Miracle-dz/UniFAR-FTUs huggingface dataset:
Proteasome ubiquitin receptor PSMD4 is an amplification target in breast cancer and may predict sensitivity to PARPi

Poly (ADP‐ribose) polymerase 1 (PARP1) is an enzyme involved in DNA repair under investigation as a chemotherapeutic target. Current randomized phase three trials of PARPi in metastatic breast cancer are limited to patients with documented BRCA1/2 mutations and no biomarker of PARPi beyond BRCA status is available. In an effort to identify novel biomarkers for PARP inhibition, we created a cell line (HCC1187/TALRES) resistant to the PARP1 inhibitor talazoparib. Herein we show by array‐CGH that HCC1187/TALRES has a selective loss of the proteasome ubiquitin receptor PSMD4 amplicon resulting in significant down‐regulation of PSMD4. Conversely, we find that breast cancer cell lines that have copy number gain or amplification for PSMD4 are significantly more sensitive to talazoparib. Functional studies reveal that knock‐down of PSMD4 in amplified breast cancer cells and loss of the PSMD4 amplicon result in knock‐down of PARP1 protein. We show that PSMD4 is amplified and overexpressed in breast cancer and its overexpression correlates with poor survival. Knock‐down of PSMD4 results in a significant decrease in cell growth. We provide evidence that PSMD4 is a proteasomal amplification target in breast cancer that PSMD4 amplification confers sensitivity to PARP inhibition, and that PSMD4 amplification is lost in the process of acquiring resistance to PARPi. Finally, this study shows not only that PSMD4 copy number correlates with PARPi sensitivity, but also, that it may be a better predictor of sensitivity to PARPi than BRCA1/2 mutation.
Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

Accurately predicting protein-ligand binding is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the domi-nant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increas-ingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC)
Excess free fructose, high-fructose corn syrup and adult asthma: the Framingham Offspring Cohort

Abstract There is growing evidence that intakes of high-fructose corn syrup (HFCS), HFCS-sweetened soda, fruit drinks and apple juice – a high-fructose 100 % juice – are associated with asthma, possibly because of the high fructose:glucose ratios and underlying fructose malabsorption, which may contribute to enteral formation of pro-inflammatory advanced glycation end products, which bind receptors that are mediators of asthma. Cox proportional hazards models were used to assess associations between intakes of these beverages and asthma risk, with data from the Framingham Offspring Cohort. Diet soda and orange juice – a 100 % juice with a 1:1 fructose:glucose ratio – were included for comparison. Increasing intake of any combination of HFCS-sweetened soda, fruit drinks and apple juice was significantly associated with progressively higher asthma risk, plateauing at 5–7 times/week v. never/seldom, independent of potential confounders (hazard ratio 1·91, P<0·001). About once a day consumers of HFCS-sweetened soda had a 49 % higher risk (P<0·011), moderate apple juice consumers (2–4 times/week) had a 61 % higher risk (P<0·007) and moderate fruit drink consumers had a 58 % higher risk (P<0·009), as compared with never/seldom consumers. There were no associations with diet soda/orange juice. These associations are possibly because of the high fructose:glucose ratios, and fructose malabsorption. Recommendations to reduce consumption may be inadequate to address asthma risk, as associations are evident even with moderate intake of these beverages, including apple juice – a 100 % juice. The juice reductions in the US Special Supplemental Nutrition Program for Women, Infants, and Children in 2009, and the plateauing/decreasing asthma prevalence (2010–2013), particularly among non-Hispanic black children, may be related. Further research regarding the consequences of fructose malabsorption is needed.
Effects of ionic channel antagonists barium, cesium, and UL-FS-49 on vagal slowing of atrial rate in dogs.

In response to a brief vagal stimulus, the atrial rate initially slows, then transiently accelerates, and slows a second time. We determined the effects of three antagonists to two ionic channels on this characteristic triphasic pacemaker response. Brief bursts of vagal stimulation were delivered to anesthetized dogs, and atrial cycle lengths were recorded. Either barium, cesium, or UL-FS-49 was administered. Barium, which primarily blocks the acetylcholine-sensitive potassium current ( I K,ACh), attenuated the initial vagally induced bradycardia by >50% without affecting the subsequent acceleration or the secondary slowing. Cesium and UL-FS-49 [both of which primarily block the pacemaker current ( I f)] did not affect the initial vagal slowing of atrial rate but abolished the acceleratory portion of the response. The secondary slowing was abolished by cesium but not by UL-FS-49. We conclude that the initial rapid atrial response to acetylcholine is mediated mainly by the I K,ACh, with little contribution from the I f. The subsequent acceleration is mediated by activation of the I f.
Stabilizers as a design tool for new forms of the Lechner-Hauke-Zoller annealer

A new formalism to understand a novel class of quantum annealing devices and new designs obtained using the formalism. In a recent paper, Lechner, Hauke, and Zoller (LHZ) described a means to translate a Hamiltonian of N spin-1/2 particles with “all-to-all” interactions into a larger physical lattice with only on-site energies and local parity constraints. LHZ used this mapping to propose a novel form of quantum annealing. We provide a stabilizer-based formulation within which we can describe both this prior approach and a wide variety of variants. Examples include a triangular array supporting all-to-all connectivity as well as arrangements requiring only 2N or N log N spins but providing interesting bespoke connectivities. Further examples show that arbitrarily high-order logical terms can be efficiently realized, even in a strictly two-dimensional layout. Our stabilizers can correspond to either even-parity constraints, as in the LHZ proposal, or odd-parity constraints. Considering the latter option applied to the original LHZ layout, we note that it may simplify the physical realization because the required ancillas are only spin-1/2 systems (that is, qubits rather than qutrits); moreover, the interactions are very simple. We make a preliminary assessment of the impact of these design choices by simulating small (few-qubit) systems; we find some indications that the new variant may maintain a larger minimum energy gap during the annealing process.
Patterning artificial lipid bilayer on nanostructured surfaces

Artificial lipid bilayer on solid substrate plays an important role as an interface between nanotechnology and biology. In this study, grid structures were patterned on Au-Nb-glass substrate and artificial bilayer was prepared on these structures. The fluidity was checked using fluorescence recovery after photobleaching (FRAP), and neuronal adhesion was monitored on such structure using EphrinA5-tethered lipid bilayer. EphrinA5 is a ligand that binds to the Eph receptors of rat cortical neurons and influences cellular adhesion. Our result elucidated that influence of these nanopatterned protein-tethered lipid bilayer on cellular guidance and signaling can address many underlying mechanisms of cellular functioning and help us to understand and differentiate the signaling procedure in cancer and neurodegenerative diseases.
Automatic calibration of multi-modal sensor systems using a gradient orientation measure

A novel technique for calibrating a multi-modal sensor system has been developed. Our calibration method is based on the comparative alignment of output gradients from two candidate sensors. The algorithm is applied to the calibration of the extrinsic parameters of several camera-lidar systems. In this calibration the lidar scan is projected onto the camera's image using a camera model. Particle swarm optimization is used to find the optimal parameters for this model. This method requires no markers to be placed in the scene. While the system can use a set of scans, unlike many existing techniques it can also automatically calibrate the system reliably using a single scan. The method presented is successfully validated on a variety of cameras, lidars and locations. It is also compared to three existing techniques and shown to give comparable or superior results on the datasets tested.
Flow cytometric measurement of microparticles: Pitfalls and protocol modifications

Upon activation, many cells shed components of their plasma membranes as microparticles. Depending on the methods of preparation and analyses, microparticle counts may vary significantly between laboratories, making data analyses and clinical correlations challenging. To assess how variations in sample preparation affect microparticle measurements, blood samples from 13 healthy, adult volunteers were labeled with Annexin V, cell-specific antibodies, and antibodies against tissue factor (TF). Data were acquired and analysed using an EPICS XL-MCL flow cytometer. Annexin V+ monocyte-, platelet-, endothelial-, or erythrocyte-derived microparticles accounted for 10.4%, 38.5%, 43.8%, and 7.3% of the total number of microparticles (13.7 ± 3.0 × 103/ml of whole blood), respectively. A similar distribution of cell types was seen for TF+ microparticles (6.3 ± 2.6 × 103/ml of whole blood). No statistical difference was noted in microparticle distribution using either 19- or 21-gauge needles. Elevated levels of platelet- and erythrocyte-derived microparticles were detected in heparin and PPACK-anticoagulated samples as compared to samples anticoagulated with ACD or sodium citrate (P < 0.05, student's t-test). Additional centrifugation was critical for removing platelet contamination, which significantly affected microparticle counts. Finally, Annexin V+ and TF+ microparticles were significantly reduced upon sample storage at low temperatures. Microparticle levels are significantly affected by variations in sample preparation and storage. These results illustrate the need to standardize assay protocols in order to obtain consistent measurements. Our studies further optimize sample preparation for microparticle detection.
Antibody detection by agglutination–PCR (ADAP) enables early diagnosis of HIV infection by oral fluid analysis

Significance There is a substantial public health interest in identifying HIV-infected individuals through population-based screening. Oral fluid (OF) is easier to collect than blood and therefore ideal for such screening efforts. Unfortunately, OF has a very low concentration of anti-HIV antibodies (markers of HIV infection), which current assays cannot detect during the early stage of this disease. Here we report an assay for anti-HIV antibodies in OF that is up to 10,000 times more sensitive than current alternatives. This assay, called Antibody Detection by Agglutination–PCR (ADAP), could be broadly deployed to screen at-risk populations using OF in many settings, including those where cold chain shipping is not available (low-resource settings) and where needles are inconvenient (pediatrics) or unsafe (prisons). Oral fluid (OF) is a highly effective substrate for population-based HIV screening efforts, as it is noninfectious and significantly easier to collect than blood. However, anti-HIV antibodies are found at far lower concentrations in OF compared with blood, leading to poor sensitivity and a longer period of time from infection to detection threshold. Thus, despite its inherent advantages in sample collection, OF is not widely used for population screening. Here we report the development of an HIV OF assay based on Antibody Detection by Agglutination–PCR (ADAP) technology. This assay is 1,000–10,000 times more analytically sensitive than clinical enzyme-linked immunoassays (EIAs), displaying both 100% clinical sensitivity and 100% specificity for detecting HIV antibodies within OF samples. We show that the enhanced analytical sensitivity enables this assay to correctly identify HIV-infected individuals otherwise missed by current OF assays. We envision that the attributes of this improved HIV OF assay can increase testing rates of at-risk individuals while enabling diagnosis and treatment at an earlier time point.
Built-in self-test for GHz embedded SRAMs using flexible pattern generator and new repair algorithm

This paper presents a built-in self-test (BIST) scheme, which consists of a flexible pattern generator and a practical on-macro two-dimensional redundancy analyzer, for GHz embedded SRAMs. In order to meet the system requirements and to detect a wide variety of faults or performance degradation resulting from recent technology advances, the microcode-based pattern generator can generate flexible patterns. A practical new repair algorithm for the Finite State Machine (FSM)-based on-macro redundancy analyzer is also presented. It can be implemented with simple hardware and can show fairly good performance compared with conventional software-based algorithms.
Interaction between the moss Physcomitrella patens and Phytophthora: a novel pathosystem for live‐cell imaging of subcellular defence

Live‐cell imaging of plant–pathogen interactions is often hampered by the tissue complexity and multicell layered nature of the host. Here, we established a novel pathosystem with the moss Physcomitrella patens as host for Phytophthora. The tip‐growing protonema cells of this moss are ideal for visualizing interactions with the pathogen over time using high‐resolution microscopy. We tested four Phytophthora species for their ability to infect P. patens and showed that P. sojae and P. palmivora were only rarely capable to infect P. patens. In contrast, P. infestans and P. capsici frequently and successfully penetrated moss protonemal cells, showed intracellular hyphal growth and formed sporangia. Next to these successful invasions, many penetration attempts failed. Here the pathogen was blocked by a barrier of cell wall material deposited in papilla‐like structures, a defence response that is common in higher plants. Another common response is the upregulation of defence‐related genes upon infection and also in moss we observed this upregulation in tissues infected with Phytophthora. For more advanced analyses of the novel pathosystem we developed a special set‐up that allowed live‐cell imaging of subcellular defence processes by high‐resolution microscopy. With this set‐up, we revealed that Phytophthora infection of moss induces repositioning of the nucleus, accumulation of cytoplasm and rearrangement of the actin cytoskeleton, but not of microtubules.
SYNTHESIS OF Ca3Co4O9 AND CuAlO2 CERAMICS OF THERMOELECTRIC APPLICATION USING A REACTION-SINTERING PROCESS

Synthesis of Ca3Co4O9 and CuAlO2 ceramics for thermoelectric application using a reaction-sintering process were investigated in this study. Without any calcination involved, the mixture of raw materials was pressed and sintered directly. Decomposition of Ca3Co4O9 at 926 o C limited a sintering temperature above 926 o
Distributed component technologies and their software engineering implications

In this state-of-the-art report, we review advances in distributed component technologies, such as the Enterprise JavaBeans (EJB) specification and the CORBA component model (CCM). We assess the state of industrial practice in the use of distributed components. We show several architectural styles for whose implementation distributed components have been used successfully. We review the use of iterative and incremental development processes and the notion of a model-driven architecture. We then assess the state of the art in research into novel software engineering methods and tools for the modelling, reasoning and deployment of distributed components. The open problems identified during this review result in the formulation of a research agenda that will contribute to the systematic engineering of distributed systems based on component technologies.
Transcript Profiling Identifies NAC-Domain Genes Involved in Regulating Wall Ingrowth Deposition in Phloem Parenchyma Transfer Cells of Arabidopsis thaliana

Transfer cells (TCs) play important roles in facilitating enhanced rates of nutrient transport at key apoplasmic/symplasmic junctions along the nutrient acquisition and transport pathways in plants. TCs achieve this capacity by developing elaborate wall ingrowth networks which serve to increase plasma membrane surface area thus increasing the cell's surface area-to-volume ratio to achieve increased flux of nutrients across the plasma membrane. Phloem parenchyma (PP) cells of Arabidopsis leaf veins trans-differentiate to become PP TCs which likely function in a two-step phloem loading mechanism by facilitating unloading of photoassimilates into the apoplasm for subsequent energy-dependent uptake into the sieve element/companion cell (SE/CC) complex. We are using PP TCs in Arabidopsis as a genetic model to identify transcription factors involved in coordinating deposition of the wall ingrowth network. Confocal imaging of pseudo-Schiff propidium iodide-stained tissue revealed different profiles of temporal development of wall ingrowth deposition across maturing cotyledons and juvenile leaves, and a basipetal gradient of deposition across mature adult leaves. RNA-Seq analysis was undertaken to identify differentially expressed genes common to these three different profiles of wall ingrowth deposition. This analysis identified 68 transcription factors up-regulated two-fold or more in at least two of the three experimental comparisons, with six of these transcription factors belonging to Clade III of the NAC-domain family. Phenotypic analysis of these NAC genes using insertional mutants revealed significant reductions in levels of wall ingrowth deposition, particularly in a double mutant of NAC056 and NAC018, as well as compromised sucrose-dependent root growth, indicating impaired capacity for phloem loading. Collectively, these results support the proposition that Clade III members of the NAC-domain family in Arabidopsis play important roles in regulating wall ingrowth deposition in PP TCs.
Enhancing Tor's performance using real-time traffic classification

Tor is a low-latency anonymity-preserving network that enables its users to protect their privacy online. It consists of volunteer-operated routers from all around the world that serve hundreds of thousands of users every day. Due to congestion and a low relay-to-client ratio, Tor suffers from performance issues that can potentially discourage its wider adoption, and result in an overall weaker anonymity to all users. We seek to improve the performance of Tor by defining different classes of service for its traffic. We recognize that although the majority of Tor traffic is interactive web browsing, a relatively small amount of bulk downloading consumes an unfair amount of Tor's scarce bandwidth. Furthermore, these traffic classes have different time and bandwidth constraints; therefore, they should not be given the same Quality of Service (QoS), which Tor offers them today. We propose and evaluate DiffTor, a machine-learning-based approach that classifies Tor's encrypted circuits by application in real time and subsequently assigns distinct classes of service to each application. Our experiments confirm that we are able to classify circuits we generated on the live Tor network with an extremely high accuracy that exceeds 95%. We show that our real-time classification in combination with QoS can considerably improve the experience of Tor clients, as our simple techniques result in a 75% improvement in responsiveness and an 86% reduction in download times at the median for interactive users.
What is an acceptable false negative rate in the detection of prostate cancer?

Background In prostate cancer (PCa) screening men and their physicians aim to rule out the presence of potentially life threatening PCa. To date, prostate specific antigen (PSA) testing and systematic prostate biopsy (Bx)—in case of an elevated PSA—are still the main modes of PCa detection. Often uncertainty remains when a PSA-test is <3.0 ng/mL or a Bx shows a benign result, leading to the continuous repeating of procedures. Here we assess the potential consequences of false negatives by studying follow-up data of a purely PSA-based approach with applying sextant Bx, an approach considered to have a high risk of missing PCa diagnosis. Methods Our study population consisted of 19,970 men from the ERSPC project section Rotterdam, initially screened in 1993–1999. We assessed clinically significant Gleason ≥3+4 PCa (csPCa) diagnosis within the 4-year screening interval and subsequent screening round 4 years later in men having a PSA <3.0 ng/mL at initial screening (no Bx) and men with Bx (PSA >3.0 ng/mL), but no PCa detected at that time. In addition, we addressed PCa mortality and PCa diagnosis for men with a negative PSA test and negative Bx, who were retested every 4 years covering a 15-year follow-up. Results A total of 14,935 men had PSA <3.0 ng/mL in the initial screening round, of whom 75 (0.5%) were diagnosed with csPCa at a subsequent screening examination and 2 (<0.1%) in the 4-year screening interval. For 2,260 men with a previously negative Bx at first screening, the figures were 17 (0.8%) and 2 (0.1%) respectively. Indolent PCa (Gleason ≤3+3) was diagnosed in 312 (2%) men with PSA <3.0 ng/mL initially and 115 (5%) men with initial negative Bx. After a 15-year follow-up, 45 (0.3%) PCa deaths occurred in men with initially low PSA, and 29 men (0.2%) had metastasis. For men with negative Bx, 11 (0.5%) PCa deaths occurred and 4 (0.2%) experienced metastasis. Conclusions The false negative rates for men with PSA <3.0 ng/mL and negative sextant Bx are extremely low but not negligible. Proper risk stratification before deciding to biopsy is expected to hardly miss any clinical significant PCa diagnosis. This is especially relevant with the increased use of the relatively expensive multi-parametric magnetic resonance imaging (mpMRI) guided targeted Bx procedures.
Therapeutic efficacy of renin—angiotensin blockade in patients receiving dialysis

Observational data in dialysis patients has indicated an increased cardiovascular mortality. One pathophysiological cause of this cardiovascular mortality in these patients is volume overload. In addition, an inappropriately activated renin—angiotensin system (RAS) has been proposed as another possible mechanism for the increased cardiovascular mortality. With these possible causes in mind, blockade of the RAS with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) have both emerged as means of preventing cardiovascular events in this population. This review focuses on clinical evidence of the beneficial effects of ACE inhibitors and ARBs in dialysis patients with regard to the improvement of cardiovascular events as well as blood pressure control and maintenance of dialysis therapy.