Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential and synergistic actions of nerve growth factor and cyclic AMP in PC12 cells

When a clonal line of rat pheochromocytoma (PC12) was exposed to beta- nerve growth factor (beta NGF), N6, O2-dibutyryl adenosine 3':5' cyclic monophosphate (Bt2cAMP), or a combination of the two, 10, 26, or 70% of the cell clumps, respectively, displayed neurites after 1.d. Increases in the cellular RNA concentration were also found to be additive or greater when both agents were present. Neurites induced by Bt2cAMP alone were not maintained after replacement with beta NGF. The degree of potentiated neurite outgrowth was a function of the time of simultaneous exposure to both agents. The initiation of neurite outgrowth in the presence of Bt2cAMP was independent of RNA synthesis, in contrast to that induced by beta NGF alone. We conclude that beta NGF-induced initiation of morphological differentiation of these cells is not mediated by a cAMP-dependent mechanism. Consideration of Bt2cAMP effects upon other cell lines suggest that Bt2cAMP causes a rapid, but unstable, reorganization of the PC12 cytoskeleton, resulting in the initiation of neurite outgrowth from these cells. In contrast, beta NGF alone achieves a more stable cytoskeleton reorganization by an RNA synthesis-dependent mechanism.
The Host E3-Ubiquitin Ligase TRIM6 Ubiquitinates the Ebola Virus VP35 Protein and Promotes Virus Replication

ABSTRACT Ebola virus (EBOV), a member of the Filoviridae family, is a highly pathogenic virus that causes severe hemorrhagic fever in humans and is responsible for epidemics throughout sub-Saharan, central, and West Africa. The EBOV genome encodes VP35, an important viral protein involved in virus replication by acting as an essential cofactor of the viral polymerase as well as a potent antagonist of the host antiviral type I interferon (IFN-I) system. By using mass spectrometry analysis and coimmunoprecipitation assays, we show here that VP35 is ubiquitinated on lysine 309 (K309), a residue located on its IFN antagonist domain. We also found that VP35 interacts with TRIM6, a member of the E3-ubiquitin ligase tripartite motif (TRIM) family. We recently reported that TRIM6 promotes the synthesis of unanchored K48-linked polyubiquitin chains, which are not covalently attached to any protein, to induce efficient antiviral IFN-I-mediated responses. Consistent with this notion, VP35 also associated noncovalently with polyubiquitin chains and inhibited TRIM6-mediated IFN-I induction. Intriguingly, we also found that TRIM6 enhances EBOV polymerase activity in a minigenome assay and TRIM6 knockout cells have reduced replication of infectious EBOV, suggesting that VP35 hijacks TRIM6 to promote EBOV replication through ubiquitination. Our work provides evidence that TRIM6 is an important host cellular factor that promotes EBOV replication, and future studies will focus on whether TRIM6 could be targeted for therapeutic intervention against EBOV infection. IMPORTANCE EBOV belongs to a family of highly pathogenic viruses that cause severe hemorrhagic fever in humans and other mammals with high mortality rates (40 to 90%). Because of its high pathogenicity and lack of licensed antivirals and vaccines, EBOV is listed as a tier 1 select-agent risk group 4 pathogen. An important mechanism for the severity of EBOV infection is its suppression of innate immune responses. The EBOV VP35 protein contributes to pathogenesis, because it serves as an essential cofactor of the viral polymerase as well as a potent antagonist of innate immunity. However, how VP35 function is regulated by host cellular factors is poorly understood. Here, we report that the host E3-ubiquitin ligase TRIM6 promotes VP35 ubiquitination and is important for efficient virus replication. Therefore, our study identifies a new host factor, TRIM6, as a potential target in the development of antiviral drugs against EBOV.
Potential Therapeutic Applications of Adenosine A2A Receptor Ligands and Opportunities for A2A Receptor Imaging

Adenosine A2A receptors (A2ARs) are highly expressed in the human striatum, and at lower densities in the cerebral cortex, the hippocampus, and cells of the immune system. Antagonists of these receptors are potentially useful for the treatment of motor fluctuations, epilepsy, postischemic brain damage, or cognitive impairment, and for the control of an immune checkpoint during immunotherapy of cancer. A2AR agonists may suppress transplant rejection and graft‐versus‐host disease; be used to treat inflammatory disorders such as asthma, inflammatory bowel disease, and rheumatoid arthritis; be locally applied to promote wound healing and be employed in a strategy for transient opening of the blood–brain barrier (BBB) so that therapeutic drugs and monoclonal antibodies can enter the brain. Increasing A2AR signaling in adipose tissue is also a potential strategy to combat obesity. Several radioligands for positron emission tomography (PET) imaging of A2ARs have been developed in recent years. This review article presents a critical overview of the potential therapeutic applications of A2AR ligands, the use of A2AR imaging in drug development, and opportunities and limitations of PET imaging in future research.
Sobriety Treatment and Recovery Teams: Implementation Fidelity and Related Outcomes

Background: Although integrated programs between child welfare and substance abuse treatment are recommended for families with co-occurring child maltreatment and substance use disorders, implementing integrated service delivery strategies with fidelity is a challenging process. Objective: This study of the first five years of the Sobriety Treatment and Recovery Team (START) program examines implementation fidelity using a model proposed by Carroll et al. (2007). The study describes the process of strengthening moderators of implementation fidelity, trends in adherence to START service delivery standards, and trends in parent and child outcomes. Methods: Qualitative and quantitative measures were used to prospectively study three START sites serving 341 families with 550 parents and 717 children. Results: To achieve implementation fidelity to service delivery standards required a pre-service year and two full years of operation, persistent leadership, and facilitative actions that challenged the existing paradigm. Over four years of service delivery, the time from the child protective services report to completion of five drug treatment sessions was reduced by an average of 75 days. This trend was associated with an increase in parent retention, parental sobriety, and parent retention of child custody. Conclusions/Importance: Understanding the implementation processes necessary to establish complex integrated programs may support realistic allocation of resources. Although implementation fidelity is a moderator of program outcome, complex inter-agency interventions may benefit from innovative measures of fidelity that promote improvement without extensive cost and data collection burden. The implementation framework applied in this study was useful in examining implementation processes, fidelity, and related outcomes.
Medullary Epithelial Cells of the Human Thymus Express a Highly Diverse Selection of Tissue-specific Genes Colocalized in Chromosomal Clusters

Promiscuous expression of tissue-specific self-antigens in the thymus imposes T cell tolerance and protects from autoimmune diseases, as shown in animal studies. Analysis of promiscuous gene expression in purified stromal cells of the human thymus at the single and global gene level documents the species conservation of this phenomenon. Medullary thymic epithelial cells overexpress a highly diverse set of genes (>400) including many tissue-specific antigens, disease-associated autoantigens, and cancer-germline genes. Although there are no apparent structural or functional commonalities among these genes and their products, they cluster along chromosomes. These findings have implications for human autoimmune diseases, immuno-therapy of tumors, and the understanding of the nature of this unorthodox regulation of gene expression.
Human Norovirus NS3 Has RNA Helicase and Chaperoning Activities

ABSTRACT RNA-remodeling proteins, including RNA helicases and chaperones, act to remodel RNA structures and/or protein-RNA interactions and are required for all processes involving RNAs. Although many viruses encode RNA helicases and chaperones, their in vitro activities and their roles in infected cells largely remain elusive. Noroviruses are a diverse group of positive-strand RNA viruses in the family Caliciviridae and constitute a significant and potentially fatal threat to human health. Here, we report that the protein NS3 encoded by human norovirus has both ATP-dependent RNA helicase activity that unwinds RNA helices and ATP-independent RNA-chaperoning activity that can remodel structured RNAs and facilitate strand annealing. Moreover, NS3 can facilitate viral RNA synthesis in vitro by norovirus polymerase. NS3 may therefore play an important role in norovirus RNA replication. Lastly, we demonstrate that the RNA-remodeling activity of NS3 is inhibited by guanidine hydrochloride, an FDA-approved compound, and, more importantly, that it reduces the replication of the norovirus replicon in cultured human cells. Altogether, these findings are the first to demonstrate the presence of RNA-remodeling activities encoded by Caliciviridae and highlight the functional significance of NS3 in the noroviral life cycle. IMPORTANCE Noroviruses are a diverse group of positive-strand RNA viruses, which annually cause hundreds of millions of human infections and over 200,000 deaths worldwide. For RNA viruses, cellular or virus-encoded RNA helicases and/or chaperones have long been considered to play pivotal roles in viral life cycles. However, neither RNA helicase nor chaperoning activity has been demonstrated to be associated with any norovirus-encoded proteins, and it is also unknown whether norovirus replication requires the participation of any viral or cellular RNA helicases/chaperones. We found that a norovirus protein, NS3, not only has ATP-dependent helicase activity, but also acts as an ATP-independent RNA chaperone. Also, NS3 can facilitate in vitro viral RNA synthesis, suggesting the important role of NS3 in norovirus replication. Moreover, NS3 activities can be inhibited by an FDA-approved compound, which also suppresses norovirus replicon replication in human cells, raising the possibility that NS3 could be a target for antinoroviral drug development.
MWPCR: Multiscale Weighted Principal Component Regression for High-Dimensional Prediction

ABSTRACT We propose a multiscale weighted principal component regression (MWPCR) framework for the use of high-dimensional features with strong spatial features (e.g., smoothness and correlation) to predict an outcome variable, such as disease status. This development is motivated by identifying imaging biomarkers that could potentially aid detection, diagnosis, assessment of prognosis, prediction of response to treatment, and monitoring of disease status, among many others. The MWPCR can be regarded as a novel integration of principal components analysis (PCA), kernel methods, and regression models. In MWPCR, we introduce various weight matrices to prewhitten high-dimensional feature vectors, perform matrix decomposition for both dimension reduction and feature extraction, and build a prediction model by using the extracted features. Examples of such weight matrices include an importance score weight matrix for the selection of individual features at each location and a spatial weight matrix for the incorporation of the spatial pattern of feature vectors. We integrate the importance of score weights with the spatial weights to recover the low-dimensional structure of high-dimensional features. We demonstrate the utility of our methods through extensive simulations and real data analyses of the Alzheimer’s disease neuroimaging initiative (ADNI) dataset. Supplementary materials for this article are available online.
Communication changes in Parkinson’s disease

This review looks at the nature and impact of communication changes in Parkinson’s disease, approaches to assessment and directions for intervention. This is especially important since medical and surgical interventions that help limb movement are largely ineffective, or even detrimental, for speech. Most people with Parkinson’s disease notice changes to their communication. Voice alters early on—even in the prodromal stage. Later, articulation may impair intelligibility further. These changes impact on mood and social participation. However, a full characterisation of communication changes in Parkinson’s must acknowledge that changes are far more pervasive and varied than a quiet voice. Communication is affected by marked dysprosody, cognitive-linguistic impairment, alterations to social interaction and pragmatics. Changes entail not just expressive elements but also receptive. A comprehensive evaluation of potential communication challenges faced by people with Parkinson’s disease must cover all these aspects. Similarly, interventions that ignore the breadth and depth of changes will always remain incomplete.
A Fully Serial-In Parallel-Out Digit-Level Finite Field Multiplier in 𝔽2m Using Redundant Representation

Redundant basis (RB) is one of the appealing representation systems for finite field arithmetic due to its specific features in providing cost-free squaring operation in hardware implementation and because it eliminates the need for modular reduction. In this brief, a new architecture for digit-level finite field multiplication in $\mathbb {F}_{2^{m}}$ using redundant representation is proposed. Contrary to previously presented redundant basis multipliers, in the proposed architecture one digit of each operand is concurrently fed into the multiplier at each clock cycle which, in turn, reduces the total number of the clock cycles required in the multiplication process. To draw an accurate comparison, the proposed multiplier together with several existing digit-level RB multipliers were fully implemented in 65-nm CMOS technology.
Expeditus: Congestion-Aware Load Balancing in Clos Data Center Networks

Data center networks often use multi-rooted Clos topologies to provide a large number of equal cost paths between two hosts. Thus, load balancing traffic among the paths is important for high performance and low latency. However, it is well known that ECMP—the de facto load balancing scheme—performs poorly in data center networks. The main culprit of ECMP’s problems is its congestion agnostic nature, which fundamentally limits its ability to deal with network dynamics. We propose Expeditus, a novel distributed congestion-aware load balancing protocol for general 3-tier Clos networks. The complex 3-tier Clos topologies present significant scalability challenges that make a simple per-path feedback approach infeasible. Expeditus addresses the challenges by using simple local information collection, where a switch only monitors its egress and ingress link loads. It further employs a novel two-stage path selection mechanism to aggregate relevant information across switches and make path selection decisions. Testbed evaluation on Emulab and large-scale ns-3 simulations demonstrate that, Expeditus outperforms ECMP by up to 45% in tail flow completion times (FCT) for mice flows, and by up to 38% in mean FCT for elephant flows in 3-tier Clos networks.
Levofloxacin effect on erlotinib absorption. Evaluation of the interaction in undernutrition situations through population pharmacokinetic analysis in rats

The main objective of this study was to develop a pharmacokinetic model in order to describe the intestinal absorption of erlotinib in rat and to quantify the interaction of levofloxacin on this process in well‐ and under‐nourished rats. Absorption studies were performed in male Wistar rats. Concentration–time profiles in proximal and distal intestine were analysed through non‐linear mixed effect modelling using the NONMEM software version 7.3. Simulations were performed in order to explore the influence of covariates on the apparent absorption rate constant. A passive absorption and an active secretion process best‐described erlotinib absorption from lumen to enterocyte. The developed model indicates that levofloxacin exerts an inhibition on erlotinib efflux transporters of the gut epithelium. Undernourishment proved to significantly decrease the maximum capacity of the secretion process. Simulations evidenced that erlotinib absorption only takes place at high enough drug concentrations to overcome the effect of efflux transporters. On the other hand, when levofloxacin is present in the intestinal lumen of undernourished rats, erlotinib drug absorption takes place even at low erlotinib concentrations. In the clinical setting, this interaction may result in increased exposure to erlotinib, especially in undernourished cancer patients. Copyright © 2017 John Wiley & Sons, Ltd.
Highly Tigecycline-Resistant Klebsiella pneumoniae Sequence Type 11 (ST11) and ST147 Isolates from Companion Animals

ABSTRACT In this study, we characterized two tigecycline-resistant Klebsiella pneumoniae isolates from dog urine samples. The isolates were genetically unrelated, belonging to sequence type 11 (ST11) and ST147, both classically related to human isolates. To the best of our knowledge, this is the first identification of tigecycline-resistant isolates from animals. We unveil here the worrisome circulation among animals of bacterial clones resistant to this last-resort antibiotic.
Heat-induced masculinization in domesticated zebrafish is family-specific and yields a set of different gonadal transcriptomes

Significance Fish exhibit remarkable sexual plasticity. However, the underlying mechanism of heat-induced sex reversal is still unclear. Here we first established the conditions for heat-induced reprogramming of sexual phenotypes in zebrafish through sex ratio analysis and gonad transcriptomics. Sex ratio response to heat was family-specific and resulted in masculinization. We observed two heat-induced gonadal transcriptomic profiles per sex in adults, among them neomales and, strikingly, females with an ovary but a “male-like” transcriptome. The latter indicates major transcriptomic reprogramming with preserved organ structure, an interesting observation in vertebrates. In all heat-treated juveniles, we also observed a male-like transcriptome. Overall, this study reveals novel lasting thermal effects on fish gonads, with practical implications for studying the effects of global warming in natural populations. Understanding environmental influences on sex ratios is important for the study of the evolution of sex-determining mechanisms and for evaluating the effects of global warming and chemical pollution. Fishes exhibit sexual plasticity, but the underlying mechanisms of environmental effects on their reproduction are unclear even in the well-established teleost research model, the zebrafish. Here we established the conditions to study the effects of elevated temperature on zebrafish sex. We showed that sex ratio response to elevated temperature is family-specific and typically leads to masculinization (female-to-male sex reversal), resulting in neomales. These results uncovered genotype-by-environment interactions that support a polygenic sex determination system in domesticated (laboratory) zebrafish. We found that some heat-treated fish had gene expression profiles similar to untreated controls of the same sex, indicating that they were resistant to thermal effects. Further, most neomales had gonadal transcriptomes similar to that of regular males. Strikingly, we discovered heat-treated females that displayed a normal ovarian phenotype but with a “male-like” gonadal transcriptome. Such major transcriptomic reprogramming with preserved organ structure has never been reported. Juveniles were also found to have a male-like transcriptome shortly after exposure to heat. These findings were validated by analyzing the expression of genes and signaling pathways associated with sex differentiation. Our results revealed a lasting thermal effect on zebrafish gonads, suggesting new avenues for detection of functional consequences of elevated temperature in natural fish populations in a global warming scenario.
Low drug levels and thrombotic complications in high‐risk atrial fibrillation patients treated with direct oral anticoagulants

Essentials Direct oral anticoagulants (DOACs) do not require laboratory monitoring currently. DOAC specific measurements were performed at trough in patients with atrial fibrillation. Patients who developed thromboembolic events showed lower DOAC plasma levels. This study supports the concept of measuring DOAC levels at steady state.
High Throughput and Low Cost Architecture for the Forward Quantization of the H.264/AVC Video Compression Standard

This work presents a dedicated hardware design for the Forward Quantization Module (Q module) of the H.264/AVC Video Coding Standard, using optimized multipliers. The goal of this design is to achieve high throughput rates com bined with low hardware consumption. The architecture was described in VHDL and synthesized to the EP2S60F1020C3 Altera Stratix II FPGA and to the TSMC 0. 18µm Standard Cell technology. The architecture is able to operate at 364.2 MHz as a maximum operation frequency. At this frequency, the architecture is able to process 117 QHDTV frames (3840x2048 pixels) per second. The designed architecture can be used in low power and low cost applications, since it can process high resolution in real time even with ve ry low operation frequencies and with low hardware consumption. In the comparison with related works, the designed Q module achieves the best results of throughput and hardwar e consumption.
Fruit and Juice Epigenetic Signatures Are Associated with Independent Immunoregulatory Pathways

Epidemiological evidence strongly suggests that fruit consumption promotes many health benefits. Despite the general consensus that fruit and juice are nutritionally similar, epidemiological results for juice consumption are conflicting. Our objective was to use DNA methylation marks to characterize fruit and juice epigenetic signatures within PBMCs and identify shared and independent signatures associated with these groups. Genome-wide DNA methylation marks (Illumina Human Methylation 450k chip) for 2,148 individuals that participated in the Framingham Offspring exam 8 were analyzed for correlations between fruit or juice consumption using standard linear regression. CpG sites with low P-values (P < 0.01) were characterized using Gene Set Enrichment Analysis (GSEA), Ingenuity Pathway Analysis (IPA), and epigenetic Functional element Overlap analysis of the Results of Genome Wide Association Study Experiments (eFORGE). Fruit and juice-specific low P-value epigenetic signatures were largely independent. Genes near the fruit-specific epigenetic signature were enriched among pathways associated with antigen presentation and chromosome or telomere maintenance, while the juice-specific epigenetic signature was enriched for proinflammatory pathways. IPA and eFORGE analyses implicate fruit and juice-specific epigenetic signatures in the modulation of macrophage (fruit) and B or T cell (juice) activities. These data suggest a role for epigenetic regulation in fruit and juice-specific health benefits and demonstrate independent associations with distinct immune functions and cell types, suggesting that these groups may not confer the same health benefits. Identification of such differences between foods is the first step toward personalized nutrition and ultimately the improvement of human health and longevity.