Miracle-dz/UniFAR-FTUs huggingface dataset:
CREB and Its Associated Proteins Act as Survival Factors for Human Melanoma Cells*

cAMP response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), members of the CREB/ATF family, have been implicated in cAMP- and calcium-induced transcriptional activation. We have previously demonstrated that quenching of CREB-associated proteins in metastatic melanoma cells by a dominant-negative CREB (KCREB) that is mutated within its DNA-binding domain decreased their radiation resistance, and their tumorigenic and metastatic potential in nude mice. As the induction of apoptosis by diverse exogenous signals is dependent on the elevation of intracellular Ca2+, the purpose of this study was to determine the role of CREB and its associated proteins in apoptosis using KCREB. We used thapsigargin (Tg), which inhibits endoplasmic reticulum-dependent Ca2+-ATPase and thereby increases cytosolic Ca2+, to induce apoptosis. MeWo human melanoma cells were transfected with the KCREB expression vector and subsequently analyzed for their susceptibility to Tg-induced apoptosis. Here we demonstrate that expression of KCREB in MeWo cells rendered them susceptible to Tg-induced apoptosis. Tg treatment induced phosphorylation of CREB and possibly ATF-1 transcription factors. Treatment with Tg induced CRE-dependent transcription in parental cells, whereas this activation was reduced in the KCREB-transfected cells. In addition, CAT activity driven by the CRE-dependent promoter was inhibited in parental MeWo cells cotransfected with increasing concentrations of KCREB in a dose-dependent manner. We did not observe any changes in Bcl-2 or Bcl-2-related proteins (Bcl-x, Bax, and Bad) in control or KCREB-transfected cells before or after treatment with Tg. Collectively, these data indicate that CREB and its associated proteins act as survival factors for human melanoma cells, and hence contribute to the acquisition of the malignant phenotype.
CHANGES IN VISUAL ACUITY AND FOVEAL PHOTORECEPTOR INTEGRITY IN EYES WITH CHRONIC CYSTOID MACULAR EDEMA ASSOCIATED WITH RETINAL VEIN OCCLUSION

Purpose: To investigate the change in integrity and thickness of the foveal outer retina in eyes with chronic cystoid macula edema associated with retinal vein occlusion. Methods: We reviewed retrospectively the medical records of 30 eyes of 30 patients who had chronic cystoid macula edema associated with retinal vein occlusion and who had a follow-up of more than 12 months without any treatment. Using optical coherence tomography, we assessed the thickness of the outer retina and status of the junction between the inner and outer segments of the photoreceptors and of the external limiting membrane in the fovea. Results: Visual acuity showed a correlation with thickness of the foveal outer retina (R = −0.37) and with the detection of a line of the inner and outer segments of the photoreceptors (R = 0.65) and that of an external limiting membrane (R = 0.75) beneath the fovea. During the observation period (17.2 ± 5.5 months), neither visual acuity nor the condition of the foveal outer retina showed a significant change, and in no eyes were previously detectable lines of the inner and outer segments of the photoreceptors and external limiting membrane just beneath the foveal cystoid space became undetectable. Conclusion: Even if a large cystoid space is located in the fovea, its effect on deterioration of the underlying foveal photoreceptor cells is not as strong as is generally thought.
Spontaneous physiological variability modulates dynamic functional connectivity in resting-state functional magnetic resonance imaging

It is well known that the blood oxygen level-dependent (BOLD) signal measured by functional magnetic resonance imaging (fMRI) is influenced—in addition to neuronal activity—by fluctuations in physiological signals, including arterial CO2, respiration and heart rate/heart rate variability (HR/HRV). Even spontaneous fluctuations of the aforementioned physiological signals have been shown to influence the BOLD fMRI signal in a regionally specific manner. Related to this, estimates of functional connectivity between different brain regions, performed when the subject is at rest, may be confounded by the effects of physiological signal fluctuations. Moreover, resting functional connectivity has been shown to vary with respect to time (dynamic functional connectivity), with the sources of this variation not fully elucidated. In this context, we examine the relation between dynamic functional connectivity patterns and the time-varying properties of simultaneously recorded physiological signals (end-tidal CO2 and HR/HRV) using resting-state fMRI measurements from 12 healthy subjects. The results reveal a modulatory effect of the aforementioned physiological signals on the dynamic resting functional connectivity patterns for a number of resting-state networks (default mode network, somatosensory, visual). By using discrete wavelet decomposition, we also show that these modulation effects are more pronounced in specific frequency bands.
Phosphorylation on histidine is accompanied by localized structural changes in the phosphocarrier protein, HPr from Bacillus subtilis

The histidine‐containing protein (HPr) of bacterial phosphoenolpyruvate:sugar phosphotransferase system (PTS) serves a central role in a series of phosphotransfer reactions used for the translocation of sugars across cell membranes. These studies report the high‐definition solution structures of both the unphosphorylated and histidine phosphorylated (P‐His) forms of HPr from Bacillus subtilis. Consistent with previous NMR studies, local conformational adjustments occur upon phosphorylation of His 15, which positions the phosphate group to serve as a hydrogen bond acceptor for the amide protons of Ala 16 and Arg 17 and to interact favorably with the α‐helix macrodipole. However, the positively charged side chain of the highly conserved Arg 17 does not appear to interact directly with phospho‐His 15, suggesting that Arg 17 plays a role in the recognition of other PTS enzymes or in phosphotransfer reactions directly. Unlike the results reported for Escherichia coli P‐His HPr (Van Nuland NA, Boelens R, Scheek RM, Robillard GT, 1995, J Mol Biol 246:180‐193), our data indicate that phosphorylation of His 15 is not accompanied by adoption of unfavorable backbone conformations for active site residues in B. subtilis P‐Ser HPr.
Novel Outer Bounds and Inner Bounds with Uncoded Cache Placement for Combination Networks with End-User-Caches

—This paper studies the tradeoff between the memory size M and the download time / rate R (cid:63) for networks where a server with N ﬁles is connected to H relays (without caches), which in turns are connected to K users equipped with caches of size M ﬁles. When each user is connected to a different subset of r relays, i.e., K = (cid:0) Hr (cid:1) , the system is referred to as a combination network with end-user-caches . In this work, outer bounds are derived for the practically motivated case of uncoded cache contents, that is, bits of the various ﬁles are directly copied in the user caches without any coding. In this case, once the cache contents and the user demands are known, the problem reduces to a general index coding problem. This paper shows that relying on a well known “acyclic index coding outer bound” results in bounds that are not tight for combination networks with end-user-caches (as opposed to the case without relays) and provides two novel ways to derive the tightest known outer bounds to date. As a result of independent interest, an inequality that generalizes the well-known sub-modularity of entropy is derived. Several novel caching schemes are proposed, which leverage the symmetries of combination networks and interference elimination at the end-users. The proposed schemes are proved: (i) to be optimal for some choices of the parameters ( N , M , H , r ) under the constraint of uncoded cache placement, and (ii) to outperform the state-of-the-art schemes in numerical evaluations.
Gravity Compensation of Robotic Manipulators Using Cylindrical Halbach Arrays

Gravity compensation (sometimes referred to as static balancing) is achieved in a mechanism when the weight of its moving links does not produce any torque at the actuators for any configuration of the links. This condition yields many advantages such as a significant reduction of the torque needed at the actuators and easier control. Therefore, retrofitting an existing design to include gravity compensation can be greatly beneficial. However, current methods to achieve this goal are limited. The majority of them require the addition of auxiliary mechanisms that affect the performance of the robot. In the proposed concept, the concentric motion of Halbach cylinders is used for the first time to produce a joint torque that exactly compensates the torque produced by a gravitational load over a complete rotation of a revolute joint. The concept leads to a compact design that is easily integrated to an existing actuated joint. Using software to simulate the interaction between magnets, the active parameters are studied to approach optimal torque output. In order to demonstrate the viability of the proposed concept, a prototype is built and retrofitted to an existing manipulator.
The effects of caffeine on the noradrenaline‐sensitive calcium store in rabbit aorta.

The effects of caffeine on the noradrenaline‐sensitive Ca store in rabbit aorta have been studied measuring tension development and stimulated 45Ca efflux in Ca‐free solution. In addition, the inhibitory effects of caffeine on transmembrane Ca movements and on intracellular Ca release have been investigated, again comparing contractile force and 45Ca fluxes. The maximally effective caffeine concentration fully depletes the noradrenaline‐sensitive Ca store as found from both contraction and 45Ca efflux experiments. Within the concentration ranges used in this study for either caffeine and noradrenaline, a linear relation exists between the amplitude of contraction and the amount of stimulated 45Ca efflux. The Ca content of the store (presumably sarcoplasmic reticulum, s.r.) is 74 mumol/kg aorta, corresponding to an s.r. Ca concentration of 5.3 mM. After exposure of the cells to a high‐K solution the s.r. Ca concentration reached a value of 8.5 mM. At 37 degrees C the Ca is lost from the store in Ca‐free solution with a half‐time of 34 min. Although a comparable amount of 45Ca is released by the maximal doses of caffeine and noradrenaline, the caffeine‐induced contraction is much smaller than the noradrenaline‐induced one. The increase in adenosine 3',5'‐cyclic monophosphate (cyclic AMP) after caffeine was less than after noradrenaline, so could not account for the small size of the caffeine‐induced contraction. Asynchrony in response to caffeine by successive layers of smooth muscle, and a separate inhibitory action of caffeine, may contribute to the small size of caffeine‐induced contractions in thick muscle preparations. Caffeine inhibits high‐K‐induced contractions by inhibition of Ca influx. Caffeine also inhibits the noradrenaline‐induced contractions in Ca‐free solution. These inhibitory actions could be dissociated from caffeine‐induced release of intracellular Ca.
Cytotoxicity of acridine compounds for Leishmania promastigotes in vitro

The effect of mammalian and bacterial topoisomerase II inhibitors on Leishmania promastigotes was studied in vitro. Parasites were incubated with drugs, and cytotoxicity was assessed on the basis of the loss of flagellar motility and cell lysis after 48 h. 9-Aminoacridines, which are structurally related to the known antileishmanial compounds quinacrine and chlorpromazine, showed activity against the parasite at concentrations in the range of 10 to 20 microM. Adriamycin showed far less activity, while etoposide and several quinolones were inactive at 100-microM concentrations. These results demonstrate that a particular structural class of compounds is cytotoxic to Leishmania species. The unique structure-activity relationship discovered suggests that leishmanial topoisomerase II could be a useful target for chemotherapy.
Price setting behaviour in Spain: evidence from micro PPI data

This paper identifies the basic features of price setting behaviour at the producer level in the Spanish economy using a large dataset containing the micro data underlying the construction of the PPI over the period 1991 1999. The paper explores how these general features are affected by some specific factors (cost structure, degree of competition, demand conditions, government intervention, level of inflation, seasonality, and the practice of using attractive prices) and presents a comparison of price setting practices at the producer and at the consumer level to ascertain whether the retail sector augments or mitigates price stickiness. We find that prices do not change often but do so by a large amount. The cost structure, proxied by the labour share and the relevance of raw materials, and the degree of competition, proxied by import penetration, affect price flexibility. We also find some evidence that producer prices are more flexible than consumer prices.
Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression.

OBJECTIVES To study and update the clinical characteristics and long-term outcome of our patients with mycosis fungoides (MF) and Sézary syndrome (SS), and to identify important clinical factors predictive of survival and disease progression. DESIGN A single-center, retrospective cohort analysis. SETTING Academic referral center for cutaneous lymphoma. PATIENTS Five hundred twenty-five patients with MF and SS evaluated and managed at Stanford University Cutaneous Lymphoma Clinic, Stanford, Calif, from 1958 through 1999. MAIN OUTCOME MEASURES We calculated long-term actuarial overall and disease-specific survivals and disease progression by the Kaplan-Meier method, and relative risk (RR) for survival calculated from expected survivals in control populations. RESULTS The majority of our patients presented with T1 (30%) or T2 (37%) disease; 18% presented with T3 and 15% with T4 skin involvement. Forty-three percent of deaths were attributable to MF, primarily in patients with T3 or T4 disease. The patients with a more advanced T classification and clinical stage had a worse survival outcome. Except for patients with T1 or stage IA disease, the RR for death is greater in patients with MF than in a control population (RR, 2.2 in stage IB/IIA disease, 3.9 in stage IIB/III disease, and 12.8 in stage IV disease). Despite similar overall survival in patients with stage IB or IIA disease, their disease-specific survivals were significantly different (P =.006). The most significant clinical prognostic factors in the univariate analysis were patient age, TNM and B classifications, overall clinical stage groupings, and the presence or absence of extracutaneous disease. In the multivariate analysis, patient age, T classification, and the presence of extracutaneous disease were the most important independent factors. The risk for disease progression to a more advanced TNM or B classification, worse clinical stage, or death due to MF correlated with the severity of the initial T classification. The risk for development of extracutaneous disease also correlated with T classification; none of these patients had T1 disease when their extracutaneous disease was detected. CONCLUSIONS Patients with MF and SS have varying risks for disease progression or death. The most important clinical predictive factors for survival include patient age, T classification, and the presence of extracutaneous disease. The significant disease-specific survival differences between different clinical stages validate the usefulness of the present MF clinical staging system of the National Cancer Institute.
User Behavior Characterization of a Large-scale Mobile Live Streaming System

Streaming live content to mobile terminals has become prevalent. While there are extensive measurement studies of non-mobile live streaming (and in particular P2P live streaming) and video-on-demand (both mobile and non-mobile), user behavior in mobile live streaming systems is yet to be explored. This paper relies on over 4 million access logs collected from the PPTV live streaming system to study the viewing behavior and user activity pattern, with emphasis on the discrepancies that might exist when users access the live streaming system catalog from mobile and non-mobile terminals. We observe high rates of abandoned viewing sessions for mobile users and identify different reasons of that behavior for 3G- and WiFi-based views. We further examine the structure of abandoned sessions due to connection performance issues from the perspectives of time of day and mobile device types. To understand the user pattern, we analyze user activity distribution, user geographical distribution as well as user arrival/departure rates.
A 60-GHz Differential on-chip Yagi antenna using 0.18-µm CMOS technology

This paper presents a 60-GHz differential on-chip Quasi-Yagi antenna fabricated with 0.18-μm CMOS technology. A differential feeding architecture is employed for better integration in the further system. The artificial magnetic conductor (AMC) structure placed at the back side of the Yagi antenna can suppress the surface wave radiate backwards, therefore improve the front-to-back (F/B) ratio greatly. The proposed on-chip Yagi antenna size is 2.45×1.8×0.3 mm3. A finite element method (FEM)-based 3-D full-wave electromagnetic solver HFSS is used for the design simulation. The simulated antenna impedance bandwidth for |S11| less than -10 dB can cover from 50 GHz to 70 GHz. The F/B ratio of the proposed Yagi antenna is 16.66 dB and the simulated antenna gain is -2.64 dBi at 60 GHz.
Reduced apoptosis and increased inflammatory cytokines in granulomas caused by tuberculous compared to non‐tuberculous mycobacteria: role of MPT64 antigen in apoptosis and immune response

Inhibition of apoptosis of infected macrophages by pathogenic mycobacteria is suggested to be an important virulence mechanism, but little is known about the mycobacterial proteins involved in the inhibition of apoptosis. In this study we investigated differences in apoptosis and immune response and their correlation with the expression of Mycobacterium tuberculosis complex‐specific secretory protein MPT64 in lesions caused by tuberculous or non‐tuberculous mycobacteria by analysing the in situ expression of apoptosis‐related proteins (FasL, Fas, Bax, Bcl‐2), apoptotic cells, inflammatory cytokines [tumour necrosis factor (TNF)‐α, interleukin (IL)‐10, transforming growth factor (TGF)‐β, interferon (IFN)‐γ] and MPT64 antigen. The discrimination of mycobacteria was made by nested polymerase chain reaction (PCR) amplification of IS6110, which is specific for M. tuberculosis complex organisms. Forty‐seven cases of lymphadenitis with necrotic granulomas were evaluated. With nested PCR, 30/47 cases were positive for M. tuberculosis. MPT64 antigen was detected specifically in the PCR‐positive cases. Granulomas caused by tuberculous mycobacteria had fewer apoptotic cells, higher numbers of cells expressing TNF‐α and TGF‐β and less extensive necrosis than granulomas caused by non‐tuberculous mycobacteria. There was a significant negative correlation between apoptotic cells and the number of cells expressing MPT64 antigens, suggesting a role for MPT64 protein in the inhibition of apoptosis. Granulomas with higher amounts of MPT64 also showed a greater number of cells expressing TGF‐β than those with lower amounts of MPT64. In conclusion, this study supports the hypothesis that inhibition of apoptosis is a virulence mechanism for tuberculous mycobacteria. Correlation of MPT64 antigen with expression of macrophage deactivating cytokines and reduced apoptosis suggests its role in pathogenesis and bacillary persistence.
Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR

Activated EGF receptor (EGFR) plays an oncogenic role in several human malignancies. Although the intracellular effects of EGFR are well studied, its ability to induce and modulate tumor angiogenesis is less understood. We found previously that oncogenic EGFR can be shed from cancer cells as cargo of membrane microvesicles (MVs), which can interact with surfaces of other cells. Here we report that MVs produced by human cancer cells harboring activated EGFR (A431, A549, DLD-1) can be taken up by cultured endothelial cells, in which they elicit EGFR-dependent responses, including activation of MAPK and Akt pathways. These responses can be blocked by annexin V and its homodimer, Diannexin, both of which cloak phosphatidylserine residues on the surfaces of MVs. Interestingly, the intercellular EGFR transfer is also accompanied by the onset of VEGF expression in endothelial cells and by autocrine activation of its key signaling receptor (VEGF receptor-2). In A431 human tumor xenografts in mice, angiogenic endothelial cells stain positively for human EGFR and phospho-EGFR, while treatment with Diannexin leads to a reduction of tumor growth rate and microvascular density. Thus, we propose that oncogene-containing tumor cell-derived MVs could act as a unique form of angiogenesis-modulating stimuli and are capable of switching endothelial cells to act in an autocrine mode.
Incipient allochronic speciation due to non-selective assortative mating by flowering time, mutation and genetic drift

We model the evolution of flowering time using a multilocus quantitative genetic model with non-selective assortative mating and mutation to investigate incipient allochronic speciation in a finite population. For quantitative characters with evolutionary parameters satisfying empirical observations and two approximate inequalities that we derived, disjunct clusters in the population flowering phenology originated within a few thousand generations in the absence of disruptive natural or sexual selection. Our simulations and the conditions we derived showed that cluster formation was promoted by limited population size, high mutational variance of flowering time, short individual flowering phenology and a long flowering season. By contrast, cluster formation was hindered by inbreeding depression, stabilizing selection and pollinator limitation. Our results suggest that incipient allochronic speciation in populations of limited size (satisfying two inequalities) could be a common phenomenon.
Ceruloplasmin fragmentation is implicated in 'free' copper deregulation of Alzheimer disease

A dysfunction in copper homeostasis seems to occur in Alzheimer’s disease (AD). We recently demonstrated that an excess of non-ceruloplasmin-copper (i.e. ‘free’ copper) correlates with the main functional and anatomical deficits as well as the cerebrospinal markers of the disease, thus suggesting that copper contributes to AD neurodegeneration. Aim of this study was to investigate the profile of serum ceruloplasmin isoforms immunoreactive protein in relation to copper dysfunction in AD. Twenty-five AD patients and 25 controls were included in the study. All subjects underwent individual measurements of serum ceruloplasmin and copper concentrations, and the amount of ‘free’ copper was computed for each copper and ceruloplasmin pair. Serum samples were also pooled and analyzed by two dimensional polyacrylamide gel electrophoresis (2-D PAGE) and western blot analysis. The mean concentration of ’free’ copper resulted higher in AD patients than in controls. Ceruloplasmin 2-D PAGE western blot analysis of pooled sera showed in the AD samples low-molecular-weight spots in the <50 kDa range that were not detected in controls’ pooled sera (p < 0.029). Our data indicate a ceruloplasmin fragmentation in the serum of AD patients, possibly related to ‘free’ copper deregulation in this disease.