Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition of early atherogenesis by losartan in monkeys with diet-induced hypercholesterolemia.

BACKGROUND Angiotensin II may contribute to atherogenesis by facilitating the proliferative and inflammatory response to hypercholesterolemia. This study determined, in a primate model of diet-induced atherosclerosis, the effect of AT(1) blockade on fatty-streak formation, plasma lipids, and surrogate markers of vascular injury. METHODS AND RESULTS Male cynomolgus monkeys fed a diet containing 0.067 mg cholesterol/kJ for 20 weeks were given losartan (180 mg/d, n=6) or vehicle (n=8) for 6 weeks starting at week 12 of the dietary regimen. Arterial pressure, heart rate, plasma total and lipoprotein cholesterol concentrations, and lipoprotein particle sizes and subclass distributions were unaffected by treatment. Losartan caused significant (P<0.05) increases in plasma angiotensin II and angiotensin-(1-7). Compared with vehicle-treated controls, losartan reduced the extent of fatty streak in the aorta, the coronary arteries, and the carotid arteries by approximately 50% (P<0.05). A significant (P<0.05) reduction in the susceptibility of LDL to in vitro oxidation, serum levels of monocyte chemoattractant protein-1, and circulating monocyte CD11b expression were also associated with losartan treatment. In addition, serum levels of vascular cell adhesion molecule-1 and E-selectin did not change during treatment but increased after discontinuation of losartan. Serum C-reactive protein, platelet aggregability, and white cell counts were not modified by losartan. CONCLUSIONS This study demonstrates for the first time an antiatherogenic effect of AT(1) receptor blockade in nonhuman primates. Losartan inhibited fatty-streak formation through mechanisms that may include protection of LDL from oxidation and suppression of vascular monocyte activation and recruitment factors.
Evidence and policy: mind the gap.

This, first issue of the International Journal of Epidemiology (IJE) for 2015 is a lively, diverse and stimulating, if occasionally contentious, read. Undoubtedly the same will be said of the next two issues for this year; April and June: special themed issues on recent advances in the fields of epigenetic epidemiology and Mendelian randomization respectively. Although these issues are closed for submissions, a special themed issue on another recent development, metabolic phenotyping in epidemiology, is open for submissions to the 30th June 2015—see the IJE website (http://ije.oxfordjournals.org/) for details; and further information about a special themed issue on life course epidemiology and ageing, open for submissions to the 31st July 2015, can be found in this issue of the journal. Although February is a general issue, many of its contributions could easily coalesce around the theme ‘the association between evidence and policy’. Two organizations for which this association is their raison d’etre are the Cochrane Collaboration and the Campbell Collaboration.
Engineering RESTful semantic services on the fly

Real-world implementations of semantic services that could enable seamless integration of heterogeneous systems on the fly are deficient. This could be attributed to the complexity of heavy-weight semantic technologies, which mostly have a steep learning curve. As a consequence, the evolvement of modern approaches that purport to simplify the engineering of such services is a necessity. In this short paper, we present a work-in-progress model-driven approach that seeks to simplify and speed up the process of engineering RESTful semantic services. The suggested approach promotes automatic transformation of platform independent service models to partial service implementation and semantic descriptions to realize functional RESTful semantic services. The proposed solution is demonstrated and evaluated through a simple use-case scenario.
Identification of NY‐BR‐1‐specific CD4+ T cell epitopes using HLA‐transgenic mice

Breast cancer represents the second most common cancer type worldwide and has remained the leading cause of cancer‐related deaths among women. The differentiation antigen NY‐BR‐1 appears overexpressed in invasive mammary carcinomas compared to healthy breast tissue, thus representing a promising target antigen for T cell based tumor immunotherapy approaches. Since efficient immune attack of tumors depends on the activity of tumor antigen‐specific CD4+ effector T cells, NY‐BR‐1 was screened for the presence of HLA‐restricted CD4+ T cell epitopes that could be included in immunological treatment approaches. Upon NY‐BR‐1‐specific DNA immunization of HLA‐transgenic mice and functional ex vivo analysis, a panel of NY‐BR‐1‐derived library peptides was determined that specifically stimulated IFNγ secretion among splenocytes of immunized mice. Following in silico analyses, four candidate epitopes were determined which were successfully used for peptide immunization to establish NY‐BR‐1‐specific, HLA‐DRB1*0301– or HLA‐DRB1*0401‐restricted CD4+ T cell lines from splenocytes of peptide immunized HLA‐transgenic mice. Notably, all four CD4+ T cell lines recognized human HLA‐DR‐matched dendritic cells (DC) pulsed with lysates of NY‐BR‐1 expressing human tumor cells, demonstrating natural processing of these epitopes also within the human system. Finally, CD4+ T cells specific for all four CD4+ T cell epitopes were detectable among PBMC of breast cancer patients, showing that CD4+ T cell responses against the new epitopes are not deleted nor inactivated by self‐tolerance mechanisms. Our results present the first NY‐BR‐1‐specific HLA‐DRB1*0301– and HLA‐DRB1*0401‐restricted T cell epitopes that could be exploited for therapeutic intervention against breast cancer.
Planck intermediate results: V. Pressure profiles of galaxy clusters from the Sunyaev-Zeldovich effect

Taking advantage of the all-sky coverage and broad frequency range of the Planck satellite, we study the Sunyaev-Zeldovich (SZ) and pressure profiles of 62 nearby massive clusters detected at high significance in the 14-month nominal survey. Careful reconstruction of the SZ signal indicates that most clusters are individually detected at least out to R500. By stacking the radial profiles, we have statistically detected the radial SZ signal out to 3R500, i.e., at a density contrast of about 50-100, though the dispersion about the mean profile dominates the statistical errors across the whole radial range. Our measurement is fully consistent with previous Planck results on integrated SZ fluxes, further strengthening the agreement between SZ and X-ray measurements inside R500. Correcting for the effects of the Planck beam, we have calculated the corresponding pressure profiles. This new constraint from SZ measurements is consistent with the X-ray constraints from xmm in the region in which the profiles overlap (i.e., [0.1-1] R500), and is in fairly good agreement with theoretical predictions within the expected dispersion. At larger radii the average pressure profile is shallower than the predictions. Combining the SZ and X-ray observed profiles into a joint fit to a generalised pressure profile gives best-fit parameters [P0, c500, gamma, alpha, beta] = [6.41, 1.81, 0.31, 1.33, 4.13]. Using a reasonable hypothesis for the gas temperature in the cluster outskirts we reconstruct from our stacked pressure profile the gas mass fraction profile out to 3R500. Within the temperature driven uncertainties, our Planck constraints are compatible with the cosmic baryon fraction and expected gas fraction in halos.
Superiority of a Handheld Perspective-Coupled Display in Isomorphic Docking Performances

Six degrees of freedom docking is one of the most fundamental tasks when interacting with 3D virtual worlds. We investigated docking performances with isomorphic interactions that directly relate the 6-dof pose of the input device to that of the object controlled. In particular, we studied a Handheld Perspective-Coupled Display (HPCD); which is a novel form of interactive system where the display itself is handheld and used as the input device. It was compared to an opaque HMD and to a standard indirect flat display used with either a sphere or an articulated arm as the input device. A novel computation of an Index of Difficulty was introduced to measure the efficiency of each interaction. We observed superior performances with the HPCD compared with the other interactions by a large margin (17% better than the closest interaction).
Positive chronotropic responses of rabbit sino-atrial node cells to flash photolysis of caged isoproterenol and cyclic AMP

The kinetics of onset and the intracellular biochemical signalling mechanisms which are responsible for the positive chronotropic effect of sympathetic stimulation in rabbit cardiac pacemaker cells were examined by using flash photolysis of caged isoproterenol (ISO) and cyclic AMP (cAMP). When caged ISO (10 μM) was present in the superfusate, a single ultraviolet flash caused gradual increases in the spontaneous beating frequency and action potential height of S-A node cells. Both these effects developed after an initial latency of approximately 5 s. Photorelease of ISO also increased the L-type Ca2+ current (ICa-L) with a time-course similar to that of the changes in action potential waveform and heart rate. All of these ISO-induced effects were blocked completely by 1 μM propranolol, demonstrating that they were β-adrenergic responses. Flash photolysis of caged cAMP (50μM) also resulted in increased firing frequency and ICa-L. However, these responses to cAMP developed with little or no latency. Intracellular dialysis with a selective inhibitor of the cAMP-dependent protein kinase, Rp-cAMPS, completely abolished the increase in ICa-L demonstrating that it is mediated exclusively via cAMP-dependent activation of protein kinase A, as opposed to a direct G-protein mediated mechanism.
Interferon Regulatory Factor 4 (IRF4) Plays a Key Role in Osteoblast Differentiation of Postmenopausal Osteoporosis.

BACKGROUND Postmenopausal osteoporosis (PMOP) is a prevalent disease, which features decreased bone mass, bone weakness and deteriorated bone microstructure in postmenopausal women. Although many factors have been revealed to contribute to the occurrence of PMOP, its mechanism remains undefined. This work aimed to identify significant changes in gene expression during PMOP formation and to examine the most valuable differential genes in postmenopausal osteoporosis versus the control group. METHODS The GSE68303 dataset that contains 12 ovariectomize (OVX) experimental and 11 sham groups was downloaded and analyzed. The results indicated that interferon regulatory factor 4 (IRF4) might be a hub gene in the development of postmenopausal osteoporosis. Western blot and immunohistochemistry were carried out to evaluate IRF4 levels in thoracic vertebra extracts from OVX and Sham mice. To assess IRF4's impact on osteogenic differentiation in postmenopausal bone marrow mesenchymal stem cells (BM-MSCs), IRF4 overexpression (OV-IRF4) and knockdown (Sh-IRF4) plasmids were constructed. RESULTS The results showed that comparing with the sham group, bone samples from the OVX group showed higher IRF4 expression. Alkaline phosphatase (ALP) staining revealed that IRF4 overexpression significantly inhibited ALP activity, while IRF4 knockdown promoted ALP activity in BM-MSCs. Simvastatin-treated OVX mice showed increased total bone volume/total tissue volume (BV/TV) and elevated Runx2 expression by immunohistochemical staining compared with the OVX group. CONCLUSIONS This study demonstrated that IRF4 is associated with OVX induced osteoporosis, it can regulate bone stability by inhibiting the osteogenic differentiation BM-MSCs. This study may help enhance our understanding of the molecular mechanism of PMOP formation, providing new insights into estrogen defiance induced osteoporosis.
Recent developments and translational aspects in targeted therapy for metastatic breast cancer

Biologically distinct subtypes of metastatic breast cancer (MBC) have been defined by multiple efforts in recent years, showing broad heterogeneity at the molecular level of disease. Throughout this endeavour, oncogenic drivers within MBC were identified as potential therapeutic targets. With recent results from clinical trials targeting these well-known cancer-promoting pathways, this review is trying to elucidate as well as summarise current new therapeutic aspects in MBC and shed light on translational aspects within this entity.
V2G Capacity Estimation Using Dynamic EV Scheduling

An aggregated number of electric vehicles (EVs) provides a platform for smart energy storage (SES) in buildings which can be used during periods of maximum demand or high electricity price as well as for leveling the intermittent outputs of renewable energy sources (RESs). However, the vehicle to grid (V2G) capacity varies over time based on the availability of the EVs and their individual state of charge (SOC). Hence a real-time V2G capacity estimation is important for utilizing EVs as SES efficiently. In this paper, an algorithm for half-hourly V2G capacity estimation using real-time EV scheduling is proposed. The algorithm is implemented as part of the Building Energy Management System (BEMS). The BEMS uses forecasted building load demand without EVs and predicted charging profiles of the EVs connected to the building for estimating the V2G capacity. The estimated V2G capacity and the availability of RESs are considered by the BEMS to schedule the EV charging/discharging. The proposed algorithm is applied to study three case scenarios using BEMS on residential, office, and commercial buildings in Singapore. The results obtained clearly show that a group of EVs connected to any high-rise building can be effectively used as a distributed storage system.
Regression of Electrocardiographic Left Ventricular Hypertrophy by Losartan Versus Atenolol: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) Study

Background—Electrocardiographic left ventricular hypertrophy (LVH) predicts cardiovascular morbidity and mortality, and regression of ECG LVH may predict improved prognosis in hypertensive patients. However, uncertainty persists as to how best to regress ECG LVH. Methods and Results—Regression of ECG LVH with losartan versus atenolol therapy was assessed in 9193 hypertensive patients with ECG LVH by Sokolow-Lyon voltage or Cornell voltage-duration product criteria enrolled in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Patients had ECGs at study baseline and after 6 months, 1, 2, 3, 4, and 5 years of blinded losartan-based or atenolol-based therapy. After 6 months’ follow-up, adjusting for baseline ECG LVH levels, baseline and in-treatment systolic and diastolic pressures, and for diuretic therapy, losartan-based therapy was associated with greater regression of both Cornell product (adjusted means, −200 versus −69 mm · ms, P <0.001) and Sokolow-Lyon voltage (−2.5 versus −0.7 mm, P <0.001) than was atenolol-based therapy. Greater regression of ECG LVH persisted at each subsequent annual evaluation in the losartan-treated group, with between 140 and 164 mm · ms greater mean reductions in Cornell product and from 1.7 to 2.2 mm greater mean reductions in Sokolow-Lyon voltage (all P <0.001). The effect of losartan was consistent across subgroups defined by gender, age, ethnicity, and diabetes. Conclusions—After adjusting for baseline and in-treatment blood pressure and baseline severity of ECG LVH, losartan-based antihypertensive therapy resulted in greater regression of ECG LVH by Cornell voltage-duration product and Sokolow-Lyon voltage criteria than did atenolol-based therapy. These findings support the value of angiotensin receptor blockade with losartan for reversing ECG LVH.
Impact of STI Effect on Flicker Noise in 0.13-$\mu \hbox{m}$ RF nMOSFETs

This paper reports on the impact of shallow-trench isolation (STI) on flicker noise characteristics in 0.13-mum RF nMOSFETs. The drain noise current spectral density was measured in both triode and saturation regions for a more complete study. The devices with a relatively small finger width and a large finger number (W=1 mum/Nfinger=40 and W=5 mum/Nfinger=8) presented more pronounced generation-recombination (G-R) noise characteristics compared to those with W=10 mum/Nfinger=4. In addition, a wide noise level variation of more than one order of magnitude was associated with the more obvious G-R noise components. The observed trends can be explained by the nonuniform stress effect of STI and also the associated traps at the edge of the gate finger between STI and the active region. To further study the noise mechanism, the single-linger devices with different STI-to-gate distances [SA(SB)=0.6,1.2, and 10 mum] were investigated. The measured results provided a direct evidence of STI effect on flicker noise characteristics. The activation energy of the traps was extracted at various temperatures in a range from EC-0.397 to EC-0.54 eV. Moreover, the calculated standard deviation sigmadB showed a strong dependence of noise variation on device geometry (sigmadB=2.95 dB for W=1 mum/Nfinger=40 and sigmadB=1.54 dB for W=10 mum/Nfinger=4). The analysis suggests that the carrier number fluctuation model with the correlated mobility scattering is more suitable for the noise characteristics in these devices.
Shallow horizontal groundwater flow in peatlands is reduced by bacteriogenic gas production

We tested the extent to which horizontal hydraulic conductivity (Kh) below the water table in near‐surface peats is affected by the accumulation of biogenic gas bubbles. We found: (1) Immediately after water table rise the peat is not saturated. Levels of initial undersaturation were between 1 and 9 percent. (2) The production of biogenic gas bubbles below the water table causes large reductions (typically more than a factor of two) in Kh.
Jasmonate-Activated MYC2 Represses ETHYLENE INSENSITIVE3 Activity to Antagonize Ethylene-Promoted Apical Hook Formation in Arabidopsis[C][W]

This study demonstrates that the jasmonate-activated transcription factor MYC2 modulates both the quantity and quality of ethylene-activated transcription factor EIN3, by directly inducing F-box gene EBF1 expression to promote EIN3 protein degradation and interacting with EIN3 to inhibit its transcriptional activity, thus negatively regulating HLS1 expression and apical hook development. The apical hook is an essential structure that enables epigeal plants to protrude through the soil. Arabidopsis thaliana HOOKLESS1 (HLS1) is reported to be a key regulator of hook development and a direct target gene of the ethylene (ET)-activated transcription factors ETHYLENE INSENSITIVE3 (EIN3) and its close homolog EIN3-Like1. Previous research has shown that the phytohormones jasmonate (JA) and ET antagonistically regulate apical hook development, although the underlying molecular mechanism is largely unknown. Here, we report that JA represses hook formation by reducing HLS1 expression. Our results further reveal that the JA-activated transcription factor MYC2 represses EIN3 function to reduce HLS1 expression through at least the following two layers of regulation: (1) MYC2 binds to the promoter of an F-box gene, EIN3 BINDING F-BOX PROTEIN1, to induce its expression and thus promote EIN3 degradation; and (2) MYC2 physically interacts with EIN3 and inhibits its DNA binding activity. Collectively, our findings shed light on the molecular mechanism underlying the antagonism between JA and ET during apical hook development and provide insight into the coaction of multiple phytohormones in the regulation of plant growth and development.
Orphanin FQ/Nociceptin Potentiates [D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin–Induced μ-Opioid Receptor Phosphorylation

In this study, we investigate the molecular mechanisms by which acute orphanin FQ/nociceptin (OFQ/N), acting through the nociceptin opioid peptide (NOP) receptor, desensitizes the μ-opioid receptor. We described previously the involvement of protein kinase C and G-protein-coupled receptor kinases (GRK) 2 and 3 in OFQ/N-induced μ receptor desensitization. Because phosphorylation of the μ receptor triggers the successive regulatory mechanisms responsible for desensitization, such as receptor uncoupling, internalization, and down-regulation, we investigated the ability of OFQ/N to modulate [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO)-induced μ receptor phosphorylation in BE(2)-C human neuroblastoma cells transfected with epitope-tagged μ receptors. OFQ/N treatment (100 nM, 60 min) potentiated DAMGO-induced μ receptor phosphorylation; inhibition of GRK2 or protein kinase C concomitant with OFQ/N treatment blocked the OFQ/N-mediated increase in DAMGO-induced phosphorylation. Inclusion of the NOP antagonist peptide III-BTD during OFQ/N pretreatment blocked the potentiation of DAMGO-induced phosphorylation by OFQ/N, which is consistent with the potentiation being mediated via actions of the NOP receptor. In addition, in cells expressing μ receptors in which the GRK-mediated phosphorylation site Ser375 was mutated to alanine, OFQ/N treatment failed to potentiate DAMGO-induced μ receptor phosphorylation and failed to desensitize the μ receptor. However, DAMGO-induced μ receptor phosphorylation and OFQ/N-induced μ receptor desensitization occurred in cells expressing μ receptors lacking non-GRK phosphorylation sites. These data suggest that OFQ/N binds to NOP receptors and activates protein kinase C, which then increases the ability of GRK2 to phosphorylate the agonist-occupied μ receptor, heterologously regulating homologous μ receptor desensitization.
Annual Review of Neuroscience Neurophysiology of Human Perceptual Decision-Making

The discovery of neural signals that reflect the dynamics of perceptual decision formation has had a considerable impact. Not only do such signals enable detailed investigations of the neural implementation of the decision-making process but they also can expose key elements of the brain’s decision algorithms. For a long time, such signals were only accessible through direct animal brain recordings,and progress in human neuroscience was hampered by the limitations of noninvasive recording techniques. However, recent methodological advances are increasingly enabling the study of human brain signals that finely trace the dynamics of the unfolding decision process. In this review, we highlight how human neurophysiological data are now being leveraged to furnish new insights into the multiple processing levels involved in forming decisions, to inform the construction and evaluation of mathematical models that can explain intra-and interindividual differences, and to examine how key ancillary processes interact with core decision circuits.