Single polymer dynamics: coil-stretch transition in a random flow

By quantitative studies of statistics of polymer stretching in a random flow and of a flow field we demonstrate that the stretching of polymer molecules in a 3D random flow occurs rather sharply via the coil-stretch transition at the value of the criterion close to theoretically predicted.Comment: 4 pages, 5 figure

Stretching of polymers around the Kolmogorov scale in a turbulent shear flow

We present numerical studies of stretching of Hookean dumbbells in a turbulent Navier-Stokes flow with a linear mean profile, =Sy. In addition to the turbulence features beyond the viscous Kolmogorov scale \eta, the dynamics at the equilibrium extension of the dumbbells significantly below eta is well resolved. The variation of the constant shear rate S causes a change of the turbulent velocity fluctuations on all scales and thus of the intensity of local stretching rate of the advecting flow. The latter is measured by the maximum Lyapunov exponent lambda_1 which is found to increase as \lambda_1 ~ S^{3/2}, in agreement with a dimensional argument. The ensemble of up to 2 times 10^6 passively advected dumbbells is advanced by Brownian dynamics simulations in combination with a pseudospectral integration for the turbulent shear flow. Anisotropy of stretching is quantified by the statistics of the azimuthal angle $\phi$ which measures the alignment with the mean flow axis in the x-y shear plane, and the polar angle theta which determines the orientation with respect to the shear plane. The asymmetry of the probability density function (PDF) of phi increases with growing shear rate S. Furthermore, the PDF becomes increasingly peaked around mean flow direction (phi= 0). In contrast, the PDF of the polar angle theta is symmetric and less sensitive to changes of S.Comment: 16 pages, 14 Postscript figures (2 with reduced quality

Elastic turbulence in curvilinear flows of polymer solutions

Following our first report (A. Groisman and V. Steinberg, \sl Nature $\bf 405$, 53 (2000)) we present an extended account of experimental observations of elasticity induced turbulence in three different systems: a swirling flow between two plates, a Couette-Taylor (CT) flow between two cylinders, and a flow in a curvilinear channel (Dean flow). All three set-ups had high ratio of width of the region available for flow to radius of curvature of the streamlines. The experiments were carried out with dilute solutions of high molecular weight polyacrylamide in concentrated sugar syrups. High polymer relaxation time and solution viscosity ensured prevalence of non-linear elastic effects over inertial non-linearity, and development of purely elastic instabilities at low Reynolds number (Re) in all three flows. Above the elastic instability threshold, flows in all three systems exhibit features of developed turbulence. Those include: (i)randomly fluctuating fluid motion excited in a broad range of spatial and temporal scales; (ii) significant increase in the rates of momentum and mass transfer (compared to those expected for a steady flow with a smooth velocity profile). Phenomenology, driving mechanisms, and parameter dependence of the elastic turbulence are compared with those of the conventional high Re hydrodynamic turbulence in Newtonian fluids.Comment: 23 pages, 26 figure

Fundamental scaling laws of on-off intermittency in a stochastically driven dissipative pattern forming system

Noise driven electroconvection in sandwich cells of nematic liquid crystals exhibits on-off intermittent behaviour at the onset of the instability. We study laser scattering of convection rolls to characterize the wavelengths and the trajectories of the stochastic amplitudes of the intermittent structures. The pattern wavelengths and the statistics of these trajectories are in quantitative agreement with simulations of the linearized electrohydrodynamic equations. The fundamental $\tau^{-3/2}$ distribution law for the durations $\tau$ of laminar phases as well as the power law of the amplitude distribution of intermittent bursts are confirmed in the experiments. Power spectral densities of the experimental and numerically simulated trajectories are discussed.Comment: 20 pages and 17 figure

High-sensitivity AC-charge detection with a MHz-frequency fluxonium qubit

Owing to their strong dipole moment and long coherence times, superconducting qubits have demonstrated remarkable success in hybrid quantum circuits. However, most qubit architectures are limited to the GHz frequency range, severely constraining the class of systems they can interact with. The fluxonium qubit, on the other hand, can be biased to very low frequency while being manipulated and read out with standard microwave techniques. Here, we design and operate a heavy fluxonium with an unprecedentedly low transition frequency of $1.8~\mathrm{MHz}$. We demonstrate resolved sideband cooling of the ``hot'' qubit transition with a final ground state population of $97.7~\%$, corresponding to an effective temperature of $23~\mu\mathrm{K}$. We further demonstrate coherent manipulation with coherence times $T_1=34~\mu\mathrm{s}$, $T_2^*=39~\mu\mathrm{s}$, and single-shot readout of the qubit state. Importantly, by directly addressing the qubit transition with a capacitively coupled waveguide, we showcase its high sensitivity to a radio-frequency field. Through cyclic qubit preparation and interrogation, we transform this low-frequency fluxonium qubit into a frequency-resolved charge sensor. This method results in a charge sensitivity of $33~\mu\mathrm{e}/\sqrt{\mathrm{Hz}}$, or an energy sensitivity (in joules per hertz) of $2.8~\hbar$. This method rivals state-of-the-art transport-based devices, while maintaining inherent insensitivity to DC charge noise. The high charge sensitivity combined with large capacitive shunt unlocks new avenues for exploring quantum phenomena in the $1-10~\mathrm{MHz}$ range, such as the strong-coupling regime with a resonant macroscopic mechanical resonator

Tumor suppressor function of the SEMA3B gene in human lung and renal cancers

The SEMA3B gene is located in the 3p21.3 LUCA region, which is frequently affected in different types of cancer. The objective of our study was to expand our knowledge of the SEMA3B gene as a tumor suppressor and the mechanisms of its inactivation. In this study, several experimental approaches were used: tumor growth analyses and apoptosis assays in vitro and in SCID mice, expression and methylation assays and other. With the use of the small cell lung cancer cell line U2020 we confirmed the function of SEMA3B as a tumor suppressor, and showed that the suppression can be realized through the induction of apoptosis and, possibly, associated with the inhibition of angiogenesis. In addition, for the first time, high methylation frequencies have been observed in both intronic (32-39%) and promoter (44-52%) CpG-islands in 38 non-small cell lung carcinomas, including 16 squamous cell carcinomas (SCC) and 22 adenocarcinomas (ADC), and in 83 clear cell renal cell carcinomas (ccRCC). Correlations between the methylation frequencies of the promoter and the intronic CpG-islands of SEMA3B with tumor stage and grade have been revealed for SCC, ADC and ccRCC. The association between the decrease of the SEMA3B mRNA level and hypermethylation of the promoter and the intronic CpG-islands has been estimated in renal primary tumors (P < 0.01). Using qPCR, we observed on the average 10- and 14-fold decrease of the SEMA3B mRNA level in SCC and ADC, respectively, and a 4-fold decrease in ccRCC. The frequency of this effect was high in both lung (92-95%) and renal (84%) tumor samples. Moreover, we showed a clear difference (P < 0.05) of the SEMA3B relative mRNA levels in ADC with and without lymph node metastases. We conclude that aberrant expression and methylation of SEMA3B could be suggested as markers of lung and renal cancer progression

Молекулярный фенотип клеток крови, ассоциированный с прогрессированием трижды негативного рака молочной железы

Introduction. triple negative breast cancer is an aggressive clinical phenotype characterized by poor prognosis. immune system plays an important role in the development, treatment response, and progression of solid tumor. The search for immune-related markers associated with the prediction of treatment efficacy and disease prognosis, and based on the use of high-resolution molecular techniques, is a promising area of research, the results of which can be translated into clinical practice. Case description. The molecular profile of blood mononuclear cells in a 48-year-old female patient with histologically proven triple negative breast cancer (estrogen Receptor – 0; progesteron Receptor – 0; Her2/neu – 0; gata-3 – 0, androgen Receptor – 0 and Ki67 – 70 %) was described. The patient did not response to neoadjuvant chemotherapy with 4 cycles of paclitaxel + carboplatin followed by 2 cycles of adriamycin + cyclophosphamide. The patient underwent surgery. disease progression (pelvic bone metastases) occurred 2 months after surgery. The features of blood lymphocytes and monocytes associated with a lack of response to neoadjuvant chemotherapy and disease progression were described.Conclusion. This clinical case demonstrates that sequencing of peripheral blood mononuclear cells can be used as a method for identifying predictive markers of therapy efficacy and developing personalized treatments for patients with triple negative breast cancer.Актуальность. Трижды негативный подтип рака молочной железы характеризуется агрессивным течением и неблагоприятным прогнозом. Компоненты иммунной системы как непосредственные участники патогенеза играют роль в развитии, ответе на терапию и прогрессировании этой нозологии. Поиск маркеров иммунных клеток, ассоциированных с предсказанием эффективности лечения и прогнозом заболевания, основанный на применении молекулярных методов высокого разрешения, является перспективным направлением поискового исследования, результаты которого можно транслировать в клиническую практику. Описание клинического случая. Представлен первый опыт описания молекулярного профиля мононуклеарных клеток крови пациентки с трижды негативным раком молочной железы. Опухоль: инвазивная карцинома неспецифического типа с экспрессией: estrogen Receptor – 0; progesteron Receptor – 0; Her2/neu – 0; gata-3 – 0, androgen Receptor – 0, Ki67 – 70 % опухолевых клеток. Отмечено отсутствие ответа на неоадъювантную химиотерапию по схеме: 4 цикла «паклитаксел + + карбоплатин», с последующими 2 курсами АС (адриамицин + циклофосфан). Пациентке проведено оперативное лечение, через 2 мес после которого выявлены метастазы в кости таза. У пациентки описаны особенности лимфоцитов и моноцитов крови, которые могут быть ассоциированы с отсутствием ответа на неоадъювантную химиотерапию и прогрессированием заболевания.Заключение. Представленное клиническое наблюдение показывает, что метод секвенирования мононуклеарных клеток периферической крови можно использовать в качестве поискового для обнаружения предиктивных маркеров эффективности терапии и создания персонифицированной системы лечения пациенток с трижды негативным раком молочной железы

Acute escitalopram treatment inhibits REM sleep rebound and activation of MCH-expressing neurons in the lateral hypothalamus after long term selective REM sleep deprivation.

RATIONALE: Selective rapid eye movement sleep (REMS) deprivation using the platform-on-water ("flower pot") method causes sleep rebound with increased REMS, decreased REMS latency, and activation of the melanin-concentrating hormone (MCH) expressing neurons in the hypothalamus. MCH is implicated in the pathomechanism of depression regarding its influence on mood, feeding behavior, and REMS. OBJECTIVES: We investigated the effects of the most selective serotonin reuptake inhibitor escitalopram on sleep rebound following REMS deprivation and, in parallel, on the activation of MCH-containing neurons. METHODS: Escitalopram or vehicle (10 mg/kg, intraperitoneally) was administered to REMS-deprived (72 h) or home cage male Wistar rats. During the 3-h-long "rebound sleep", electroencephalography was recorded, followed by an MCH/Fos double immunohistochemistry. RESULTS: During REMS rebound, the time spent in REMS and the number of MCH/Fos double-labeled neurons in the lateral hypothalamus increased markedly, and REMS latency showed a significant decrease. All these effects of REMS deprivation were significantly attenuated by escitalopram treatment. Besides the REMS-suppressing effects, escitalopram caused an increase in amount of and decrease in latency of slow wave sleep during the rebound. CONCLUSIONS: These results show that despite the high REMS pressure caused by REMS deprivation procedure, escitalopram has the ability to suppress REMS rebound, as well as to diminish the activation of MCH-containing neurons, in parallel. Escitalopram caused a shift from REMS to slow wave sleep during the rebound. Furthermore, these data point to the potential connection between the serotonergic system and MCH in sleep regulation, which can be relevant in depression and in other mood disorders

Pichia pastoris regulates its gene-specific response to different carbon sources at the transcriptional, rather than the translational, level

Background: The methylotrophic, Crabtree-negative yeast Pichia pastoris is widely used as a heterologous protein production host. Strong inducible promoters derived from methanol utilization genes or constitutive glycolytic promoters are typically used to drive gene expression. Notably, genes involved in methanol utilization are not only repressed by the presence of glucose, but also by glycerol. This unusual regulatory behavior prompted us to study the regulation of carbon substrate utilization in different bioprocess conditions on a genome wide scale. Results: We performed microarray analysis on the total mRNA population as well as mRNA that had been fractionated according to ribosome occupancy. Translationally quiescent mRNAs were defined as being associated with single ribosomes (monosomes) and highly-translated mRNAs with multiple ribosomes (polysomes). We found that despite their lower growth rates, global translation was most active in methanol-grown P. pastoris cells, followed by excess glycerol- or glucose-grown cells. Transcript-specific translational responses were found to be minimal, while extensive transcriptional regulation was observed for cells grown on different carbon sources. Due to their respiratory metabolism, cells grown in excess glucose or glycerol had very similar expression profiles. Genes subject to glucose repression were mainly involved in the metabolism of alternative carbon sources including the control of glycerol uptake and metabolism. Peroxisomal and methanol utilization genes were confirmed to be subject to carbon substrate repression in excess glucose or glycerol, but were found to be strongly de-repressed in limiting glucose-conditions (as are often applied in fed batch cultivations) in addition to induction by methanol. Conclusions: P. pastoris cells grown in excess glycerol or glucose have similar transcript profiles in contrast to S. cerevisiae cells, in which the transcriptional response to these carbon sources is very different. The main response to different growth conditions in P. pastoris is transcriptional; translational regulation was not transcript-specific. The high proportion of mRNAs associated with polysomes in methanol-grown cells is a major finding of this study; it reveals that high productivity during methanol induction is directly linked to the growth condition and not only to promoter strength

Dynamic changes in eIF4F-mRNA interactions revealed by global analyses of environmental stress responses

BACKGROUND: Translation factors eIF4E and eIF4G form eIF4F, which interacts with the messenger RNA (mRNA) 5' cap to promote ribosome recruitment and translation initiation. Variations in the association of eIF4F with individual mRNAs likely contribute to differences in translation initiation frequencies between mRNAs. As translation initiation is globally reprogrammed by environmental stresses, we were interested in determining whether eIF4F interactions with individual mRNAs are reprogrammed and how this may contribute to global environmental stress responses. RESULTS: Using a tagged-factor protein capture and RNA-sequencing (RNA-seq) approach, we have assessed how mRNA associations with eIF4E, eIF4G1 and eIF4G2 change globally in response to three defined stresses that each cause a rapid attenuation of protein synthesis: oxidative stress induced by hydrogen peroxide and nutrient stresses caused by amino acid or glucose withdrawal. We find that acute stress leads to dynamic and unexpected changes in eIF4F-mRNA interactions that are shared among each factor and across the stresses imposed. eIF4F-mRNA interactions stabilised by stress are predominantly associated with translational repression, while more actively initiating mRNAs become relatively depleted for eIF4F. Simultaneously, other mRNAs are insulated from these stress-induced changes in eIF4F association. CONCLUSION: Dynamic eIF4F-mRNA interaction changes are part of a coordinated early translational control response shared across environmental stresses. Our data are compatible with a model where multiple mRNA closed-loop complexes form with differing stability. Hence, unexpectedly, in the absence of other stabilising factors, rapid translation initiation on mRNAs correlates with less stable eIF4F interactions