Miracle-dz/UniFAR-FTUs huggingface dataset:
Latonduine analogues restore F508del-CFTR trafficking through the modulation of PARP-3 and PARP-16 activity.

Cystic Fibrosis (CF) is a major lethal genetic disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR). This encodes a chloride ion channel on the apical surface of epithelial cells. The most common mutation in CFTR (F508del-CFTR) generates a protein that is misfolded and retained in the endoplasmic reticulum. Identifying small molecules that correct this CFTR trafficking defect is a promising approach in CF therapy. To date however only modest efficacy has been reported for correctors in clinical trials. We identified the marine sponge metabolite latonduine, as a corrector. We have now developed a series of latonduine derivatives that are more potent F508del-CFTR correctors with one (MCG315) having 10 fold increased corrector activity and an EC 50 of 72.25nM. We show that the latonduine analogues inhibit poly-ADP ribose polymerase (PARP) isozymes 1, 3 and 16. Further our molecular modeling studies point to the latonduine analogues binding to the PARP nicotinamide-binding domain. We established the relationship between the ability of the latonduine analogues to inhibit PARP 16 and their ability to correct F508del-CFTR trafficking. We show that latonduine can inhibit both PARP-3 & 16 and that this is necessary for CFTR correction. We demonstrate that latonduine triggers correction by regulating the unfolded protein response (UPR) activator, inositol-requiring enzyme (IRE-1) activity via modulation of the level of its ribosylation by PARP16 . These results establish latonduines novel site of action as well as its proteostatic mechanism of action. show that latonduine appears to work via the concerted inhibition of both PARP-3 and PARP-16 together. Upon focusing on PARP-16, we provide evidence for its site of action in the NAD binding pocket of PARP-16. We demonstrate the mechanism of action for CFTR correction by latonduine through its role in PARP-16 inhibition and modulation of IRE-1 activity in this correction. The structure activity relationship and modeling studies suggest pyrrole ring replacement with a simpler ring such as in binding in the NAD pocket of PARP-16. Such insights we believe will prove crucial in future rational structure based drug design. Together these results also open new areas of investigation; for example the role of IRE-1 modulation in CFTR rescue and provides a new tool for further studies of ER quality control in CF and other protein trafficking diseases.
Epigenome-wide association study (EWAS) on lipids: the Rotterdam Study matters

Background: DNA methylation is a key epigenetic mechanism that is suggested to be associated with blood lipid levels. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol in 725 participants of the Rotterdam Study, a population-based cohort study. Subsequently, we sought replication in a non-overlapping set of 760 participants. Results: Genome-wide methylation levels were measured in whole blood using the Illumina Methylation 450 array. Associations between lipid levels and DNA methylation beta values were examined using linear mixed-effect models. All models were adjusted for sex, age, smoking, white blood cell proportions, array number, and position on array. A Bonferroni-corrected p value lower than 1.08 × 10 − 7 was considered statistically significant. Five CpG sites annotated to genes including DHCR24 , CPT1A , ABCG1 , and SREBF1 were identified and replicated. Four CpG sites were associated with triglycerides, including CpG sites annotated to CPT1A (cg00574958 and cg17058475), ABCG1 (cg06500161), and SREBF1 (cg11024682). Two CpG sites were associated with HDL-C, including ABCG1 (cg06500161) and DHCR24 (cg17901584). No significant associations were observed with LDL-C or total cholesterol. Conclusions: We report an association of HDL-C levels with methylation of a CpG site near DHCR24 , a protein-coding gene involved in cholesterol biosynthesis, which has previously been reported to be associated with other metabolic traits. Furthermore, we confirmed previously reported associations of methylation of CpG sites within CPT1A , ABCG1 , and SREBF1 and lipids. These results provide insight in the mechanisms that are involved in lipid metabolism.
Hungary MORPHOLOGICAL AND REPRODUCTIVE TRAIT-VARIABILITY OF A FOOD DECEPTIVE ORCHID, CEPHALANTHERA RUBRA ALONG DIFFERENT

2019) Abstract. As climate change is forcing plant species to migrate northward and upward, it is important to know how species’ vegetative traits and reproductive success vary along different climatic conditions. We aimed to examine the impact of elevation on the morphological and reproductive characteristics of Cephalanthera rubra in four different altitudes in Hungary: in a lowland oak forest (103 m), and in the beech forests of the Bükk-mountains (361 m, 533 m, 657 m). We counted the number of leaves, flowers, and fruits, and measured the height of each plant with the length and width of all leaves. Linear, negative binomial, and quasipoisson regressions were used to compare the populations. Our study has shown that the lowland and mountain populations of C. rubra are sharply different regarding their life history strategy and reproductive success, and altitudinal effects can be found only in the mountain populations. The number of flowers depends strongly on the vegetative production (height and leaf area) of the plants, but at the same time, the area that facilitates greater vegetative production - possibly because it also facilitates species with better competitiveness, and it is less favorable to its mimicked partners - were less beneficial in terms of fruit
Vaccine-related toxicities based on the number of treated patients

Purpose: Phase I clinical trials are generally conducted to identify themaximum tolerated dose (MTD) or the biologically active dose (BAD) using a traditional dose-escalation design. This designmaynot be applied to cancer vaccines, given their unique mechanism of action. The FDA recently published "Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines. " However, many questions about the design of cancer vaccine studies remain unanswered. Experimental Design: We analyzed the toxicity profile in 239 phase I therapeutic cancer vaccine trials. We addressed the ability of dose escalation to determine the MTD or the BAD in trials that used a dose-
Modiﬁcation of Enroﬂoxacin Treatment Regimens for Poultry Experimentally Infected with Salmonella enterica Serovar Typhimurium DT104 To Minimize Selection of Resistance (cid:1)

We hypothesized that higher doses of ﬂuoroquinolones for a shorter duration could maintain efﬁcacy (as measured by reduction in bacterial count) while reducing selection in chickens of bacteria with reduced susceptibility. Chicks were infected with Salmonella enterica serovar Typhimurium DT104 and treated 1 week later with enroﬂoxacin at the recommended dose for 5 days (water dose adjusted to give 10 mg/kg of body weight of birds or equivalence, i.e., water at 50 ppm) or at 2.5 or 5 times the recommended dose for 2 days or 1 day, respectively. The dose was delivered continuously (ppm) or pulsed in the water (mg/kg) or by gavage (mg/kg). In vitro in sera, increasing concentrations of 0.5 to 8 (cid:1) g/ml enroﬂoxacin correlated with increased activity. In vivo, the efﬁcacy of the 1-day treatment was signiﬁcantly less than that of the 2- and 5-day treatments. The 2-day treatments showed efﬁcacy similar to that of the 5-day treatment in all but one repeat treatment group and signiﬁcantly
Functional Genomic Analysis of the AUXIN RESPONSE FACTOR Gene Family Members in Arabidopsis thaliana : Unique and Overlapping Functions of ARF7 and ARF19 W

a,6 The AUXIN RESPONSE FACTOR (ARF) gene family products, together with the AUXIN/INDOLE-3-ACETIC ACID proteins, regulate auxin-mediated transcriptional activation/repression. The biological function(s) of most ARFs is poorly understood. Here, we report the identiﬁcation and characterization of T-DNA insertion lines for 18 of the 23 ARF gene family members in Arabidopsis thaliana . Most of the lines fail to show an obvious growth phenotype except of the previously identiﬁed arf2 / hss , arf3 / ett , arf5 / mp , and arf7 / nph4 mutants, suggesting that there are functional redundancies among the ARF proteins. Subsequently, we generated double mutants. arf7 arf19 has a strong auxin-related phenotype not observed in the arf7 and arf19 single mutants, including severely impaired lateral root formation and abnormal gravitropism in both hypocotyl and root. Global gene expression analysis revealed that auxin-induced gene expression is severely impaired in the arf7 single and arf7 arf19 double mutants. For example, the expression of several genes, such as those encoding members of LATERAL ORGAN BOUNDARIES domain proteins and AUXIN-REGULATED GENE INVOLVED IN ORGAN SIZE , are disrupted in the double mutant. The data suggest that the ARF7 and ARF19 proteins play essential roles in auxin-mediated plant development by regulating both unique and partially overlapping sets of target genes. These observations provide molecular insight into the unique and overlapping functions of ARF gene family members in Arabidopsis.
High level synthesis:performance analysis and code optimization

With increasing FPGA chip density, it is possible to implement more sophisticated algorithms on FPGA. However, programming an FPGA using a register transfer level (RTL) language is timeconsuming and error-prone. To make use of the re-programmability of FPGAs for fast design space exploration and fast time-to-market it becomes more and more necessary to raise the abstraction level from structural design to behavioral design. High level synthesis (HLS) seems a promising solution for this issue. The sequential nature of C as input specification is an issue in HLS and code transformations are often necessary to produce better quality of results. The question is if HLS can compete with handwritten RTL designs, with regard to several performance metrics such as resource utilization, execution time and design time. If HLS can compete with handwritten RTL design, the question is which code transformations are required to achieve good quality of results. Using the HLS tools AutoESL and Synphony, two image processing kernels are benchmarked for an in-depth analysis of HLS performance. To avoid performance pitfalls by using only small toy examples, a real application called Fast Focus on Structures (FFoS) is ported to FPGA to investigate performance with regard to a comparable handwritten RTL design. The benchmarks using two image processing kernels have shown that it is possible to efficiently mimic a datapath from a reference manual RTL design. However, the analysis also shows that in HLS it is impossible to describe fine-grained interface and memory control. Both AutoESL and Synphony are capable of producing a design similar to the reference design. AutoESL requires 5% less flip flops and 4% more LUTs whereas Synphony requires 62% more flip flops and 61% more LUTs. Design time, for both tools, is reduced by a factor 6 and the latency stays within 2% of the reference. The explored code transformations, in combination with an existing algorithm classification and source-to-source compiler, are used to create a skeleton library for HLS to decrease design time by a factor 15 compared to handwritten RTL design. From the two HLS tools, AutoESL seems the most promising although Synphony might produce better results in a different application domain. Furthermore, it is shown that small modifications at behavioral level can have a large positive impact on the performance results without requiring time-consuming and error-prone RTL modifications. The code transformations show that in many cases tool specific code optimizations need to be done to achieve good results, making it debatable if it can be automated.
Chamber for Analysis of Neuron-to-Cell Spread and Axonal Transport of an AlphaHerpesvirus

: Alpha-herpesviruses, including herpes simplex virus and pseudorabies virus (PRV), infect the peripheral nervous system (PNS) of their hosts. Here, we describe an in vitro method for studying neuron-to-cell spread of infection as well as viral transport in axons. The method centers on a novel microfluidic chamber system that directs growth of axons into a fluidically isolated environment. The system uses substantially smaller amounts of virus inoculum and media than previous chamber systems and yet offers the flexibility of applying multiple virology and cell biology assays including live-cell optical imaging. Using PRV infection of cultured PNS neurons, we demonstrate that the microfluidic chamber recapitulates all known facets of neuron-to-cell spread demonstrated in animals and other compartmented cell systems. Abstract Alpha-herpesviruses, including herpes simplex virus and pseudorabies virus (PRV), infect the peripheral nervous system (PNS) of their hosts. Here, we describe an in vitro method for studying neuron-to-cell spread of infection as well as viral transport in axons. The method centers on a novel microfluidic chamber system that directs growth of axons into a fluidically isolated environment. The system uses substantially smaller amounts of virus inoculum and media than previous chamber systems and yet offers the flexibility of applying multiple virology and cell biology assays including live-cell optical imaging. Using PRV infection of cultured PNS neurons, we demonstrate that the microfluidic chamber recapitulates all known facets of neuron-to-cell spread demonstrated in animals and other compartmented cell systems.
Use of lithium tracers to quantify drilling ﬂ uid contamination for groundwater monitoring in Southeast Asia Applied Geochemistry

Drilling is widely used in groundwater monitoring and many other applications but has the inherent problem of introducing some degree of external contamination into the natural systems being moni-tored. Contamination from drilling ﬂ uid is particularly problematic for (i) wells with relatively low water ﬂ ow rates which are dif ﬁ cult to ﬂ ush; and for (ii) hydrogeochemical research studies of groundwaters hosted by incompletely consolidated shallow sediments, which are widely utilized as sources of drinking water and irrigation water across many parts of Asia. Here, we develop and evaluate a method that can be simply used to quantify the extent of drilling ﬂ uid contribution to a water sample either to optimize sample collection for reduced contamination, or to allow a correction for contamination to be made. We report the utility of lithium chloride tracers using both ﬁ eld and laboratory analytical techniques to quantitatively evaluate and correct for drilling ﬂ uid contamination of casing waters through an investigation of 15 sites in Kandal Province, Cambodia. High analytical errors limit the practicality and res- olution of ﬁ eld-based lithium ion selective electrode measurements for purposes other than broad estimates of gross contamination. However, when laboratory analysis is integrated with the method ( e.g. via inductively coupled plasma atomic emission spectrometry analysis), lithium tracers can provide a robust and accurate method for evaluating drilling-related contamination if appropriate samples are collected. Casing water is susceptible to contamination from drilling ﬂ uid which was shown to be signi ﬁ cantly reduced within two to three well volumes of ﬂ ushing but can still persist above background for greater than seven well volumes of ﬂ ushing. A waiting period well ﬂ ushing from relatively low and high permeability groundwater wells to further illustrate the technique.
Orientation Regulation of BiVO 4 by Self-Assembling of Surfactant with Enhanced Photocatalytic Activity

Herein, we demonstrate that the internal spontaneous polarization of BiVO 4 photocatalyst can be modulated by a homogeneous precipitation in the presence of Polyvinylpyrrolidone (PVP) at various concentrations to assist the orientation formation. XRD, SEM, Raman, and DRS were used to evaluate the crystal orientation of the as-synthesized BiVO 4 samples. XRD revealed that single- phase BiVO 4 samples can be synthesized in the presence of non-ionic polymer surfactant Polyvinylpyrrolidone (PVP). Raman spectra offered distinctive evidence that the sample synthesized has the shortest V-O bond length which led to the narrowest bandgap. The photoelectrochemical results revealed that there are decreasing in the electron-hole recombination rate as Electrochemical Impedance Spectroscopy (EIS) results and swelling of band pinning of the Fermi energy edge toward the negative direction according to Mott-Schottky (MS) curve. These observations demonstrated that the orientation of BiVO 4 and therefore the polarization can be regulated by the concentration of the coupling agent. The truncated Bipyramid like shape of BiVO 4 which created via the self- assembly owing effect PVP surfactant shows the best effect. These variations in the local structure orientation enhanced built-in electric field and therefore improved the photodegradation of Methylene Blue (MB) dye as a wastewater module.
Revisiting Mobility, Devices and Business Models A user-centric perspective

— Given the array of devices now available to users, how can one make sense of the evolution of user-side mobility? The purpose of this paper is to revisit mobility from a user-centric perspective. We use a mixed methods approach based on action research and case studies. We find that mobility’s pervasiveness leads to changes in habits that have a profound effect on devices and business models. We conclude by looking into possible directions for new advances in light of the present research and recent trends in the IT industry.
Collaborative 3D Terrain Editing Application

In 3D content creation, developing a terrain may be time consuming due to most of current 3D applications require a vast terrain. In this paper, we introduce a collaborative terrain editor that allows multiple users to collaborate in real time. The objective of the application is to increase the productivity in developing a vast terrain in 3D environment. The application is based on a client server architecture where each editor applications are connected to a single server that collects and distributes the editing process done by each user. We perform our test in a local area network environment with multiple clients connected to a server and observe the performance and the usability of the software. The test results show the system is capable to perform real-time collaborative terrain editing with insignificant delay. More-over, most of our users agree that using the system may increase the speed in 3D terrain creation.
Replication During Immune Activation Lacking Activation Markers Support HIV T Cells + Nonproliferating Bystander CD4

HIV replicates primarily in lymphoid tissue and immune activation is a major stimulus in vivo. To determine the cells responsible for HIV replication during Ag-driven T cell activation, we used a novel in vitro model employing dendritic cell presentation of superantigen to CD4 1 T cells. Dendritic cells and CD4 1 T cells are the major constituents of the paracortical region of lymphoid organs, the main site of Ag-speciﬁc activation and HIV replication. Unexpectedly, replication occurred in nonproliferating bystander CD4 1 T cells that lacked activation markers. In contrast, activated Ag-speciﬁc cells were relatively protected from infection, which was associated with CCR5 and CXC chemokine receptor 4 down-regulation. The ﬁnding that HIV replication is not restricted to highly activated Ag-speciﬁc CD4 1 T cells has implications for therapy, efforts to eradicate viral reservoirs, immune control of HIV, and Ag-speciﬁc immune defects. The Journal of Immunology, 2001, 166: 6437–6443.
Survey of VLSI Test Data Compression Methods

It has been seen that the test data compression has been an emerging need of VLSI field and hence the hot topic of research for last decade. Still there is a great need and scope for further reduction in test data volume. This reduction may be lossy for output side test data but must be lossless for input side test data. This paper summarizes the different methods applied for lossless compression of the input side test data, starting with simple code based methods to combined/hybrid methods. The basic goal here is to prepare survey on current methodologies applied for test data compression and prepare a platform for further development in this avenue.
CLEP_A_270249 1269..1279

1AmbuFlex/WestChronic, Occupational Medicine, University Research Clinic, Aarhus University, Herning, Denmark; 2Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 3Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Background: Knowledge about the long-term course of health following stroke is sparse and relies mainly on studies with short follow-up or few measurements per patient. We aimed to describe the course and analyze the determinants of the course of physical and mental health status after stroke with repeated measurements in a large population-based cohort of first time Danish stroke patients. Methods: We followed 2,414 first time stroke patients admitted to any hospital in the Central Denmark Region, Denmark, between October 1, 2008 and January 1, 2012, with five questionnaires over a 2 years period. Self-rated health was assessed by the SF-12 instrument. Information on possible clinical and patient-related determinants of self-rated health was obtained from questionnaires and national registers. The scores were analyzed at five selected fixed time-points and as well as longitudinally with mixed models. Results: The SF-12 mental component summary score (MCS) increased with 0.89 points/ year (95% CI=0.6–1.2), while the increase in the physically component summary score (PCS) did not reach statistical significance (0.13/year; 95% CI=−0.2–0.5). The most pronounced changes were seen in the Vitality and Role Physical SF-12 subscales, which both increased by 2.1 points/year. No statistically significant changes over time were found in the Physical Functioning and Bodily Pain subscales. Variables associated with increasing selfrated mental health (MCS) were no comorbidity, older age, male gender, and mild stroke severity. Variables associated with increasing ratings of physical health (PCS) were mild stroke severity, no comorbidity, higher educational level, and younger age. The negative impact of age increased significantly with time during the follow-up period for physical as well as mental health, while the effects of the other variables were stable over time. The results were similar in the two analytical approaches. Conclusion: In a large, geographically well-defined population of first time stroke patients, the majority of SF-12 sub-scales and the mental component score improved slightly over time. Small improvements in self-rated mental health may be observed during the first 2 years after the stroke. Stroke is a disease with long-term consequences on a wide range of health aspects. Level as well as course differ between sub-groups, and treatment of comorbidity may be an important target with respect to rehabilitation.