Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of Dynamics in the Autoinhibition and Activation of the Exchange Protein Directly Activated by Cyclic AMP (EPAC)*

The exchange protein directly activated by cAMP (EPAC) is a key receptor of cAMP in eukaryotes and controls critical signaling pathways. Currently, no residue resolution information is available on the full-length EPAC dynamics, which are known to be pivotal determinants of allostery. In addition, no information is presently available on the intermediates for the classical induced fit and conformational selection activation pathways. Here these questions are addressed through molecular dynamics simulations on five key states along the thermodynamic cycle for the cAMP-dependent activation of a fully functional construct of EPAC2, which includes the cAMP-binding domain and the integral catalytic region. The simulations are not only validated by the agreement with the experimental trends in cAMP-binding domain dynamics determined by NMR, but they also reveal unanticipated dynamic attributes, rationalizing previously unexplained aspects of EPAC activation and autoinhibition. Specifically, the simulations show that cAMP binding causes an extensive perturbation of dynamics in the distal catalytic region, assisting the recognition of the Rap1b substrate. In addition, analysis of the activation intermediates points to a possible hybrid mechanism of EPAC allostery incorporating elements of both the induced fit and conformational selection models. In this mechanism an entropy compensation strategy results in a low free-energy pathway of activation. Furthermore, the simulations indicate that the autoinhibitory interactions of EPAC are more dynamic than previously anticipated, leading to a revised model of autoinhibition in which dynamics fine tune the stability of the autoinhibited state, optimally sensitizing it to cAMP while avoiding constitutive activation.
Swept GNSS jamming mitigation through pulse blanking

Global Navigation Satellite System (GNSS) jammers generally broadcast frequency modulated signals which are instantaneously narrow band and can sweep several tens of MHz in few microseconds. The frequency band swept by a jamming signal can be significantly larger than the input bandwidth of the victim receiver. In this way, the jamming signal is significantly filtered and periodically enters and exits the receiver bandwidth. As a result, the jamming signal is perceived by the GNSS receiver as a form of pulsed interference. In this paper, Pulse Blanking (PB) is proposed as an effective tool for mitigating the impact of jamming on narrow band GNSS receivers. Several experiments involving real jamming signals have been conducted and the benefits of PB are empirically investigated. Finally, a real-time demonstration of PB in the presence of jamming is provided: PB is a low-complexity technique which can significantly improve the performance of a GNSS receiver even in the presence of strong jamming signals.
Progression of white matter lesions and hemorrhages in cerebral amyloid angiopathy

Objective: To determine the rate of progression of white matter lesions and hemorrhages in a cohort with cerebral amyloid angiopathy (CAA). Methods: The authors analyzed data from 26 patients with possible (3) or probable (23) CAA, diagnosed by the Boston Criteria. Brain maps of white matter hyperintensities, normalized to head size (nWMH), were created by blinded computer-assisted segmentation of MRI images obtained at baseline and after a median follow-up interval of 1.1 year. Results: There was a substantial nWMH volume increase over the interscan interval (median 0.5 mL/year, interquartile range 0.1 to 2.8, p < 0.001). The median yearly increase, expressed as a percentage of the baseline WMH volume, was 18%. The characteristic most strongly associated with nWMH volume increase was the baseline nWMH volume (r = 0.57, p = 0.002). The volume of nWMH progression was also associated with history of cognitive impairment (median 5.0 mL/year in cognitively impaired subjects vs 0.3 mL/year in cognitively unimpaired, p = 0.02) but not age or hypertension. This association remained present in an analysis stratified by baseline WMH volume. New hemorrhages, including asymptomatic microbleeds, were seen in 46% of subjects. The number of new MRI hemorrhages correlated strongly with baseline nWMH (r = 0.53, p = 0.005) but not with nWMH progression (r = 0.22, p = 0.28). Conclusions: There is a progressive increase in white matter lesions in subjects with cerebral amyloid angiopathy. The association of white matter lesions with incident lobar hemorrhages suggests that white matter damage may reflect a progressive microangiopathy due to cerebral amyloid angiopathy.
Strategy sequential difficulty effects in Alzheimer patients: A study in arithmetic

Objective: Consistent with Uittenhove and Lemaire (2012), we expected that strategy execution would be slower following execution of a difficult strategy than after an easy strategy (strategy sequential difficulty, SSD, effects). Moreover, we expected larger SSD effects in older adults than in young adults, and especially in Alzheimer's disease (AD) patients, a population with marked cognitive impairments. Method: A total of 25 young and older (41 AD and 25 healthy) adults were asked to execute rounding strategies to solve arithmetic problems (e.g., solving 43 + 68 by rounding operands down or up, e.g., 40 + 70 = 110). We measured solution latencies and percentage errors with a strategy as a function of the difficulty of the just-executed strategy. Results: Solution latencies were significantly shorter following the easier rounding-down strategy than following the harder rounding-up strategy, F(2, 156) = 35.8. Moreover, this effect was significantly larger in AD patients, F(1, 78) = 117.4. Conclusions: We found comparable SSD effects in young and healthy older adults but dramatically increased SSD effects in AD patients. This has implications to further our understanding of strategic aspects underlying decreased cognitive functioning in AD patients.
Quantitative Analysis of Small-Subunit rRNA Genes in Mixed Microbial Populations via 5′-Nuclease Assays

ABSTRACT Few techniques are currently available for quantifying specific prokaryotic taxa in environmental samples. Quantification of specific genotypes has relied mainly on oligonucleotide hybridization to extracted rRNA or intact rRNA in whole cells. However, low abundance and cellular rRNA content limit the application of these techniques in aquatic environments. In this study, we applied a newly developed quantitative PCR assay (5′-nuclease assay, also known as TaqMan) to quantify specific small-subunit (SSU) rRNA genes (rDNAs) from uncultivated planktonic prokaryotes in Monterey Bay. Primer and probe combinations for quantification of SSU rDNAs at the domain and group levels were developed and tested for specificity and quantitative reliability. We examined the spatial and temporal variations of SSU rDNAs from Synechococcus plusProchlorococcus and marine Archaea and compared the results of the quantitative PCR assays to those obtained by alternative methods. The 5′-nuclease assays reliably quantified rDNAs over at least 4 orders of magnitude and accurately measured the proportions of genes in artificial mixtures. The spatial and temporal distributions of planktonic microbial groups measured by the 5′-nuclease assays were similar to the distributions estimated by quantitative oligonucleotide probe hybridization, whole-cell hybridization assays, and flow cytometry.
Open Innovation and Social Big Data for Sustainability: Evidence from the Tourism Industry

This paper aims to contribute to the debate on Open Innovation in the age of Big Data by shedding new light on the role that social networks can play as enabling platforms for tourists’ involvement and sources for the creation and management of valuable knowledge assets. The huge amount of data generated on social media by tourists related to their travel experiences can be a valid source of open innovation. To achieve this aim, this paper presents evidence of a digital tourism experience, through a longitudinal case study of a destination in Apulia, a Southern European region. The findings of the study demonstrate how social Big Data could open up innovation processes that could be of support in defining sustainable tourism experiences in a destination.
Innovation Motives in Family Firms: A Transgenerational View

Drawing on the transgenerational entrepreneurship perspective, we employ a multiple case study approach to investigate why multigenerational family firms innovate. The data collection process drew upon five in-depth cases comprising 42 semistructured interviews, 25 participant observations, and several thousand pages of historical data dating from 1916 to 2017. We find patterns on how the firms’ long-term view—embracing both the past and the future—influences the innovation motives of these firms. Specifically, we identify three innovation patterns: conserving, persisting and legacy-building. We introduce a set of propositions and a framework linking long-term orientation dimensions to innovation motives and innovation outcomes. Our research thus contributes to a more fine-grained understanding of innovation behavior in family firms.
A Family of Five-Level Dual-Buck Full-Bridge Inverters for Grid-Tied Applications

Dual-buck inverters feature some attractive merits, such as no reverse recovery issues of the body diodes and free of shoot-through. However, since the filter inductors of dual-buck inverters operate at each half cycle of the utility grid alternately, the inductor capacity of dual-buck inverters is twice as much as H-bridge inverters. Thus, the power density of dual-buck converters needs to be improved, as well as the conversion efficiency. In this paper, the detailed derivation process of two five-level full-bridge topology generation rules are presented and explained. One is the combination of a conventional three-level full-bridge inverter, a two-level capacitive voltage divider, and a neutral point clamped branch. The other method is to combine a three-level half-bridge inverter and a two-level half-bridge inverter. Furthermore, in order to enhance the reliability of existing five-level DBFBI topologies, an extended five-level DBFBI topology generation method is proposed. The two-level half-bridge inverter is replaced by a two-level dual-buck half-bridge inverter; thus, a family of five-level DBFBI topologies with high reliability is proposed. The operation modes, modulation methods, and control strategies of the series-switch five-level DBFBI topology are analyzed in detail. The power device losses of the three-level DBFBI topology and five-level DBFBI topologies, with different switching frequencies, are calculated and compared. Both the relationship between the neutral point potential self-balancing and the modulation index of inverters are revealed. A universal prototype was built up for the experimental tests of the three-level DBFBI topology, the five-level H-bridge inverter topology, and the existing three five-level DBFBI topologies. Experimental results have shown that the five-level DBFBI topologies exhibit higher efficiency than the five-level H-bridge inverter topology and the three-level DBFBI topology. As well, the higher power density has been achieved by the five-level DBFBI topologies compared with the three-level DBFBI topology.
The Multisubstrate Adapter Gab1 Regulates Hepatocyte Growth Factor (Scatter Factor)–c-Met Signaling for Cell Survival and DNA Repair

ABSTRACT Hepatocyte growth factor (scatter factor) (HGF/SF) is a pleiotrophic mediator of epithelial cell motility, morphogenesis, angiogenesis, and tumorigenesis. HGF/SF protects cells against DNA damage by a pathway from its receptor c-Met to phosphatidylinositol 3-kinase (PI3K) to c-Akt, resulting in enhanced DNA repair and decreased apoptosis. We now show that protection against the DNA-damaging agent adriamycin (ADR; topoisomerase IIα inhibitor) requires the Grb2-binding site of c-Met, and overexpression of the Grb2-associated binder Gab1 (a multisubstrate adapter required for epithelial morphogenesis) inhibits the ability of HGF/SF to protect MDCK epithelial cells against ADR. In contrast to Gab1 and its homolog Gab2, overexpression of c-Cb1, another multisubstrate adapter that associates with c-Met, did not affect protection. Gab1 blocked the ability of HGF/SF to cause the sustained activation of c-Akt and c-Akt signaling (FKHR phosphorylation). The Gab1 inhibition of sustained c-Akt activation and of cell protection did not require the Gab1 pleckstrin homology or SHP2 phosphatase-binding domain but did require the PI3K-binding domain. HGF/SF protection of parental MDCK cells was blocked by wortmannin, expression of PTEN, and dominant negative mutants of p85 (regulatory subunit of PI3K), Akt, and Pak1; the protection of cells overexpressing Gab1 was restored by wild-type or activated mutants of p85, Akt, and Pak1. These findings suggest that the adapter Gab1 may redirect c-Met signaling through PI3K away from a c-Akt/Pak1 cell survival pathway.
A distortion model for pipeline Analog-to-Digital converters

Pipeline analog-to-digital converters (ADC) are widely used to achieve high resolution and moderately high sampling frequency. In typical implementations, linearity is often limited by capacitor mismatch and finite amplifier gain. The impact of these non ideal effects on the overall linearity of the ADC has been addressed in this paper, obtaining a model to estimate total harmonic distortion (THD), given capacitors' sizing and amplifiers' gain. This model enables the designer to analyze the impact of error sources in each stage separately, and to perform Monte Carlo simulations. In this way, design rules can be obtained to properly size each multiplying digital-to-analog converter (MDAC) in the first stages of the design process.
Mutational analysis of VAMP domains implicated in Ca2+‐induced insulin exocytosis.

Vesicle‐associated membrane protein‐2 (VAMP‐2) and cellubrevin are associated with the membrane of insulin‐containing secretory granules and of gamma‐aminobutyric acid (GABA)‐containing synaptic‐like vesicles of pancreatic beta‐cells. We found that a point mutation in VAMP‐2 preventing targeting to synaptic vesicles also impairs the localization on insulin‐containing secretory granules, suggesting a similar requirement for vesicular targeting. Tetanus toxin (TeTx) treatment of permeabilized HIT‐T15 cells leads to the proteolytic cleavage of VAMP‐2 and cellubrevin and causes the inhibition of Ca2+‐triggered insulin exocytosis. Transient transfection of HIT‐T15 cells with VAMP‐1, VAMP‐2 or cellubrevin made resistant to the proteolytic action of TeTx by amino acid replacements in the cleavage site restored Ca2+‐stimulated secretion. Wild‐type VAMP‐2, wild‐type cellubrevin or a mutant of VAMP‐2 resistant to TeTx but not targeted to secretory granules were unable to rescue Ca2+‐evoked insulin release. The transmembrane domain and the N‐terminal region of VAMP‐2 were not essential for the recovery of stimulated exocytosis, but deletions preventing the binding to SNAP‐25 and/or to syntaxin I rendered the protein inactive in the reconstitution assay. Mutations of putative phosphorylation sites or of negatively charged amino acids in the SNARE motif recognized by clostridial toxins had no effect on the ability of VAMP‐2 to mediate Ca2+‐triggered secretion. We conclude that: (i) both VAMP‐2 and cellubrevin can participate in the exocytosis of insulin; (ii) the interaction of VAMP‐2 with syntaxin and SNAP‐25 is required for docking and/or fusion of secretory granules with the plasma membrane; and (iii) the phosphorylation of VAMP‐2 is not essential for Ca2+‐stimulated insulin exocytosis.
The assessment of perceived information pollution in banking sector

Infollution management is a substantial dilemma in this century. There is lacking empirical evidence about infollution management. Perceived infollution has been explored based on information quality. This study aims to identify the factors of perceived infollution (information pollution) and validate those factors using confirmatory factor analysis (CFA). Researchers have personally collected data from employees of the banking sector. Factor analysis was performed to explore the factors using Statistical Package for the Social Science, and CFA was conducted to check the reliability, validity, and the model fitness in SmartPLS. The scale developed in this study has exhibited high values of reliability and validity and ensured the presence of both discriminant validity and convergent validity. The newly developed scale of perceived infollution provides a basis for most of the academicians and researchers to empirically investigate the relationship of perceived infollution with individual’s performance and organizational effectiveness, which is considered an important area of interest among the academic researchers in recent years. Extent literature review suggests that it is the first study conducted to develop measurement scale of perceived infollution (information pollution).
Translational Mini‐Review Series on Type 1 Diabetes: Systematic analysis of T cell epitopes in autoimmune diabetes

T cell epitopes represent the molecular code words through which the adaptive immune system communicates. In the context of a T cell‐mediated autoimmune disease such as type 1 diabetes, CD4 and CD8 T cell recognition of islet autoantigenic epitopes is a key step in the autoimmune cascade. Epitope recognition takes place during the generation of tolerance, during its loss as the disease process is initiated, and during epitope spreading as islet cell damage is perpetuated. Epitope recognition is also a potentially critical element in therapeutic interventions such as antigen‐specific immunotherapy. T cell epitope discovery, therefore, is an important component of type 1 diabetes research, in both human and murine models. With this in mind, in this review we present a comprehensive guide to epitopes that have been identified as T cell targets in autoimmune diabetes. Targets of both CD4 and CD8 T cells are listed for human type 1 diabetes, for humanized [human leucocyte antigen (HLA)‐transgenic] mouse models, and for the major spontaneous disease model, the non‐obese diabetic (NOD) mouse. Importantly, for each epitope we provide an analysis of the relative stringency with which it has been identified, including whether recognition is spontaneous or induced and whether there is evidence that the epitope is generated from the native protein by natural antigen processing. This analysis provides an important resource for investigating diabetes pathogenesis, for developing antigen‐specific therapies, and for developing strategies for T cell monitoring during disease development and therapeutic intervention.
Energy Demand Patterns in an Office Building: A Case Study in Kraków (Southern Poland)

Office buildings play a significant role in shaping the current electricity demand and its trends. Their energy demand patterns impact the power system operation on a national and regional level. What is more, both (office buildings and the power system) are also simultaneously influenced by meteorological parameters. Considering the above, the aim of this paper is to analyze a three-year hourly energy demand time series recorded in a relatively large office building in Kraków (Southern Poland). This paper will fill a gap in the literature as there is a lack of evidence from Central European countries in the area of office buildings’ energy demand and its relationship with meteorological parameters. The data was obtained from a local electricity provider whereas meteorological parameters came from weather station and satellite measurements. The analyses focused on determining the typical weekly and daily demand patterns as well as on investigating the correlation between meteorological parameters (wind speed, irradiation, humidity, and air temperature) and observed energy consumption. To estimate the correlation between investigated variables, a Pearson coefficient of correlation was used. For distinguishing typical load patterns, a k-means clustering method was applied. The relationship between meteorological parameters and load was also tested based on multiple linear regression analysis. The results indicated that energy demand had a relatively strong positive correlation with irradiation and with temperature and a negative one with humidity. The correlation with wind speed was not greater than 0.25. Dividing the data into three subsets shows that energy demand generally exhibits a stronger correlation with meteorological parameters on working days. Additionally, clustering analysis has shown that it is possible to distinguish three typical daily patterns of energy demand and meteorological parameters that correspond to a hot/warm day, cold days and days that are intermediary between those two. The regression analysis showed that meteorological parameters can explain/model a significant part of the load variability (up to 50%) although the quality of such models is relatively poor (in terms of mean absolute percentage error the best model exhibited a value of 16%). The results of this study can be used as a benchmark for similar office buildings that received the same level of sustainability certification, or in the future analysis of climate change impact on power demand.
ES2, a gene deleted in DiGeorge syndrome, encodes a nuclear protein and is expressed during early mouse development, where it shares an expression domain with a Goosecoid-like gene.

ES2 is a gene deleted in DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS) which has homologs in species as distant as Caenorhabditis elegans and Drosophila . The function of ES2 is unknown, and the predicted protein sequence does not contain motifs which suggest a particular role in the developmental defects present in DGS and VCFS. Here we show that the mouse homolog, Es2 , is transcribed in two forms resulting from the use of alternative polyadenylation signals. Structural analysis programs predict that the Es2 -encoded peptide has a coiled-coil domain, and transfection experiments with an Es2 -green fluorescent protein (GFP) fusion construct show that the peptide is recruited into the nucleus. Es2 is highly expressed during mouse embryogenesis from E7 onwards. In situ hybridization with an RNA probe revealed that the gene is widely expressed; however, relatively higher expression was detected in the nervous system, with a particularly high area of expression in a sub-region of the pons. The Es2 expression domain in the pons is shared with a Goosecoid-like gene ( Gscl) which is located upstream of Es2 , and raises the possibility that the two genes share regulatory elements and/or interact in this region of the developing brain. This finding suggests that different genes in the deleted region may be functionally related and might explain the occurrence of the characteristic phenotype in patients with non-overlapping genetic lesions.