anisotropy with Dexp = +35.2 cm-1 and large rhombicity (E/D = 0.31) in this complex (Dcalc = +34.5 cm-1, E/Dcalc = 0.30). The dynamic magnetic data confirm that the complex shows a slow field-induced (HDC = 1000 Oe) magnetic relaxation behaviour.
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http://dx.doi.org/10.1039/d0dt02747bDOI Listing
November 2020

Primary Immunodeficiencies in Russia: Data From the National Registry.

Front Immunol 2020 6;11:1491. Epub 2020 Aug 6.

Tatarstan Pediatric Republican Clinical Hospital, Kazan, Russia.

Primary immunodeficiencies (PID) are a group of rare genetic disorders with a multitude of clinical symptoms. Characterization of epidemiological and clinical data via national registries has proven to be a valuable tool of studying these diseases. The Russian PID registry was set up in 2017, by the National Association of Experts in PID (NAEPID). It is a secure, internet-based database that includes detailed clinical, laboratory, and therapeutic data on PID patients of all ages. The registry contained information on 2,728 patients (60% males, 40% females), from all Federal Districts of the Russian Federation. 1,851/2,728 (68%) were alive, 1,426/1,851 (77%) were children and 425/1,851 (23%) were adults. PID was diagnosed before the age of 18 in 2,192 patients (88%). Antibody defects (699; 26%) and syndromic PID (591; 22%) were the most common groups of PID. The minimum overall PID prevalence in the Russian population was 1.3:100,000 people; the estimated PID birth rate is 5.7 per 100,000 live births. The number of newly diagnosed patients per year increased dramatically, reaching the maximum of 331 patients in 2018. The overall mortality rate was 9.8%. Genetic testing has been performed in 1,740 patients and genetic defects were identified in 1,344 of them (77.2%). The median diagnostic delay was 2 years; this varied from 4 months to 11 years, depending on the PID category. The shortest time to diagnosis was noted in the combined PIDs-in WAS, DGS, and CGD. The longest delay was observed in AT, NBS, and in the most prevalent adult PID: HAE and CVID. Of the patients, 1,622 had symptomatic treatment information: 843 (52%) received IG treatment, mainly IVIG (96%), and 414 (25%) patients were treated with biological drugs. HSCT has been performed in 342/2,728 (16%) patients, of whom 67% are currently alive, 17% deceased, and 16% lost to follow-up. Three patients underwent gene therapy for WAS; all are currently alive. Here, we describe our first analysis of the epidemiological features of PID in Russia, allowing us to highlight the main challenges around PID diagnosis and treatment.
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http://dx.doi.org/10.3389/fimmu.2020.01491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424007PMC
May 2021

Statistical properties of a laser beam propagating in a turbulent medium.

Phys Rev E 2020 Apr;101(4-1):042137

Landau Institute for Theoretical Physics, RAS, 142432 Chernogolovka, Moscow region, Russia.

We examine statistical properties of a laser beam propagating in a turbulent medium. We prove that the intensity fluctuations at large propagation distances possess a Gaussian probability density function and establish quantitative criteria for realizing the Gaussian statistics depending on the laser propagation distance, laser beam waist, laser frequency, and turbulence strength. We calculate explicitly the laser envelope pair correlation function and corrections to its higher-order correlation functions breaking Gaussianity. We discuss also statistical properties of the brightest spots in the speckle pattern.
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http://dx.doi.org/10.1103/PhysRevE.101.042137DOI Listing
April 2020

Who are you, Griselda? A replacement name for a new genus of the Asiatic short-tailed shrews (Mammalia, Eulipotyphla, Soricidae): molecular and morphological analyses with the discussion of tribal affinities.

Zookeys 2019 11;888:133-158. Epub 2019 Nov 11.

Zoological Institute, Russian Academy of Sciences, Universitetskaya nab. 1, Saint-Petersburg 199034, Russia Zoological Institute, Russian Academy of Sciences Saint-Petersburg Russia.

The first genetic study of the holotype of the Gansu short-tailed shrew, Thomas, 1912, is presented. The mitochondrial analysis demonstrated that the type specimen of is close to several recently collected specimens from southern Gansu, northern Sichuan and Shaanxi, which are highly distinct from the two species of Asiatic short-tailed shrews of southern Sichuan, Yunnan, and Vietnam, and . Our analysis of four nuclear genes supported the placement of as sister to / , with the level of divergence between these two clades corresponding to that among genera of Soricinae. A new generic name, , is proposed for the Gansu short-tailed shrew. Karyotypes of (2 = 49, NF = 50) and (2 = 49, NF = 62) from southern Gansu are described. The tribal affinities of Blarinellini and Blarinini are discussed.
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http://dx.doi.org/10.3897/zookeys.888.37982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861342PMC
November 2019

Rituximab and reduced-intensity chemotherapy in children and adolescents with mature B-cell lymphoma: interim results for 231 patients enrolled in the second Russian-Belorussian multicentre study B-NHL-2010M.

Br J Haematol 2019 08 9;186(3):477-483. Epub 2019 May 9.

Dmitri Rogachev National Research Centre for Paediatric Haematology, Oncology and Immunology, Moscow, Russian Federation.

The value of adding rituximab to chemotherapy in children with aggressive B-cell non-Hodgkin lymphoma (B-NHL) is still insufficiently studied. We enrolled 231 patients [mean age 9 years old (range 2-17); male:female ratio 3·4:1] with Burkitt (BL, 179 patients, 76·7%), diffuse large B-cell (32 patients, 14%), primary mediastinal B-cell (14 patients, 6%), and other (6 patients, 2·6%) B-cell lymphomas in a prospective study of immuno-chemotherapy. Stages were I-II in 32% and III-IV in 68% of the patients. Four doses of 375 mg/m rituximab were added to the Berlin-Frankfurt-Munster-NHL-90-like chemotherapy, with methotrexate being reduced or omitted in the first 2 induction blocks. The complete remission rate was 100% in limited-stage and 91·4% in advanced-stage patients. Five advanced-stage patients (2·2%) died in induction and 1 patient with stage 2 B-NHL died in remission; 11 patients in the high-risk group progressed on therapy (3 non-BL are alive after salvage) and 5 relapsed. Sixteen patients (9·7%) with advanced stage disease proceeded to transplant. With a median follow-up of 46 months, 98·5 ± 1% of patients with limited disease and 88·1 ± 2% (88·1% in Risk Group 3; 82·6% in Risk Group 4) in advanced stages are alive. This study confirmed that combined immunochemotherapy for B-lymphomas is highly effective in children, despite reducing the intensity of the induction blocks.
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http://dx.doi.org/10.1111/bjh.15944DOI Listing
August 2019

Field-induced single-ion magnet behaviour of a hexacoordinated Co(ii) complex with easy-axis-type magnetic anisotropy.

Dalton Trans 2019 May;48(20):6960-6970

Department of Chemistry, Southern Federal University, 7, Zorge Str., Rostov-on-Don, 344090, Russia.

A coordination compound with the composition [CoLCl2]·H2O (L = bis-condensation product of diacetyl and 2-hydrazinyl-4,6-dimethylpyrimidine) was synthesized, in which the Co(ii) ion was hexacoordinated. Under applied DC fields, this compound exhibited single-ion magnet behavior. Two relaxation processes were observed when increasing the applied magnetic field from 1000 to 3200 Oe. The first relaxation (high-frequency) was observed both at 1000 Oe and 3200 Oe, while the second relaxation was only registered under a field of 3200 Oe at low frequencies (<1 Hz) and low temperatures (<5 K). Modeling of the magnetic DC properties using the Griffith Hamiltonian accompanied by quantum chemical calculations revealed easy-axis-type magnetic anisotropy with weak rhombic contributions.
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http://dx.doi.org/10.1039/c9dt00770aDOI Listing
May 2019

Reduced vs. standard dose native E. coli-asparaginase therapy in childhood acute lymphoblastic leukemia: long-term results of the randomized trial Moscow-Berlin 2002.

J Cancer Res Clin Oncol 2019 Apr 6;145(4):1001-1012. Epub 2019 Mar 6.

Department of Pediatric Oncology/Hematology, Regional Oncological Hospital, Orenburg, Russia.

Purpose: Favorable outcomes were achieved for children with acute lymphoblastic leukemia (ALL) with the first Russian multicenter trial Moscow-Berlin (ALL-MB) 91. One major component of this regimen included a total of 18 doses of weekly intramuscular (IM) native Escherichia coli-derived asparaginase (E. coli-ASP) at 10000 U/m during three consolidation courses. ASP was initially available from Latvia, but had to be purchased from abroad at substantial costs after the collapse of Soviet Union. Therefore, the subsequent trial ALL-MB 2002 aimed at limiting costs to a reasonable extent and also at reducing toxicity by lowering the dose for standard risk (SR-) patients to 5000 U/m without jeopardizing efficacy.

Methods: Between April 2002 and November 2006, 774 SR patients were registered in 34 centers across Russia and Belarus, 688 of whom were randomized. In arm ASP-5000 (n = 334), patients received 5000 U/m and in arm ASP-10000 (n = 354) 10 000 U/m IM.

Results: Probabilities of disease-free survival, overall survival and cumulative incidence of relapse at 10 years were comparable: 79 ± 2%, 86 ± 2% and 17.4 ± 2.1% (ASP-5000) vs. 75 ± 2% and 82 ± 2%, and 17.9 ± 2.0% (ASP-10000), while death in complete remission was significantly lower in arm ASP-5000 (2.7% vs. 6.5%; p = 0.029).

Conclusion: Our findings suggest that weekly 5000 U/mE. coli-ASP IM during consolidation therapy are equally effective, more cost-efficient and less toxic than 10000 U/m for SR patients with childhood ALL.
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http://dx.doi.org/10.1007/s00432-019-02854-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435612PMC
April 2019

Use of paracrine factors from stem cells to treat local radiation burns in rats.

Stem Cells Cloning 2018 26;11:69-76. Epub 2018 Oct 26.

State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), Moscow, Russia.

Background: Mesenchymal stem cells based paracrine bioactive factors that deploy their task as an essential mechanism, but their efficiency for skin regeneration still requires clarification.

Methods: The mesenchymal stem cell-based paracrine factors were administered by subcutaneous injection of 0.5 mL peptides (general protein 8 mg/mL). These were performed after radiation on different days like the first, third, sixth, eighth, and 10th. To determine the consequences, we performed photography, planimetry, and preclinical test each week after 15 days of radiation. MSC-based peptides were injected into a rat that had radiation burns, and its observation encouraged cell-free therapeutic remedies to regenerate skin. Both control and experimental groups were exposed to 110 Gy of X-rays, which resulted in the formation of localized radiation burns on the skin (=6 cm) 15 days later. Thirty days after radiation, the wound stabilized (surface of the wound was =2.2±0.2 cm) and fluctuated throughout the course of the pathological process.

Results: The wounded area on the skin from the 15th to the 29th day after radiation was practically the same in both groups. The wounded area gradually reduced by 6.1±0.4 cm (experimental group) and 5.9±0.6 cm (control group) 15 days after radiation up to 2.2±0.3 cm (in both control and experimental groups) on the 29th day after radiation. However, starting from the 36th day, there was a constant reduction in the burn area in the experimental group up to 0.2±0.1 cm till the 71st day after radiation.

Conclusion: In the control group, the area of the lesion ranged from 1.4±0.6 cm on the 50th day to 1.9±0.8 cm on the 71st day. During the 57th to the 71st day, the difference between the affected area in the experimental and control groups was 1:8. The experimental group has a significantly higher level of skin regeneration and significant decrease in the level of leukocyte infiltration, thereby reducing necrosis.
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http://dx.doi.org/10.2147/SCCAA.S164630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208552PMC
October 2018

A broadly distributed species instead of an insular endemic? A new find of the poorly known Hainan gymnure (Mammalia, Lipotyphla).

Zookeys 2018 5(795):77-81. Epub 2018 Nov 5.

Joint Vietnamese-Russian Tropical Research and Technological Centre, Nguyen Van Huyen, Nghia Do, Cau Giay, Hanoi, Vietnam.

The Hainan gymnure (Mammalia, Lipotyphla), endemic to Hainan Island (China), is one of the rarest and least-known species within the family Galericidae. The IUCN Red List inferred it as an endangered species due to ongoing population decline caused by natural habitat loss. A recent biodiversity survey has revealed to be rather common in northern Vietnam. This is the first record of the species outside Hainan Island. New data have allowed us to re-assess the conservation status of this poorly known mammal. The occurrence of in mainland Vietnam also supports the hypothesis that Hainan Island could have been previously connected to Guangxi and northern Vietnam rather than to neighbouring Guangdong.
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http://dx.doi.org/10.3897/zookeys.795.28218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232251PMC
November 2018

Cenozoic aridization in Central Eurasia shaped diversification of toad-headed agamas (; Agamidae, Reptilia).

PeerJ 2018 19;6:e4543. Epub 2018 Mar 19.

Biological Faculty, Department of Vertebrate Zoology, Lomonosov Moscow State University, Moscow, Russia.

We hypothesize the phylogenetic relationships of the agamid genus to assess how past environmental changes shaped the evolutionary and biogeographic history of these lizards and especially the impact of paleogeography and climatic factors. is one of the most diverse and taxonomically confusing lizard genera. As a key element of Palearctic deserts, it serves as a promising model for studies of historical biogeography and formation of arid habitats in Eurasia. We used 51 samples representing 33 of 40 recognized species of covering all major areas of the genus. Molecular data included four mtDNA (, , , ; 2,703 bp) and four nuDNA protein-coding genes (, , , ; 4,188 bp). AU-tests were implemented to test for significant differences between mtDNA- and nuDNA-based topologies. A time-calibrated phylogeny was estimated using a Bayesian relaxed molecular clock with nine fossil calibrations. We reconstructed the ancestral area of origin, biogeographic scenarios, body size, and the evolution of habitat preference. Phylogenetic analyses of nuDNA genes recovered a well-resolved and supported topology. Analyses detected significant discordance with the less-supported mtDNA genealogy. The position of conflicted greatly between the two datasets. MtDNA introgression due to ancient hybridization best explained this result. Monophyletic contained three main clades: (I) oviparous species from south-western and Middle Asia; (II) viviparous species of Qinghai-Tibetan Plateau (QTP); and (III) oviparous species of the Caspian Basin, Middle and Central Asia. originated in late Oligocene (26.9 Ma) and modern species diversified during the middle Miocene (14.8-13.5 Ma). The reconstruction of ancestral areas indicated that originated in Middle East-southern Middle Asia. Body size miniaturization likely occurred early in the history of . The common ancestor of probably preferred sandy substrates with the inclusion of clay or gravel. The time of Agaminae radiation and origin of in the late Oligocene significantly precedes the landbridge between Afro-Arabia and Eurasia in the Early Miocene. Diversification of coincides well with the mid-Miocene climatic transition when a rapid cooling of climate drove progressing aridification and the Paratethys salinity crisis. These factors likely triggered the spreading of desert habitats in Central Eurasia, which occupied. The origin of the viviparous Tibetan clade has been associated traditionally with uplifting of the QTP; however, further studies are needed to confirm this. Progressing late Miocene aridification, the decrease of the Paratethys Basin, orogenesis, and Plio-Pleistocene climate oscillations likely promoted further diversification within . We discuss taxonomy in scope of the new analyses.
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http://dx.doi.org/10.7717/peerj.4543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863718PMC
March 2018

Karyotype Evolution and Phylogenetic Relationships of Cricetulus sokolovi Orlov et Malygin 1988 (Cricetidae, Rodentia) Inferred from Chromosomal Painting and Molecular Data.

Cytogenet Genome Res 2017 19;152(2):65-72. Epub 2017 Jul 19.

A.N. Severtsov Institute of Ecology and Evolution, RAS, Moscow State University, Moscow, Russia.

Sokolov's dwarf hamster (Cricetulus sokolovi) is the least studied representative of the striped hamsters (Cricetulus barabensis species group), the taxonomy of which remains controversial. The species was described based on chromosome morphology, but neither the details of the karyotype nor the phylogenetic relationships with other Cricetulus are known. In the present study, the karyotype of C. sokolovi was examined using cross-species chromosome painting. Molecular and cytogenetic data were employed to determine the phylogenetic position of Sokolov's hamster and to analyze the potential pathways of chromosome evolution in Cricetulus. Both the chromosome and molecular data support the species status of Sokolov's hamster. Phylogenetic analysis of the CYTB data placed C. sokolovi as sister to all other striped hamsters (sequence divergence of 8.1%). FISH data revealed that the karyotype of C. sokolovi is highly rearranged, with the most parsimonious scenario of its origin implying at least 4 robertsonian events and a centromere shift. Comparative cytogenetic data on Cricetinae suggest that their evolutionary history includes both periods of chromosomal conservatism and episodes of rapid chromosomal change.
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http://dx.doi.org/10.1159/000477521DOI Listing
September 2017

Revision of Chimarrogale (Lipotyphla: Soricidae) from Vietnam with comments on taxonomy and biogeography of Asiatic water shrews.

Zootaxa 2017 Feb 15;4232(2):zootaxa.4232.2.5. Epub 2017 Feb 15.

Zoological Institute, Russian Academy of Sciences, Universitetskaya nab. 1, Saint Petersburg 199034, Russia..

We analyzed the complete mitochondrial cytochrome b (cytb) gene and fragments of four nuclear loci: ApoB, RAG2, IRBP1 and BRCA1. These data allowed us to provide new insights into the diversity of the Asiatic water shrews of Indochina. A new, highly divergent genetic lineage of Chimarrogale was found in southern Vietnam, and this lineage included specimens from the provinces of Kon Tum, Dak Lak, and Lam Dong. Such finding represents the newest and southernmost records of Chimarrogale in Indochina. Morphological analysis classified the specimens from southern Vietnam as C. varennei proper, which is restricted to that region, whereas the polymorphic C. himalayica, which contained at least four cytochrome b haplogroups, occurred in central and northern Vietnam and southern China. This distinct C. varennei lineage closely related to the C. platycephalus + C. leander clade suggests the existence of an unknown glacial refuge in Tay Nguyen Plateau, southern Vietnam. Because the Bornean C. phaeura (i) was sister-group of the rest of Chimarrogale sensu lato and (ii) had a high genetic divergence (~15% for cytochrome b) and geographical isolation, we suggest that C. phaeura be placed into a separate genus, Crossogale Thomas, 1921. This genus should also include C. sumatrana (Sumatra) and C. hantu (Peninsular Malaysia). On those grounds, we propose a new classification system for Asiatic water shrews.
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http://dx.doi.org/10.11646/zootaxa.4232.2.5DOI Listing
February 2017

Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial.

Lancet 2015 Oct 28;386(10004):1649-58. Epub 2015 Jul 28.

GlaxoSmithKline, Collegeville, PA, USA.

Background: The thrombopoietin receptor agonist eltrombopag has been shown to be safe, tolerable, and effective for adults with chronic immune thrombocytopenia. We aimed to investigate the safety and efficacy of eltrombopag for children with chronic immune thrombocytopenia.

Methods: PETIT2 was a two part, randomised, multicentre, placebo-controlled study done at 38 centres in 12 countries (Argentina, Czech Republic, Germany, Hong Kong, Israel, Italy, Russia, Spain, Taiwan, Thailand, UK, and USA). Paediatric patients aged 1-17 years who had chronic immune thrombocytopenia and platelet counts less than 30 × 10(9) per L were randomly assigned (2:1) to receive eltrombopag or placebo. We stratified patients by age into three cohorts (patients aged 12-17 years, 6-11 years, and 1-5 years) before randomly entering them into a 13 week, double-blind period. Randomisation was done by the GlaxoSmithKline Registration and Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who were allocated eltrombopag received tablets (except for those aged 1-5 years who received an oral suspension formulation) once per day for 13 weeks. Starting doses for patients aged 6-17 were based on bodyweight, and ethnic origin and ranged between 50 mg/day and 25 mg/day (starting dose for patients aged 1-5 years was 1·2 mg/kg/day or 0·8 mg/kg/day for east Asian patients). Patients who completed the double-blind period entered a 24 week open-label treatment period in which all patients received eltrombopag at either the starting dose (if they were formerly on placebo) or their established dose. The primary outcome was the proportion of patients achieving platelet counts of at least 50 × 10(9) per L in the absence of rescue therapy for 6 or more weeks from weeks 5 to 12 of the double-blind period. The intention-to-treat population included in the efficacy assessment consisted of all patients who were randomly assigned to one of the treatment groups, and the safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01520909.

Findings: Beginning in March 15, 2012, 92 patients were enrolled, and the trial was completed on Jan 2, 2014. 63 patients were assigned to receive eltrombopag and 29 were assigned to receive placebo. In the double-blind period, three patients discontinued treatment because of adverse events: two patients in the eltrombopag group withdrew because of increased liver aminotransferases and one in the placebo group withdrew because of abdominal haemorrhage. 25 (40%) patients who received eltrombopag compared with one (3%) patient who received placebo achieved the primary outcome of platelet counts of at least 50 × 10(9) per L for 6 of the last 8 weeks of the double-blind period (odds ratio 18·0, 95% CI, 2·3-140·9; p=0·0004). Responses were similar in all cohorts (eltrombopag vs placebo: 39% vs 10% for patients aged 12-17 years, 42% vs 0% for patients aged 6-11 years, and 36% vs 0% for patients aged 1-5 years). Proportionately fewer patients who received eltrombopag (23 [37%] of 63 patients) had WHO grades 1-4 bleeding at the end of the double-blind period than did those who received placebo (16 [55%] of 29 patients); grades 2-4 bleeding were similar (three [5%] patients who received eltrombopag vs two [7%] patients who received placebo). During the 24-week open-label treatment period, 70 [80%] of 87 patients achieved platelet counts of 50 × 10(9) per L or more at least once. Adverse events that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (11 [17%] patients), rhinitis (10 [16%] patients), upper respiratory tract infection (7 [11%] patients), and cough (7 [11%] patients). Serious adverse events occurred in five (8%) patients who received eltrombopag and four (14%) who received placebo. Safety was consistent between the open-label and double-blind periods. No deaths, malignancies, or thromboses occurred during the trial.

Interpretation: Eltrombopag, which produced a sustained platelet response in 40% of patients with chronic immune thrombocytopenia, is a suitable therapeutic option for children with chronic symptomatic immune thrombocytopenia. We identified no new safety concerns and few patients discontinued treatment because of adverse events.

Funding: GlaxoSmithKline.
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http://dx.doi.org/10.1016/S0140-6736(15)61107-2DOI Listing
October 2015

Universal profile of the vortex condensate in two-dimensional turbulence.

Phys Rev Lett 2014 Dec 17;113(25):254503. Epub 2014 Dec 17.

Landau Institute for Theoretical Physics, Kosygina 2, Moscow 119334, Russia and Moscow Institute of Physics and Technology, Dolgoprudny, Moscow 141700, Russia.

An inverse turbulent cascade in a restricted two-dimensional periodic domain creates a condensate-a pair of coherent system-size vortices. We perform extensive numerical simulations of this system and carry out theoretical analysis based on momentum and energy exchanges between the turbulence and the vortices. We show that the vortices have a universal internal structure independent of the type of small-scale dissipation, small-scale forcing, and boundary conditions. The theory predicts not only the vortex inner region profile, but also the amplitude, which both perfectly agree with the numerical data.
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http://dx.doi.org/10.1103/PhysRevLett.113.254503DOI Listing
December 2014

Vibrational states of a water molecule in a nano-cavity of beryl crystal lattice.

J Chem Phys 2014 Jun;140(22):224317

1. Physikalisches Institut, Universität Stuttgart, Pfaffenwaldring 57, 70550 Stuttgart, Germany.

Low-energy excitations of a single water molecule are studied when confined within a nano-size cavity formed by the ionic crystal lattice. Optical spectra are measured of manganese doped beryl single crystal Mn:Be3Al2Si6O18, that contains water molecules individually isolated in 0.51 nm diameter voids within the crystal lattice. Two types of orientation are distinguished: water-I molecules have their dipole moments aligned perpendicular to the c axis and dipole moments of water-II molecules are parallel to the c-axis. The optical conductivity σ(ν) and permittivity ɛ'(ν) spectra are recorded in terahertz and infrared ranges, at frequencies from several wavenumbers up to ν = 7000 cm(-1), at temperatures 5-300 K and for two polarizations, when the electric vector E of the radiation is parallel and perpendicular to the c-axis. Comparative experiments on as-grown and on dehydrated samples allow to identify the spectra of σ(ν) and ɛ'(ν) caused exclusively by water molecules. In the infrared range, well-known internal modes ν1, ν2, and ν3 of the H2O molecule are observed for both polarizations, indicating the presence of water-I and water-II molecules in the crystal. Spectra recorded below 1000 cm(-1) reveal a rich set of highly anisotropic features in the low-energy response of H2O molecule in a crystalline nano-cavity. While for E∥c only two absorption peaks are detected, at ~90 cm(-1) and ~160 cm(-1), several absorption bands are discovered for E⊥c, each consisting of narrower resonances. The bands are assigned to librational (400-500 cm(-1)) and translational (150-200 cm(-1)) vibrations of water-I molecule that is weakly coupled to the nano-cavity "walls." A model is presented that explains the "fine structure" of the bands by a splitting of the energy levels due to quantum tunneling between the minima in a six-well potential relief felt by a molecule within the cavity.
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http://dx.doi.org/10.1063/1.4882062DOI Listing
June 2014

Quantum Behavior of Water Molecules Confined to Nanocavities in Gemstones.

J Phys Chem Lett 2013 Jun 3;4(12):2015-20. Epub 2013 Jun 3.

‡1. Physikalisches Institut, Universität Stuttgart, Pfaffenwaldring 57, 70550 Stuttgart, Germany.

When water is confined to nanocavities, its quantum mechanical behavior can be revealed by terahertz spectroscopy. We place H2O molecules in the nanopores of a beryl crystal lattice and observe a rich and highly anisotropic set of absorption lines in the terahertz spectral range. Two bands can be identified, which originate from translational and librational motions of the water molecule isolated within the cage; they correspond to the analogous broad bands in liquid water and ice. In the present case of well-defined and highly symmetric nanocavities, the observed fine structure can be explained by macroscopic tunneling of the H2O molecules within a six-fold potential caused by the interaction of the molecule with the cavity walls.
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http://dx.doi.org/10.1021/jz400782jDOI Listing
June 2013

Vorticity statistics in the direct cascade of two-dimensional turbulence.

Phys Rev E Stat Nonlin Soft Matter Phys 2011 Apr 11;83(4 Pt 2):045301. Epub 2011 Apr 11.

Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel.

For the direct cascade of steady two-dimensional (2D) Navier-Stokes turbulence, we derive analytically the probability of strong vorticity fluctuations. When ϖ is the vorticity coarse-grained over a scale R, the probability density function (PDF), P(ϖ), has a universal asymptotic behavior lnP~-ϖ/ϖ(rms) at ϖ≫ϖ(rms)=[Hln(L/R)](1/3), where H is the enstrophy flux and L is the pumping length. Therefore, the PDF has exponential tails and is self-similar, that is, it can be presented as a function of a single argument, ϖ/ϖ(rms), in distinction from other known direct cascades.
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http://dx.doi.org/10.1103/PhysRevE.83.045301DOI Listing
April 2011

Unconditionally gradient-stable computational schemes in problems of fast phase transitions.

Phys Rev E Stat Nonlin Soft Matter Phys 2011 Feb 14;83(2 Pt 2):026705. Epub 2011 Feb 14.

Department of Theoretical Physics, Udmurt State University, 426034 Izhevsk, Russia.

Equations of fast phase transitions, in which the phase boundaries move with velocities comparable with the atomic diffusion speed or with the speed of local structural relaxation, are analyzed. These equations have a singular perturbation due to the second derivative of the order parameter with respect to time, which appears due to phenomenologically introduced local nonequilibrium. To develop unconditionally stable computational schemes, the Eyre theorem [D. J. Eyre, unpublished] proved for the classical equations, based on hypotheses of local equilibrium, is used. An extension of the Eyre theorem for the case of equations for fast phase transitions is given. It is shown that the expansion of the free energy on contractive and expansive parts, suggested by Eyre for the classical equations of Cahn-Hilliard and Allen-Cahn, is also true for the equations of fast phase transitions. Grid approximations of these equations lead to gradient-stable algorithms with an arbitrary time step for numerical modeling, ensuring monotonic nonincrease of the free energy. Special examples demonstrating the extended Eyre theorem for fast phase transitions are considered.
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http://dx.doi.org/10.1103/PhysRevE.83.026705DOI Listing
February 2011

Age-dependent role of steroids in the regulation of growth of the hen follicular wall.

Reprod Biol Endocrinol 2010 Feb 15;8:15. Epub 2010 Feb 15.

Department of Functional Genomics and Bioregulation, Institute of Animal Genetics, FLI, Mariensee, 31535 Neustadt, Germany.

Background: The ovaries are the primary targets of senescence effects in mammalian and avian species. In the present study, relationships between reproductive aging, sex steroids and the growth pattern of the pre-ovulatory follicle wall were investigated using young hens with long clutch (YLC), old hens with long clutch (OLC), old hens with short clutch (OSC), and old hens with interrupted long clutch (OILC).

Methods: Experiment 1: Hens were sacrificed 1.5 and 14.5 h after ovulation. Experiment 2: YLC and OILC hens were sacrificed 3.5 h after treatments with LH and/or aminoglutethimide (AG), an inhibitor of steroid synthesis. Volumes of pre-ovulatory follicles (F1-F5) and plasma concentrations of ovarian steroids were determined. Experiment 3: Granulosa and theca cells from F3 follicles of OSC and/or YLC hens were exposed in vitro to estradiol-17beta (E2), testosterone (T) and LH and the proliferative activity of the cells was examined using CellTiter 96 Aqueous One Solution Assay.

Results: In YLC and OLC groups, the total volume of F1-F5 follicles rose between 1.5 and 14.5 h after ovulation (P < 0.01), negatively correlating with the plasma level of E2 (P < 0.01). There was no growth of pre-ovulatory follicles in the middle of the ovulatory cycle in the OSC group, with a positive correlation being present between E2 and the follicular volume (P < 0.05). In young hens, AG caused a rise in the total follicular volume. This rise was associated with a fall in E2 (r = -0.54, P < 0.05). E2 enhanced proliferation of granulosa cells from YLC and OSC groups. The proliferative activity of granulosa and theca cells of YLC hens depended on the interaction between T and LH (P < 0.01).

Conclusions: These data indicate for the first time that the growth pattern of pre-ovulatory follicles during the ovulatory cycle changes in the course of reproductive aging. E2 seems to play a dual role in this adjustment; it stimulates the growth of the follicular wall in reproductive aged hens, whereas it may inhibit this process in young birds. T and LH are apparently involved in the growth regulation during the pre-ovulatory surge in young hens.
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http://dx.doi.org/10.1186/1477-7827-8-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2833167PMC
February 2010

Phase-field-crystal and Swift-Hohenberg equations with fast dynamics.

Phys Rev E Stat Nonlin Soft Matter Phys 2009 May 12;79(5 Pt 1):051110. Epub 2009 May 12.

Institut für Materialphysik im Weltraum, Deutsches Zentrum für Luft- und Raumfahrt (DLR), 51170 Köln, Germany.

A phenomenological description of transition from an unstable to a (meta)stable phase state, including microscopic and mesoscopic scales, is presented. It is based on the introduction of specific memory functions which take into account contributions to the driving force of transformation from the past. A region of applicability for phase-field crystals and Swift-Hohenberg-type models is extended by inclusion of inertia effects into the equations of motion through a memory function of an exponential form. The inertia allows us to predict fast degrees of freedom in the form of damping perturbations with finite relaxation time in the instability of homogeneous and periodic model solutions.
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http://dx.doi.org/10.1103/PhysRevE.79.051110DOI Listing
May 2009

Karyotype evolution and phylogenetic relationships of hamsters (Cricetidae, Muroidea, Rodentia) inferred from chromosomal painting and banding comparison.

Chromosome Res 2007 10;15(3):283-97. Epub 2007 May 10.

Institute of Cytology and Genetics, SB RAS, Novosibirsk, 630090, Russia.

The evolutionary success of rodents of the superfamily Muroidea makes this taxon the most interesting for evolution studies, including study at the chromosomal level. Chromosome-specific painting probes from the Chinese hamster and the Syrian (golden) hamster were used to delimit homologous chromosomal segments among 15 hamster species from eight genera: Allocricetulus, Calomyscus, Cricetulus, Cricetus, Mesocricetus, Peromyscus, Phodopus and Tscherskia (Cricetidae, Muroidea, Rodentia). Based on results of chromosome painting and G-banding, comparative maps between 20 rodent species have been established. The integrated maps demonstrate a high level of karyotype conservation among species in the Cricetus group (Cricetus, Cricetulus, Allocricetulus) with Tscherskia as its sister group. Species within the genera Mesocricetus and Phodopus also show a high degree of chromosomal conservation. Our results substantiate many of the conclusions suggested by other data and strengthen the topology of the Muroidea phylogenetic tree through the inclusion of genome-wide chromosome rearrangements. The derivation of the muroids karyotypes from the putative ancestral state involved centric fusions, fissions, addition of heterochromatic arms and a great number of inversions. Our results provide further insights into the karyotype relationships of all species investigated.
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http://dx.doi.org/10.1007/s10577-007-1124-3DOI Listing
August 2007

Molecular phylogeny of the Cricetinae subfamily based on the mitochondrial cytochrome b and 12S rRNA genes and the nuclear vWF gene.

Mol Phylogenet Evol 2006 Apr 17;39(1):135-48. Epub 2006 Feb 17.

Institute of Zoology, Martin-Luther-University Halle-Wittenberg, Domplatz 4, D-06108 Halle (Saale), Germany.

Despite some popularity of hamsters as pets and laboratory animals there is no reliable phylogeny of the subfamily Cricetinae available so far. Contradicting views exist not only about the actual number of species but also concerning the validity of several genera. We used partial DNA sequences of two mitochondrial (cytochrome b, 12S rRNA) and one partial nuclear gene (von Willebrand Factor exon 28) to provide a first gene tree of the Cricetinae based on 15 taxa comprising six genera. According to our data, Palaearctic hamsters fall into three distinct phylogenetic groups: Phodopus, Mesocricetus, and Cricetus-related species which evolved during the late Miocene about 7-12MY ago. Surprisingly, the genus Phodopus, which was previously thought to have appeared during the Pleistocene, forms the oldest clade. The largest number of extant hamster genera is found in a group of Cricetus-related hamsters. The genus Cricetulus itself proved to be not truly monophyletic with Cricetulus migratorius appearing more closely related to Tscherskia, Cricetus, and Allocricetulus. We propose to place the species within a new monotypic genus. Molecular clock calculations are not always in line with the dating of fossil records. DNA based divergence time estimates as well as taxonomic relationships demand a reevaluation of morphological characters previously used to identify fossils and extant hamsters.
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http://dx.doi.org/10.1016/j.ympev.2006.01.010DOI Listing
April 2006

Ovulatory cycle-related alterations in the thecal growth and membrane protein content of thecal tissue of hen preovulatory follicles.

Theriogenology 2006 Jul 2;66(2):217-23. Epub 2005 Dec 2.

Department of Functional Genomics and Bioregulation, Institute of Animal Science, FAL, Mariensee, 31535 Neustadt, Germany.

In the hen ovary, each preovulatory follicle in the hierarchy, irrespective of its size and the level of its maturity is exposed to the preovulatory LH surge in each ovulatory cycle of an egg laying sequence. In the present study, the thecal weight and membrane protein content of theca layers at different stages of hen ovulatory cycle were assessed. Hens were killed 2 h (stage I), 9 h (stage II), 16 h (stage III), and 23 h (stage IV) after oviposition. The first (F1), second (F2), third (F3), fourth (F4) and fifth (F5) largest yellow follicles were utilized. In all follicles except F1, the thecal weight rose considerably between stages I and III (P < 0.05) followed by a slight cessation of the thecal growth at stage IV. The mean content of the theca membrane protein in F1-F5 follicles was lowest at stage III, increasing at stage IV (P < 0.05), although, in the case of individual follicles the difference was significant (P < 0.05) in F3 follicles only. Estradiol-17beta levels in the plasma were lowest (but not significant) at stage III, and a fourfold increase in the plasma progesterone concentration occurred at stage IV. These findings demonstrate for the first time the ovulatory cycle-related alterations in the thecal weight and membrane protein content in the hen preovulatory follicles. Data suggest that the preovulatory rise in ovarian steroid hormones is probably involved in transient termination of the growth and induction of differentiation of the theca in preovulatory follicles as they pass from one category to the next.
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http://dx.doi.org/10.1016/j.theriogenology.2005.11.004DOI Listing
July 2006

Characterization of growth hormone binding sites in granulosa and theca layers at different stages of follicular maturation and ovulatory cycle in the domestic hen.

Biol Reprod 2004 Oct 9;71(4):1174-81. Epub 2004 Jun 9.

Department of Functional Genomics and Bioregulation, Institute of Animal Science, Mariensee, 31535 Neustadt, Germany.

The currently available evidence points to a possible influence of growth hormone (GH) on avian folliculogenesis, which can be mediated by both hepatic- and ovarian-derived IGF-I. Therefore, the purpose of the present study was to reveal GH-binding sites in granulosa and theca layers of preovulatory follicles and to determine the binding characteristics depending on the degree of follicular maturation and the stage of the ovulatory cycle in the hen. Hens were killed 2 h (stage I), 9 h (stage II), 16 h (stage III), and 23 h (stage IV) after oviposition, and the five largest yellow follicles (from F1 to F5) were removed. GH-binding sites in granulosa and theca layers from F1 to F5 follicles were characterized using a radioreceptor assay. Equilibrium dissociation constants (K(d)) and binding capacities (B(max)) were determined by Scatchard analysis of saturation curves, which revealed a single class of high-affinity GH-binding sites in both theca tissue and granulosa cells. In F1, F2, and F5 follicles, B(max) and K(d) for GH-binding sites in the granulosa layer changed during the ovulatory cycle, decreasing between stages I and III, to increase again at stage IV, with alterations in K(d) being less profound. No significant differences in binding capacities and affinities of GH-binding sites in the theca layer were found between various stages of the cycle. Furthermore, the concentration of GH-binding sites in the granulosa layer rose, whereas that in the theca layer fell with follicular enlargement. These findings indicate the presence of high-affinity GH-binding sites in both granulosa and theca layers of hen preovulatory follicles. Data also demonstrate that GH-binding sites in these tissues are regulated in a tissue-specific manner. Furthermore, the regulation of binding capacity of GH binding in granulosa cells by hormonal factors associated with ovulatory cycle is apparently not dependent on the state of follicular maturation.
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http://dx.doi.org/10.1095/biolreprod.104.030056DOI Listing
October 2004

Extreme outages caused by polarization mode dispersion.

Opt Lett 2003 Nov;28(22):2159-61

Corning, Inc., SP-DV-02-8, Corning, New York 14831, USA.

We study the dependence on fiber birefringence of the bit-error rate (BER) caused by amplifier noise in a linear optical fiber telecommunication system. We show that the probability-distribution function of the BER obtained by averaging over many realizations of birefringent disorder has an extended tail that corresponds to anomalously large values of BER. We specifically discuss the dependence of the tail on such details of pulse detection at the fiber output as setting the clock and filtering procedures.
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http://dx.doi.org/10.1364/ol.28.002159DOI Listing
November 2003

Compensation for extreme outages caused by polarization mode dispersion and amplifier noise.

Opt Express 2003 Jul;11(14):1607-12

Fluctuations of Bit-Error-Rate (BER) stimulated by birefringent disorder in an optical fiber system are found to be strong. The effect may not be analyzed in terms of the average BER but rather requires analyzing the Probability Distribution Function (PDF) of BER. We report the emergence of the extremely extended algebraic-like tail of the PDF, corresponding to anomalously large values of BER. We analyze the dependence of the PDF tail, and thus the outage probability, on the first-order PMD compensation scheme. Effectiveness of compensation is illustrated quantitatively using a simple, however, practical example.
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http://dx.doi.org/10.1364/oe.11.001607DOI Listing
July 2003
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