Full Response Research Articles

Load-deformation response of long span prestressed concrete wide beams

This paper examines the full deformational response of prestressed wide beams. The results from full-scale prestressed wide beam tests are used to validate the nonlinear numerical modelling procedures adopted in this paper. Three-dimensional modelling with detailed representation of the prestressing action is used to evaluate the response including strain distributions within the member. Simplified sectional models are also validated against the tests and detailed modelling, and are further used for an extensive parametric investigation. The parameters examined in the study include the section size, amount of non-prestressed and prestressed reinforcement, concrete strengths, and member spans. The numerical results enabled a direct assessment of the full behaviour including the forces and deflections at initial camber, cracking and ultimate state. It is shown that modelling approaches were able to predict well the overall deformation and failure modes, with the three-dimensional approach giving a more detailed insight into the internal strain distributions. Parametric studies showed that the reinforcement ratio has the greatest influence on the overall behaviour, governing the post-cracking response, compared with other parameters varied. Based on the findings, design-oriented expressions are proposed to evaluate the cracked stiffness and ultimate state deflection of prestressed wide beams. These expressions are shown to offer a reliable and practical approach for assessing the full response of such members.

Travel behaviour differences among Indonesian youth in Generations Y and Z: pre-, during and post-travel

PurposeThis study aims to explore the differences in the travel behaviour of Indonesian youth of Generations Y and Z in the pre-, during and post-travel stages and their associated use of information and communication technology.Design/methodology/approachData were gathered through a questionnaire that was distributed via the internet for six weeks; 569 people provided their full responses. Chi-square tests and linear regression were used for data analysis.FindingsThese generations use digital media and word of mouth differently when searching for travel information. The differences are also apparent in the pre-, during and post-travel stages. Generation Z tends to use digital media and share travel experiences through a certain social media platform more frequently than Generation Y.Research limitations/implicationsThis study covers the travel history prior to and during the COVID-19 pandemic and equalises the situation in these two periods. The number of samples was relatively small to capture the current population of both generations.Practical implicationsThis study promotes a new understanding of the travel behaviours of the two generations based on the stages of the travel examined. The findings suggest that the travel industry can distinguish between promotional media and types of services to serve each of the generational cohorts more effectively.Originality/valueTo the best of the authors’ knowledge, this is the first study to reveal differences in travel behaviour between Generations Y and Z in Indonesia.

High-pressure investigations in CH3NH3PbX3 ( X = I, Br, and Cl): Suppression of ion migration and stabilization of low-temperature structure

Hybrid organic-inorganic halide perovskites represent a promising next-generation photovoltaic material with drawbacks for structure stability and composition concerns. Demonstrations of ion migration and molecular dynamics suggest room for structural contraction and subsequent property adjustments. Here, we deploy dielectric and infrared spectroscopy under external pressure to probe the full structural phase diagram and dielectric response of methylammonium lead halide perovskites ${\mathrm{CH}}_{3}{\mathrm{NH}}_{3}\mathrm{Pb}{X}_{3}$ ($X\phantom{\rule{4pt}{0ex}}=$ I, Br, or Cl). Ion migration can be fully suppressed by pressure beyond 4 GPa. The low-temperature orthorhombic phase transition can be gradually enhanced and stabilized at ambient conditions with increasing pressure. A slow relaxation mode, presumably the motion of the ${\mathrm{CH}}_{3}{\mathrm{NH}}_{3}^{+}$ cation, is observed at lower pressure and is absent in the orthorhombic phase for every halide.

Outcomes of budesonide multimatrix prescriptions in the COVID-19 pandemic

Background: Budesonide multimatrix is prescribed to treat forms of inflammatory bowel disease (IBD) during periods of relapse, and it is licensed to treat mild-to-moderate ulcerative colitis (UC). However, during the COVID-19 pandemic, there was a rise in the use of budesonide multimatrix to treat all forms of IBD after fears that systemic corticosteroid use, such as prednisolone, could increase the risk of COVID-19 severity. Methods: This audit included records of all patients who were prescribed the budesonide multimatrix Cortiment (9 mg once a day) over a year in NHS Lothian. Patients were grouped by disease activity at the point of prescription (Partial Mayo Score (PMS) less than 5 showed milder disease and above 5 showed more severe disease) and disease phenotype. The primary endpoint was response at 8 weeks from start of treatment, grouped into full response, partial response, no response and escalation. Results: The full response rate to budesonide multimatrix was 52% among all patients, but 80% in those with PMS ≤4 and only 15% in those with a PMS ≥5. By phenotype, response rates were 41% in Crohn's disease, 50% in IBD unclassified, 56% in proctitis, 56% in left-sided colitis and 51% in pancolitis. Conclusions: Budesonide multimatrix is effective to treat mild disease but is not effective in patients who are having a moderate-to-severe flare of IBD. This medication was 80% effective if the PMS was below 5, suggesting that it is very effective in mild disease.

Mechano-Node-Pore Sensing: A Rapid, Label-Free Platform for Multi-Parameter Single-Cell Viscoelastic Measurements.

Cellular mechanical properties are involved in a wide variety of biological processes and diseases, ranging from stem cell differentiation to cancer metastasis. Conventional methods for measuring these properties, such as atomic force microscopy (AFM) and micropipette aspiration (MA), capture rich information, reflecting a cell's full viscoelastic response; however, these methods are limited by very low throughput. High-throughput approaches, such as real-time deformability cytometry (RT-DC), can only measure limited mechanical information, as they are often restricted to single-parameter readouts that only reflect a cell's elastic properties. In contrast to these methods, mechano-node-pore sensing (mechano-NPS) is a flexible, label-free microfluidic platform that bridges the gap in achieving multi-parameter viscoelastic measurements of a cell with moderate throughput. A direct current (DC) measurement is used to monitor cells as they transit a microfluidic channel, tracking their size and velocity before, during, and after they are forced through a narrow constriction. This information (i.e., size and velocity) is used to quantify each cell's transverse deformation, resistance to deformation, and recovery from deformation. In general, this electronics-based microfluidic platform provides multiple viscoelastic cell properties, and thus a more complete picture of a cell's mechanical state. Because it requires minimal sample preparation, utilizes a straightforward electronic measurement (in contrast to a high-speed camera), and takes advantage of standard soft lithography fabrication, the implementation of this platform is simple, accessible, and adaptable to downstream analysis. This platform's flexibility, utility, and sensitivity have provided unique mechanical information on a diverse range of cells, with the potential for many more applications in basic science and clinical diagnostics.

Regorafenib and trifluridine/tipiracil in real clinical practice.

Colorectal cancer is the ninth leading cause of death in Spain. The latest therapeutic developments in the advanced stages of this disease are the oral drugs trifluridine/tipiracil and regorafenib. Results of clinical trials (CTs) are not in real conditions and therefore, we want to study the effectiveness and the safety profile in the usual clinical practice and compare it with the bibliography. A retrospective and unicentric study was carried out in a health area of 500,000 inhabitants. Patients who started treatment with regorafenib and/or trifluridine/tipiracil were included from the date of marketing until June 2019. Patient-related variables, pathology, effectiveness, and treatment toxicity were collected. The statistical analysis was carried out with the PSPP program. Fifty-four patients were analyzed. Men accounted for 59.3% of patients. Regorafenib was the treatment for 22.2% of patients and 77.8% received trifluridine/tipiracil. The reason for the drug's suspension was the disease progression in 85.2% of patients. No patient had a full response and 3.2% achieved partial response. The median progression-free survival time in treatments with regorafenib was 2.5 months (95% confidence interval [CI]: 0.0-5.4) and the overall survival time was 3.1 months (95% CI: 0.0-6.7), while in treatments with trifluridine/tipiracil, these data were, respectively, 2.8 (95% CI: 2.5-3.2) and 5.7 months (95% CI: 3.8-7.6). Side effects occurred in 91.7% of patients treated with regorafenib and in 100% of treated with trifluridine/tipiracil. Hematological adverse reactions were, on average, 0.4 ± 0.5/patient with regorafenib and 1.5 ± 0.9 with trifluridine/tipiracil. General (77.8%) and gastrointestinal disorders (50%) were common with both drugs. The effectiveness results of standard clinical practice are lower than those described in CTs and in the literature. The toxicity profile does reproduce what is described in the bibliography.

Harvesting BAT-GUANO with NITRATES (Non-Imaging Transient Reconstruction and Temporal Search): Detecting and Localizing the Faintest Gamma-Ray Bursts with a Likelihood Framework

The detection of the gravitational wave (GW) counterpart GRB 170817A, underluminous compared to the cosmological gamma-ray burst (GRB) population by a factor of 10,000, motivates significant effort in detecting and localizing a dim, nearby, and slightly off-axis population of short GRBs. Swift’s Burst Alert Telescope (BAT) is one of the most sensitive GRB detectors in operation, and the only one that regularly localizes GRBs to arcminute precision, critical to rapid follow-up studies. However, the utility of BAT in targeted subthreshold searches had been historically curtailed by the unavailability of the necessary raw data for analysis. The new availability of time-tagged event data from the GUANO system motivates a renewed focus on developing sensitive targeted search analysis techniques to maximally exploit these data. While computationally cheap, we show that the typical coded-mask deconvolution imaging is limited in its sensitivity due to several factors. We formalize a maximum likelihood framework for the analysis of BAT data wherein signals are forward modeled through the full instrument response, and—coupled with the development of new response models—demonstrate its superior sensitivity to typical imaging via archival comparisons, injection campaigns, and a large number of low-latency GRB discoveries and confirmed arcminute localizations to date. We also demonstrate independent localization of some out-of-field-of-view GRBs for the first time. NITRATES’s increased sensitivity boosts the discovery rate of GRB 170817A–like events in BAT by a factor of at least 3−4×, along with enabling joint analyses and searches with other GRB, GW, neutrino, and FRB instruments. We provide public access to the response functions and search pipeline code.

Neurons of the median preoptic nucleus contribute to chronic angiotensin II-salt induced hypertension in the rat.

Experiments were designed to test the hypothesis that median preoptic (MnPO) neurons are necessary for the full hypertensive response to chronic angiotensin II (AngII) in rats consuming a high salt diet. The MnPO is implicated in many of the physiologic actions of AngII, primarily acting as a downstream nucleus to AngII binding at circumventricular organs such as the organum vasculosum of the lamina terminalis (OVLT). We have previously shown a prominent effect of lesion of the OVLT on the chronic hypertensive effects of AngII in rats consuming high salt. Additionally, we have shown that lesion of the MnPO attenuated the hypertensive response to chronic intravenous infusion of AngII in rats. However, whether MnPO neurons or fibers of passage contribute to this response is not clear. Male Sprague Dawley rats were randomly assigned to either sham (SHAM; n=8) or ibotenic acid lesion of the MnPO (MnPOx; n=6). In the MnPOx group, 200 nl of ibotenic acid in phosphate buffer saline (5 μg/μl) was injected into each of 3 predetermined coordinates targeted at the entire MnPO. After a week of recovery, rats were instrumented with radiotelemetric pressure transducers, provided 2.0% NaCl diet and distilled water ad libitum and given another week to recover. After 3 days of baseline measurements, osmotic minipumps were implanted subcutaneously in all rats for administration of AngII at a rate of 150 ng/kg/min. Blood pressure measurements were made for 14 days after minipump implantation. By day 7 of AngII treatment, blood pressure responses appeared to plateau in both groups while the hypertensive response was markedly attenuated in MnPOx rats (MnPOx, 122 ± 6 mmHg; SHAM, 143 ± 8 mmHg). These results support the hypothesis that neurons of the MnPO are involved in the central pathway mediating the chronic hypertensive effects of AngII in rats consuming a high salt diet.

Sensitive Chirality Measurements with Electrical Readout Utilizing the CISS Effect

AbstractChirality is a fundamental chemical property that can be found in almost all aspects of life. Generally, in nature chirality exists in only one of the possible enantiomeric forms. Bitter experience showed that chiral drugs having the same chemical composition but opposite chirality may have extremely different biological effects. It is therefore that detecting and quantifying chirality is important in multiple fields ranging from analytical and biological chemistry to pharmacology, biotechnology, and fundamental physics. To date, the most widely used analytical methods for chiral detection, remain the traditional approaches of measuring circular dichroism and optical rotation. However, these methods suffer from low signal‐to‐noise due to large time‐dependent backgrounds and require complicated optical setups. Recent works associate circular dichroism measurements with the Chiral Induced Spin Selectivity (CISS) spin current measurements. The CISS effect relates the probability of electron spin transmission through chiral molecules to chirality. Depending on the handedness of the molecule, electrons of a certain spin can traverse the molecule more easily in one direction than in the other. It is therefore that the CISS effect could be utilized to electronically measure chirality using spin currents and spin induced dipoles. The review summarizes the different approaches for utilizing the CISS effect for electrical measurements of chirality. Starting with a Hall device that can measure the chirality of the lowest energetic CD band of a monolayer in dry or wet systems. Presenting an enhancement of the effect as well as achieving a wider CD spectrum using electrical gating. Going down to 100 molecules limit with full spectrum response utilizing electro‐optical nano floret devices.

Distributed model predictive control‐oriented network decomposition based on full dynamic response

AbstractThis article addresses network decomposition for distributed model predictive control (DMPC), which includes two improvements. First, in the weighted input–output bipartite graph construction of a process network, a new measure called frequency affinity is proposed to characterize the input–output interaction considering the full dynamic response and structural information of a process. Then, in community detection, which is used to decompose the process network, the gap metric is added to quantify stability and the loss of control performance of each subsystem. Through the proposed decomposition, the obtained subsystems can be dynamically well‐decoupled since both transient and steady‐state responses are measured by the frequency affinity. As structural information is considered, the decomposition is consistent with the process physical topology. Furthermore, the utilization of gap metric can facilitate controller design for DMPC. Case studies on a reactor separator process and an air separation process demonstrate the effectiveness of the proposed decomposition method.

Allogeneic Donor-Derived Myeloid Antigen Directed CAR-T Cells - for Relapsed/Refractory Acute Myeloid Leukemia in Children after Allogeneic Hematopoietic Stem Cell Transplantation: Report of Three Cases

Introduction The outcome of HSCT among children with chemorefractory acute myeloid leukemia (AML) is poor. The incidence of relapse exceeds 50%. We hypothesized that myeloid antigen-directed CAR-T cell therapy may induce remission in children with refractory AML. Patients and methods Three pediatric patients with R/R AML were enrolled in a compassionate-use program. All cases had AML, relapsing after multiple lines of treatment, including previous HSCT (n=3). One patient had CD123-positive leukemia cell population in the bone marrow, 2 pts had CD33-positive population. At the time of allogeneic CAR-T application disease burden was overt leukemia (n=3), all patients had full donor chimerism in the CD3 cells. Baseline characteristics of the pts are summarized in table 1. Allo-CAR-T were derived from previous HSCT donors (haplo n=2, MRD n=1). The FlA chemotherapy regimen was used to reduce tumor burden, followed by the fludarabine and cyclophosphamide for lymphodepletion before CAR-T cell infusion in all patients. One patient received CD123 directed allo-CAR-T cells, 2 pts - CD33 CAR-T cells. Both CD33 and CD123 constructs were 2-nd generation 4-1BBz CARs, modified based on the published Ukrainskaya et al. Clinical grade manufacturing was performed on Prodigy bioreactor platform with retroviral transduction. Results Cytokine release syndrome (CRS) occurred in 3 patients and was grade ≤3, all pts received tocilizumab with good effect. Two patients had neurologic events (ICANS grade 1-2). In one patient rash and liver toxicity coincided with CRS, potentially representing aGVHD, with full response to corticosteroids. All pts had grade III/IV hematological toxicities. The median time to CAR-T cell peak expansion was 14 days. At 4 weeks after CAR-T infusion two patients achieved complete MRD negative remission with incomplete count recovery and good CAR-T cell expansion. One pt. had MRD positive remission with CD33 loss on residual blast cells. Two patients (#1 and #2) on d +37 and +45 receivedTotal body irradiation (TBI) at 4 Gy and TCRαβ+ depleted graft from original donors. Abatacept on d 0, +7, +14 was used as GVHD prophylaxis. One pt. (#3) received second HSCT on d +30 from haploidentical donor with full intensity TBI-based regimen. All patients engrafted recovered hematopoietic function) and had MRD-negative remission with full donors chimerism on d+30. Two patients, #1 and #2, relapsed after 4 and 2 months after graft infusion, respectively. Patient #3 remains in MRD-negative remission on day +100. All patients alive with median follow up 164 days (102-196). Conclusion Our early experience suggests that allogeneic myeloid antigen-directed CAR-T cells are effective as cytoreduction and have manageable toxicity. Myeloid antigen-directed CAR-T therapy can be used as a bridge to allo HSCT in r/r AML. We have documented CAR-T expansion and persistence. Prospective testing of the approach is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficient Rigorous Coupled-Wave Analysis Simulation of Mueller Matrix Ellipsometry of Three-Dimensional Multilayer Nanostructures.

Mueller matrix ellipsometry (MME) is a powerful metrology tool for nanomanufacturing. The application of MME necessitates electromagnetic computations for inverse problems of metrology determination in both the conventional optimization process and the recent neutral network approach. In this study, we present an efficient, rigorous coupled-wave analysis (RCWA) simulation of multilayer nanostructures to quantify reflected waves, enabling the fast simulation of the corresponding Mueller matrix. Wave propagations in the component layers are characterized by local scattering matrices (s-matrices), which are efficiently computed and integrated into the global s-matrix of the structures to describe the optical responses. The performance of our work is demonstrated through three-dimensional (3D) multilayer nanohole structures in the practical case of industrial Muller matrix measurements of optical diffusers. Another case of plasmonic biosensing is also used to validate our work in simulating full optical responses. The results show significant numerical improvements for the examples, demonstrating the gain in using the RCWA method to address the metrological studies of multilayer nanodevices.

Performance of strengthened RC beams with torsional CFRP wraps in monolithic framed structures: Experimental and numerical investigation

The performance of externally applied wraps to simply supported reinforced concrete (RC) beams under pure torsion has been well-defined in the literature. In most cases, the previous research works utilised carbon fibre reinforced polymers (CFRP) wraps with different configurations to enhance the beams torsional capacities. While the effectiveness of these wraps in monolithic framed beams in RC buildings is less understood. Further, there is still a lack of information regarding the influence of interacted-combined loads on both the wrapped beams and the joined columns. This paper deals with the presence of different wrapping schemes on the response of framed beams that joined to columns, and how different levels of eccentric torsional forces combined with bending and shear forces can alter the damage state. The experimental programme of this study involved a series of beam-column assemblies tested under concentric and eccentric combined loads. Based on the test observations, a nonlinear finite element (FE) procedure is proposed and validated for simulating the full response of RC beam-column assemblies. This validated FE procedure is then used to explore critical parameters which govern the wraps performance and the failure modes. The outcomes of this study provide comprehensive insights into the role of the interacted forces and the wrapping configurations on the developed deformations and the members integrity. In particular, the results confirmed that the torsional force adversely affected the flexural capacities in proportion to the ratio of the torsion applied. Meanwhile, the interacted forces can induce substantial strain and damage levels that can be extended to the joined column. The contribution of CFRP wraps is found to be limited to the concrete strut’s capacity and the extent of torsional shear-flow in consistent with the imposed loads ratios and the developed truss mechanism.

Iterative-Bayesian unfolding of cosmic-ray isotope fluxes measured by AMS-02

The measurement of the isotopic composition of cosmic rays (CRs) provides essential insights into the understanding of the origin and propagation of these particles, namely the CR source spectra, the propagation processes and the galactic halo size. The Alpha Magnetic Spectrometer (AMS-02), a CR experiment operating aboard the International Space Station since May 2011, has the capability of performing these measurements due to its precise determination of the velocity provided by its Time of Flight (TOF) and Ring Imaging Cherenkov (RICH) detectors. The correct interpretation of the data requires the measurements to be deconvoluted from the instrumental effects. The unique design of AMS-02, with more than one detector being used to measure the same particle flux, requires a novel approach to unfold the measured fluxes. In this work, we apply for the first time the so-called iterative-bayesian approach in the context of the direct measurement of the cosmic-ray fluxes. Moreover, we introduce a non-parametric regularization method for the detector response functions and a single, smooth flux prior covering the range of measurements from both detectors, TOF and RICH. The accuracy of the method is assessed using a simulated flux based on previous AMS-02 measurements and taking into account the full detector response. In addition, the estimation of the errors and a discussion about the performance of the method are also shown, demonstrating that the method is fast and reliable, allowing for the recovery of the true particle fluxes in the whole energy range.

Transcriptomic Studies of Antidepressant Action in Rodent Models of Depression: A First Meta-Analysis.

Antidepressants (ADs) are, for now, the best everyday treatment we have for moderate to severe major depressive episodes (MDEs). ADs are among the most prescribed drugs in the Western Hemisphere; however, the trial-and-error prescription strategy and side-effects leave a lot to be desired. More than 60% of patients suffering from major depression fail to respond to the first AD they are prescribed. For those who respond, full response is only observed after several weeks of treatment. In addition, there are no biomarkers that could help with therapeutic decisions; meanwhile, this is already true in cancer and other fields of medicine. For years, many investigators have been working to decipher the underlying mechanisms of AD response. Here, we provide the first systematic review of animal models. We thoroughly searched all the studies involving rodents, profiling transcriptomic alterations consecutive to AD treatment in naïve animals or in animals subjected to stress-induced models of depression. We have been confronted by an important heterogeneity regarding the drugs and the experimental settings. Thus, we perform a meta-analysis of the AD signature of fluoxetine (FLX) in the hippocampus, the most studied target. Among genes and pathways consistently modulated across species, we identify both old players of AD action and novel transcriptional biomarker candidates that warrant further investigation. We discuss the most prominent transcripts (immediate early genes and activity-dependent synaptic plasticity pathways). We also stress the need for systematic studies of AD action in animal models that span across sex, peripheral and central tissues, and pharmacological classes.

Boron-loaded deuterated liquid scintillator response characterization for neutron spectroscopy

This research presents the characterization methods and results for determining the pulse-integral response calibration, resolution, efficiency, and heavy charged particle light yield functions of boron-loaded deuterated liquid scintillators (BLDLS) through a combination of experimental neutron and gamma-ray measurements coupled with GEometry ANd Tracking (Geant4) Monte Carlo radiation transport simulations. These methods were used to characterize the scintillator light output, pulse-shape discrimination performance, and response matrix for a boron-loaded deuterated liquid scintillator to be used for future neutron spectrum unfolding measurements. These results were compared against an un-loaded deuterated liquid scintillator and a commercially-available hydrogen-based liquid scintillator, EJ-309, to benchmark the performance of the methods and scintillators to comparable measurements in literature. EJ-309 was shown to have only a 3.5 ± 2.3% and 8.1 ± 1.4% higher relative light output at 477 keV compared to Tol-D8 and Tol-D8−10B, respectively, a significant increase in performance over previous BLDLS results. Additionally, Tol-D8 and Tol-D8−10B have similar PSD performance, both exceeding that of EJ-309 as a function of light yield. Finally, full detector response matrices, used for neutron spectrum unfolding, were generated for each scintillator, and the condition of these response matrices were evaluated. The deuterated scintillators resulted in worse conditioned response matrices compared to EJ-309 for neutron energies ranging between 0.5 MeV to 6 MeV, primarily due to having a lower pulse-integral resolution at the smaller detector sizes used in this work. The boron-loaded scintillator shows a similarly conditioned response matrix to the un-loaded variant, thereby lowering the characterizable neutron energy threshold to thermal energies while also enhanced the neutron detection efficiency.

Allergen management under a voluntary PAL regulatory framework – A survey of Canadian food processors

Canadian regulations require food business operators (FBOs) to implement preventive controls to manage allergens and ensure their accurate declaration. However, the use of precautionary allergen labelling (PAL) is voluntary and competent authorities provide limited guidance on its use. The objective of this study was to present an overview of Canadian FBOs' current allergen management practices, including the mechanisms used to evaluate the need for PAL in finished products, and to investigate potential areas for improvement. Canadian FBOs were invited to answer an online survey of 48 questions covering allergen management practices and perceptions. Eighty-four full survey responses (margin of error of 9% at a 90% confidence level) were obtained. Differences in responses to multiple choice questions per company size were determined using chi-square and Fisher's exact tests. Kruskal-Wallis tests were used to analyse responses to rating or forced ranking questions. Survey respondents' allergen management practices were based on a combination of recognized best practices, third-party quality systems' standards, and regulatory requirements. Concerning practices related to the criteria used to reach PAL decisions were noted, which could be addressed with increased awareness and use of risk-based approaches and a clearer regulatory policy. Analytical testing applicability and interpretation, access to information on unintentional allergen presence in raw materials, and clarity on the expectations related to the current regulatory framework on food allergens and its enforcement, were identified as challenges faced by Canadian FBOs. The results of this survey and its analysis could be used by regulators – to inform potential policy changes, by FBOs – to map industry practices, and by allergic consumers – to better understand how manufacturers manage allergens in their operations.

Hepatic GATA4 regulates cholesterol and triglyceride homeostasis in collaboration with LXRs.

GATA4 is a transcription factor known for its crucial role in the development of many tissues, including the liver; however, its role in adult liver metabolism is unknown. Here, using high-throughput sequencing technologies, we identified GATA4 as a transcriptional regulator of metabolism in the liver. GATA4 expression is elevated in response to refeeding, and its occupancy is increased at enhancers of genes linked to fatty acid and lipoprotein metabolism. Knocking out GATA4 in the adult liver (Gata4LKO) decreased transcriptional activity at GATA4 binding sites, especially during feeding. Gata4LKO mice have reduced plasma HDL cholesterol and increased liver triglyceride levels. The expression of a panel of GATA4 binding genes involved in hepatic cholesterol export and triglyceride hydrolysis was down-regulated in Gata4LKO mice. We further demonstrate that GATA4 collaborates with LXR nuclear receptors in the liver. GATA4 and LXRs share a number of binding sites, and GATA4 was required for the full transcriptional response to LXR activation. Collectively, these results show that hepatic GATA4 contributes to the transcriptional control of hepatic and systemic lipid homeostasis.

Statins synergize with other drugs to prevent myofibroblast transformation in in vitro model of peyronie's disease

Peyronie's disease is characterized by formation of a plaque in the tunica albuginea (TA), with myofibroblasts being the main effector cells. We have previously shown a synergy between phosphodiesterase type 5 inhibitors (PDE5is) and selective estrogen receptor modulators (SERMs) in inhibiting myofibroblast formation in models of PD. Further research revealed statins to be anti-fibrotic as well. Whilst the anti-fibrotic effect of statins themselves has already been described, we aimed to combine statins with our previously identified drugs. Tunica albuginea (TA) of PD patients was used to isolate primary fibroblasts. TA-derived fibroblasts were exposed to Transforming Growth Factor-ß1 (TGF-β1) and a range of concentrations of statins, PDE5i, SERM, and their combinations for 72h before quantifying α-smooth muscle actin (α-SMA) using In-Cell ELISA (ICE). Statins (simvastatin, lovastatin) showed a concentration dependent anti-fibrotic effect to prevent TGF-ß1-induced myofibroblast transformation, with IC50 values of 0.77 µM and 0.8 µM for simvastatin and lovastatin, respectively. Addition of 0.3 µM of simvastatin to a full concentration response curve of vardenafil revealed drug synergy, as 0.3 µM of simvastatin showed 12% inhibition, 0.3 µM of vardenafil 1.5% inhibition, but their combination exerted 33% inhibition. Similarly, 0.18 µM of tamoxifen showed 2% inhibition, whilst a combination with 0.3 µM simvastatin resulted in 24% inhibition. Interestingly, combining simvastatin, vardenafil, and tamoxifen was not more effective than vardenafil and tamoxifen, or vardenafil and simvastatin only. Statins, PDE5i, and SERMs are anti-fibrotic, and both double combinations (statin-PDE5i, statin-SERM) showed synergy in vitro. A triple combination did not exceed the double combinations. However, care must be taken with attempts to translate these results to bedside, as there have been reports of strong adverse effects in patients, such as myopathy due to metabolic toxicity, when treated with a statin-PDE5i combination. Authors hold patent for PDE5i-SERM use in fibrosis

Temporal frequency dependence of the polarity inversion between upper and lower visual field in the pattern-onset steady-state visual evoked potential

PurposeAccording to the cruciform model, the upper and lower halves of the visual field representation in the primary visual cortex are located mainly on the opposite sides of the calcarine sulcus. Such a shape would have consequences for the surface-recorded visual evoked potential (VEP), as V1 responses to stimulation of the upper and lower hemifield manifest with opposite polarity (i.e., polarity inversion). However, the steady-state VEP results from a complex superposition of response components from different cortical sources, which can obscure the inversion of polarity. The present study assesses the issue for different stimulation frequencies which result in different patterns of superposition in the steady-state response.MethodsSequences of brief pattern-onset stimuli were presented at different stimulation rates ranging from 2 Hz (transient VEP) to 13 Hz (steady-state VEP). The upper and lower hemifields were tested separately and simultaneously. The data were assessed both in the time domain and in the frequency domain.ResultsComparing the responses to the stimulation of upper and lower hemifield, polarity inversion was present within a limited time interval following individual stimulus onsets. With increasing frequency, this resulted in an approximate inversion of the full steady-state response and consequently in a phase shift of approximately 180° in the time-domain response. Polarity inversion was more prominent at electrode Pz, also for transient responses. Our data also demonstrated that the sum of the hemifield responses is a good approximation of the full-field response.ConclusionWhile the basic phenomenon of polarity inversion occurs irrespective of the stimulus frequency, its relative impact on the steady-state response as a whole is the largest for high stimulation rates. We propose that this is because longer-lasting response components from other visual areas are not well represented in the steady-state VEP at higher frequencies.