Miracle-dz/UniFAR-FTUs huggingface dataset:
Hepatitis B Virus Splice-Generated Protein Induces T-Cell Responses in HLA-Transgenic Mice and Hepatitis B Virus-Infected Patients

ABSTRACT Hepatitis B virus splice-generated protein (HBSP), encoded by a spliced hepatitis B virus RNA, was recently identified in liver biopsy specimens from patients with chronic active hepatitis B. We investigated the possible generation of immunogenic peptides by the processing of this protein in vivo. We identified a panel of potential epitopes in HBSP by using predictive computational algorithms for peptide binding to HLA molecules. We used transgenic mice devoid of murine major histocompatibility complex (MHC) class I molecules and positive for human MHC class I molecules to characterize immune responses specific for HBSP. Two HLA-A2-restricted peptides and one immunodominant HLA-B7-restricted epitope were identified following the immunization of mice with DNA vectors encoding HBSP. Most importantly, a set of overlapping peptides covering the HBSP sequence induced significant HBSP-specific T-cell responses in peripheral blood mononuclear cells from patients with chronic hepatitis B. The response was multispecific, as several epitopes were recognized by CD8+ and CD4+ human T cells. This study provides the first evidence that this protein generated in vivo from an alternative reading frame of the hepatitis B virus genome activates T-cell responses in hepatitis B virus-infected patients. Given that hepatitis B is an immune response-mediated disease, the detection of T-cell responses directed against HBSP in patients with chronic hepatitis B suggests a potential role for this protein in liver disease progression.
Malignant ileocaecal serotonin-producing carcinoid tumours: The presence of a solid growth pattern and/or Ki67 index above 1% identifies patients with a poorer prognosis

Patients with malignant serotonin-producing carcinoid tumours in the jejunum, ileum and caecum generally have long survival expectancy. In some patients, however, tumour progression is more rapid and there is a need to identify them at an early stage. The purpose of this study was to determine if histopathological characteristics and/or Ki67 and apoptotic indices are of prognostic value in cases of metastatic disease. Eighty-one patients with this tumour were included in the study; all had metastases and their survival range was 1–223 months. Five growth patterns were identified and described. For 57 patients whose tumour material was available, the Ki67 and apoptotic indices were calculated for ten randomly selected tumour areas and ‘hot spots’. A Cox regression analysis was used to test if histopathology and/or Ki67 index ≥1% could identify patients whose survival might be shorter than anticipated. One of the histopathological growth patterns-the solid (non-organoid) cell pattern-was correlated to shorter survival in both primary tumours and metastases, when compared with the organoid growth patterns (hazard ratio 2.9 and 2.3, p≤0.01). In 75% of primary tumours and 67% of metastases, the average Ki67 index was<0.5%. Ki67 index in ‘hot spots’ ranged from 0.1 to 14%. Ki67 index ≥1%, in both primary tumour and metastases, identified patients at increased risk of shorter survival (hazard ratio 5.4 and 2.5, p≤0.01). The apoptotic index was very low in all cases. We conclude that in patients with metastazising serotonin-producing carcinoids, two independent criteria, a solid growth pattern and Ki67 index ≥1%, can be used to identify patients with a poorer prognosis. This study also showed that Ki67 index <2% cannot, as previously suggested, be used to indicate a benign progression for this tumour category.
Activation of Plasmacytoid Dendritic Cells in Colon-Draining Lymph Nodes during Citrobacter rodentium Infection Involves Pathogen-Sensing and Inflammatory Pathways Distinct from Conventional Dendritic Cells

Dendritic cells (DCs) bear the main responsibility for initiation of adaptive immune responses necessary for antimicrobial immunity. In the small intestine, afferent lymphatics convey Ags and microbial signals to mesenteric lymph nodes (LNs) to induce adaptive immune responses against microbes and food Ags derived from the small intestine. Whether the large intestine is covered by the same lymphatic system or represents its own lymphoid compartment has not been studied until very recently. We identified three small mesenteric LNs, distinct from small intestinal LNs, which drain lymph specifically from the colon, and studied DC responses to the attaching and effacing pathogen Citrobacter rodentium in these. Transcriptional profiling of conventional (CD11chighCD103high) DC and plasmacytoid (plasmacytoid DC Ag-1highB220+CD11cint) DC (pDC) populations during steady-state conditions revealed activity of distinct sets of genes in these two DC subsets, both in small intestinal and colon-draining LNs. C. rodentium activated DC especially in colon-draining LNs, and gene expression changed in pDC more profoundly than in conventional DC. Among the genes most upregulated in pDC were C-type lectin receptor CLEC4E, IL-1Rs (IL-1R1 and -2), proinflammatory cytokines (IL-1a and IL-6), and TLR6. Our results indicate that colon immune surveillance is distinct from that of the small intestine in terms of draining LNs, and identify pDC as active sentinels of colonic inflammation and/or microbial dysbiosis.
A Virtual Impedance Optimization Method for Reactive Power Sharing in Networked Microgrid

Unlike the typical microgrid with a common ac bus, networked microgrid always suffers more serious reactive power sharing issues due to its complex inner structure. In such case, the system reactive power sharing error cannot be easily evaluated and eliminated. So, this paper proposes a wireless control strategy that employs optimized virtual impedance controllers and local load measurements for the reactive power sharing in networked microgrid. First, from the modeling of microgrid network, an estimation method for network reactive power sharing error is derived. Through the estimation method-based network feature analyses, corresponding design for virtual impedance controller is presented. Then, by introducing genetic algorithm, virtual impedance controller parameters of each distributed generation unit are optimized, which aims to minimize the microgrid global reactive power sharing error. The parameter optimization process is performed offline in microgrid configuration stage. By using these optimized virtual impedance controllers, the reactive power sharing performance of a networked microgird can be greatly improved. Finally, the accuracy of the estimation method is validated by MATLAB simulation results, and the feasibility of the proposed virtual impedance optimization method is verified through real power experiments.
Single and Combined Silencing of ERK1 and ERK2 Reveals Their Positive Contribution to Growth Signaling Depending on Their Expression Levels

ABSTRACT The proteins ERK1 and ERK2 are highly similar, are ubiquitously expressed, and share activators and substrates; however, erk2 gene invalidation is lethal in mice, while erk1 inactivation is not. We ablated ERK1 and/or ERK2 by RNA interference and explored their relative roles in cell proliferation and immediate-early gene (IEG) expression. Reducing expression of either ERK1 or ERK2 lowered IEG induction by serum; however, silencing of only ERK2 slowed down cell proliferation. When both isoforms were silenced simultaneously, compensating activation of the residual pool of ERK1/2 masked a more deleterious effect on cell proliferation. It was only when ERK2 activation was clamped at a limiting level that we demonstrated the positive contribution of ERK1 to cell proliferation. We then established that ERK isoforms are activated indiscriminately and that their expression ratio correlated exactly with their activation ratio. Furthermore, we determined for the first time that ERK1 and ERK2 kinase activities are indistinguishable in vitro and that erk gene dosage is essential for survival of mice. We propose that the expression levels of ERK1 and ERK2 drive their apparent biological differences. Indeed, ERK1 is dispensable in some vertebrates, since it is absent from chicken and frog genomes despite being present in all mammals and fishes sequenced so far.
Comparison of the kinematics of the full-instep and pass kicks in soccer.

PURPOSE The goal of this study was to gain a better understanding of the mechanics of the inside-of-the-foot passing shot used in soccer ("pass kick"). METHODS The motions of the pass kick were compared with those of the full-instep kick ("full kick"). The study followed an inverse dynamics approach, using three-dimensional cinematographic techniques. RESULTS At impact, the pelvis and the thigh-shank plane pointed more toward the right in the pass kick; the shank-foot plane also pointed further outward relative to the thigh-shank plane. Knee extension accounted for most of the speed of the foot in both kicks (86% in the full kick; 67% in the pass kick). In the pass kick, pelvis tilt toward the right and hip adduction contributed to a medial component of foot velocity (8.4 m.s-1) normal to the thigh-shank plane, which made the resultant foot velocity vector more oblique to the plane than in the full kick. This facilitated ball impact with the medial aspect of the foot. The slower ball speed in the pass kick was because of a slower foot speed (18.3 m.s-1 vs 21.6 m.s-1). Limitations in the maximum medial velocity that can be generated may force players to restrain the within-plane (and therefore also the resultant) velocity of the foot to be able to impact the ball squarely with the medial aspect of the foot. CONCLUSIONS To impact the ball with the medial aspect of the foot in the pass kick, the player orients the pelvis, the right leg, and the foot more toward the right and introduces a medial component of foot velocity. However, most of the speed of the foot is still generated through knee extension.
A Design Flow for Architecture Exploration and Implementation of Partially Reconfigurable Processors

During the last years, the growing application complexity, design, and mask costs have compelled embedded system designers to increasingly consider partially reconfigurable application-specific instruction set processors (rASIPs) which combine a programmable base processor with a reconfigurable fabric. Although such processors promise to deliver excellent balance between performance and flexibility, their design remains a challenging task. The key to the successful design of a rASIP is combined architecture exploration of all the three major components: the programmable core, the reconfigurable fabric, and the interfaces between these two. This work presents a design flow that supports fast architecture exploration for rASIPs. The design flow is centered around a unified description of an entire rASIP in an architecture description language (ADL). This ADL description facilitates consistent modeling and exploration of all three components of a rASIP through automatic generation of the software tools (compiler tool chain and instruction set simulator) and the RTL hardware model. The generated software tools and the RTL model can be used either for final implementation of the rASIP or can serve as a preoptimized starting point for implementation that can be hand optimized afterward. The design flow is further enhanced by a number of automatic application analysis tools, including a fine-grained application profiler, an instruction set extension (ISE) generator, and a data path mapper for coarse grained reconfigurable architectures (CGRAs). We present some case studies on embedded benchmarks to show how the design space exploration process helps to efficiently design an application domain specific rASIP.
Identification of a Synonymous Polymorphism Within the Cytochrome P4502C9 Gene That Interferes With Identification of the CYP2C9*2 Allele

Cytochrome P450 2C9 (CYP4502C9) genotyping is useful in dosage adjustments for several critical drug therapies, including warfarin. Potential interference compromising these genotyping results could lead to inappropriate dose adjustments that may result in adverse drug reactions. During routine clinical CYP4502C9 genotyping using multiplex allele-specific primer extension, an ambiguous result was obtained for determination of the CYP2C9 430C>T substitution, which defines the CYP2C9*2 allele. In this one patient sample submitted for CYP2C9 genotyping, the ratio for the variant 430T allele signal to the total signal (C+T alleles) was 0.29. This is above the expected ratio to be classified as wild-type (<0.15) and below the minimum expected ratio (>0.3) when the genotype is heterozygous at the 430 position. The mean fluorescence intensity for the 430C allele was consistent with that observed in subjects who are heterozygous at this nucleotide position. However, the corresponding signal for the 430T allele indicated the absence of the CYP2C9*2 allele. This suggests the assay was not able to determine the correct nucleotide at position 430 for one of the two alleles in this patient. Subsequent sequencing to investigate the allele-specific primer extension failure revealed the presence of a rare C>T nucleotide substitution at position 429. We tested this subject's CYP2C9 genotype using AvaII restriction endonuclease digestion and found that this rare substitution causes false-positive identification of the CYP2C9*2 allele when using this method. We developed a DpnII endonuclease digestion assay to specifically detect the CYP2C9 429C>T substitution and tested 100 randomly selected samples obtained from unrelated individuals. The 429C>T polymorphism was not identified in this sample set, which indicates an allele frequency of less than 2.0% (95% confidence interval, 0.0-1.8%) in the general population. Despite the rarity of this polymorphism, it has important implications for the accuracy of assays using allele-specific primers and the Ava II restriction endonuclease, when it occurs, which are two common methods currently applied for detecting the presence of the CYP2C9*2 allele.
P fimbriae‐dependent, lipopolysaccharide‐independent activation of epithelial cytokine responses

Cells in the mucosal barrier are equipped to sense and respond to microbes in the lumen and translate this molecular information into signals that can reach local or distant sites. The interaction of P‐fimbriated Escherichia coli with human uroepithelial cells is a model to study the molecular mechanism of epithelial cell activation by mucosal pathogens. Here, we examine the role of lipopolysaccharide (LPS) as a co‐stimulatory molecule in epithelial cell activation by P‐fimbriated E. coli. P‐fimbriated clinical isolates or recombinant strains were shown to trigger a fimbriae‐dependent epithelial cell cytokine response. Mutational inactivation of the msbB sequences that control lipid A myristoylation drastically impaired monocyte stimulation but not epithelial responses to P‐fimbriated bacteria. Polymyxin B or bactericidal/permeability increasing factor (BPI) neutralized the effects of lipid A in the monocyte assay, but did not reduce epithelial responses. Finally, isolated LPS of the smooth, rough and deep rough chemotypes were poor epithelial cell activators. The cells were shown to lack surface CD14 or CD14 mRNA as well as the CD14 co‐receptor function and were also very poor LPS responders in the presence of human serum. These results demonstrate that epithelial cell responses to P‐fimbriated E. coli are CD14 and LPS independent, and suggest that attaching pathogens can overcome the LPS unresponsiveness of epithelial cells by fimbriae‐dependent activation mechanisms.
Accelerating PCG power/ground network solver on GPGPU

Currently fast and precise P/G (power/ground) solvers are critical for robust P/G designs, but traditional serial P/G solvers are somewhat incapable of millions of nodes in P/G. In spite of powerful computation capability of parallel hardware, paralleled P/G solvers are far from prevailing, especially on complicated special hardware. We anticipated it, and studied on parallelizing and accelerating P/G solvers on GPU. In our work, we developed a PCG(Preconditioned Conjugate Gradient)-based P/G solver on the CUDA platform for structured P/G network, and identified advantages as well as constraints from GPU architecture. Our PCG-GPU solver can be up to 40 times faster than SuperLU, and also outperform multi-grid based solver on GPU.
ERK activation in endothelial cells is a novel marker during neovasculogenesis

Vasculogenesis is essential during early development to construct networks transporting oxygen, blood and nutrients. Tip and stalk cells are specialized endothelial cells involved in novel vessel formation because of their behavior such as sprouting as a leading cell and following tip cell. However, the spatiotemporal details determining the emergence of these cells are unknown. Here, we first show that the ERK activity in endothelial cells represents the precursor of tip and stalk cells for vasculogenesis in zebrafish. We identified that tip and stalk cells for intersegmental vessel (ISV) formation were already specialized in the dorsal aorta (DA) before sprouting. Furthermore, similar specialization was observed in tip cells during parachordal vessel (PAV) formation in lymphangiogenesis. We also identified that the ERK activity was required for specialized cells to emerge from existing blood vessels. Our data show that the ERK activity is a novel marker for determining the emergence of cells in both angiogenesis and lymphangiogenesis.
Simulation multi-agents de marchés financiers

Les simulations par agents, ou centrees individu, permettent, par opposition aux modeles centres groupe, de prendre en compte la maniere dont les entites composant un sys- teme interagissent entre elles et ainsi de faire le lien entre ses niveaux microscopiques et macroscopiques. Les marches financiers, bien qu'etant des systemes composes de nombreuses entites en interaction, sont souvent etudies a l'aide de modele centres groupe, qui montrent leur limites lorsqu'il s'agit d'expliquer l'emergence de certains phenomenes observables dans les series de prix. Nous proposons par consequent un modele de marche financier centre individu, permettant de reproduire de maniere realiste leur fonctionnement, a la fois a une echelle intra-journaliere et a une echelle inter-journaliere. Ce modele nous a permis dans un premier temps de proposer une theorie pour expliquer l'origine des faits stylises, qui sont des proprietes statistiques des cours de prix observables sur l'ensemble des marches financiers et dont l'origine est mal expliquee. Notre proposition, etayee par les experimentations que nous avons realisees avec notre modele, montre que les faits stylises semblent en majeure partie causes par la maniere dont le marche est structure et par la maniere dont les agents economiques interagissent a travers lui. Dans un second temps, nous avons utilise notre modele pour etudier les variations extremes de prix observables sur les marches financiers, que l'on nomme "bulles" quand elles sont a la hausse et "krachs" quand elles sont a la baisse. Nous avons illustre avec notre modele, en nous appuyant sur les theories proposees par certains economistes pour expliquer ces evenements, que ces episodes critiques dans les prix peuvent survenir lorsqu'une partie suffisante de la population des investisseurs adopte une strategie speculatrice.
Advance Hospital Notification by EMS in Acute Stroke Is Associated with Shorter Door-to-Computed Tomography Time andIncreased Likelihood of Administration of Tissue-Plasminogen Activator

Background. Rapid brain imaging is a critical step in facilitating the use of intravenous (IV) tissue-plasminogen activator (tPA) or catheter-based thrombolysis. We hypothesized that advance notification by emergency medical services (EMS) would shorten emergency department (ED) arrival-to-computed tomography (CT) time andincrease the use of IV andintra-arterial thrombolysis, even at a tertiary care stroke center with high baseline rates of tPA use. Methods. We analyzed data on all acute stroke patients transported from March 2004 to June 2005 by EMS from the scene to our facility arriving ≤6 hours from symptom onset. We reviewed digital voice recordings of all EMS communications to our hospital andin-hospital time intervals andoutcomes from our stroke database. Results. Among the 118 patients who met criteria, there were no significant differences between those with notification (n = 44) andthose without (n = 74) in terms of age, gender, history of prior stroke, median National Institutes of Health Stroke Scale (NIHSS) score in the ED, proportion with mild stroke (NIHSS score ≤4), or mean onset-to-ED arrival time. Door-to-CT time was 17% shorter (40 vs. 47 minutes, p = 0.01) in the advance-notification group, andthrombolysis occurred twice as often (41% vs. 21%, p = 0.04). Conclusion. Advance notification of patient arrival by EMS shortened time to CT andwas associated with a modest increase in the use of thrombolysis at our hospital. This occurred even with protocols in place to shorten the time to CT for all acute stroke patients. Further research is needed to understand how to increase rates of advance notification by EMS in potential tPA candidates.
A truncated herpes simplex virus thymidine kinase phosphorylates thymidine and nucleoside analogs and does not cause sterility in transgenic mice

Dividing eukaryotic cells expressing the herpes simplex virus type 1 thymidine kinase (TK) gene are sensitive to the cytotoxic effect of nucleoside analogs such as acyclovir or ganciclovir (GCV). Transgenic mice with cell-targeted expression of this conditional toxin have been used to create animals with temporally controlled cell-specific ablation. In these animal models, which allow the study of the physiological importance of a cell type, males are sterile. In this study, we showed that this phenomenon is due to testis-specific high-level expression of short TK transcripts initiated mainly upstream of the second internal ATG of the TK gene. This expression is DNA methylation independent. To obtain a suicide gene that does not cause male infertility, we generated and analyzed the properties of a truncated TK (delta TK) lacking the sequences upstream of the second ATG. We showed that when expressed at sufficient levels, the functional properties of delta TK are similar to those of TK in terms of thymidine or GCV phosphorylation. This translated into a similar GCV-dependent toxicity for delta TK- or TK-expressing cells, both in vitro and in transgenic mice. However, delta TK behaved differently from TK in two ways. First, it did not cause sterility in delta TK transgenic males. Second, low-level delta TK RNA expression did not confer sensitivity to GCV. The uses of delta TK in cell-specific ablation in transgenic mice and in gene therapy are discussed.
MicroRNA-378 Targets the Myogenic Repressor MyoR during Myoblast Differentiation*

MicroRNAs play important roles in many cell processes, including the differentiation process in several different lineages. For example, microRNAs can promote differentiation by repressing negative regulators of transcriptional activity. These regulated transcription factors can further up-regulate levels of the microRNA in a feed-forward mechanism. Here we show that MyoD up-regulates miR-378 during myogenic differentiation in C2C12 cells. ChIP and high throughput sequencing analysis shows that MyoD binds in close proximity to the miR-378 gene and causes both transactivation and chromatin remodeling. Overexpression of miR-378 increases the transcriptional activity of MyoD, in part by repressing an antagonist, MyoR. The 3′ untranslated region of MyoR contains a direct binding site for miR-378. The presence of this binding site significantly reduces the ability of MyoR to prevent the MyoD-driven transdifferentiation of fibroblasts. MyoR and miR-378 were anticorrelated during cardiotoxin-induced adult muscle regeneration in mice. Taken together, this shows a feed-forward loop where MyoD indirectly down-regulates MyoR via miR-378.