Miracle-dz/UniFAR-FTUs huggingface dataset:
Tiam1 Regulates the Wnt/Dvl/Rac1 Signaling Pathway and the Differentiation of Midbrain Dopaminergic Neurons

ABSTRACT Understanding the mechanisms that drive the differentiation of dopaminergic (DA) neurons is crucial for successful development of novel therapies for Parkinson's disease, in which DA neurons progressively degenerate. However, the mechanisms underlying the differentiation-promoting effects of Wnt5a on DA precursors are poorly understood. Here, we present the molecular and functional characterization of a signaling pathway downstream of Wnt5a, the Wnt/Dvl/Rac1 pathway. First, we characterize the interaction between Rac1 and Dvl and identify the N-terminal part of Dvl3 as necessary for Rac1 binding. Next, we show that Tiam1, a Rac1 guanosine exchange factor (GEF), is expressed in the ventral midbrain, interacts with Dvl, facilitates Dvl-Rac1 interaction, and is required for Dvl- or Wnt5a-induced activation of Rac1. Moreover, we show that Wnt5a promotes whereas casein kinase 1 (CK1), a negative regulator of the Wnt/Dvl/Rac1 pathway, abolishes the interactions between Dvl and Tiam1. Finally, using ventral midbrain neurosphere cultures, we demonstrate that the generation of DA neurons in culture is impaired after Tiam1 knockdown, indicating that Tiam1 is required for midbrain DA differentiation. In summary, our data identify Tiam1 as a novel regulator of DA neuron development and as a Dvl-associated and Rac1-specific GEF acting in the Wnt/Dvl/Rac1 pathway.
A novel algorithm of biclustering based on the association rules

Because of the ability of simultaneously capturing correlations among subsets of attributes (columns) and records (rows), biclustering is widely used in data mining applications such as biological data analysis, financial forecasting, and customer segmentation, etc. Since biclustering is known to be an NP-hard problem, biclusters are identified through heuristic approaches in most algorithms whose results are non-deterministic. A new algorithm based on association rules is proposed in this paper. It is deterministic and enables exhaustive discovery of coherent evolution biclusters. Furthermore, we propose the improved algorithm to avoid finding repetitive biclusters and this reduces the searching time. Finally, the improved algorithm is parallelized to accelerate the mining process, and significant speed-up ratio is achieved.
Neuroinflammation-Induced Interactions between Protease-Activated Receptor 1 and Proprotein Convertases in HIV-Associated Neurocognitive Disorder

ABSTRACT The proprotein convertases (PCs) furin, PC5, PACE4, and PC7 cleave secretory proteins after basic residues, including the HIV envelope glycoprotein (gp160) and Vpr. We evaluated the abundance of PC mRNAs in postmortem brains of individuals exhibiting HIV-associated neurocognitive disorder (HAND), likely driven by neuroinflammation and neurotoxic HIV proteins (e.g., envelope and Vpr). Concomitant with increased inflammation-related gene expression (interleukin-1β [IL-1β]), the mRNA levels of the above PCs are significantly increased, together with those of the proteinase-activated receptor 1 (PAR1), an inflammation-associated receptor that is cleaved by thrombin at ProArg41↓ (where the down arrow indicates the cleavage location), and potentially by PCs at Arg41XXXXArg46↓. The latter motif in PAR1, but not its R46A mutant, drives its interactions with PCs. Indeed, PAR1 upregulation leads to the inhibition of membrane-bound furin, PC5B, and PC7 and inhibits gp160 processing and HIV infectivity. Additionally, a proximity ligation assay revealed that furin and PC7 interact with PAR1. Reciprocally, increased furin expression reduces the plasma membrane abundance of PAR1 by trapping it in the trans-Golgi network. Furthermore, soluble PC5A/PACE4 can target/disarm cell surface PAR1 through cleavage at Arg46↓. PACE4/PC5A decreased calcium mobilization induced by thrombin stimulation. Our data reveal a new PC-PAR1-interaction pathway, which offsets the effects of HIV-induced neuroinflammation, viral infection, and potentially the development of HAND.
Mechanism of Mpk1 Mitogen-Activated Protein Kinase Binding to the Swi4 Transcription Factor and Its Regulation by a Novel Caffeine-Induced Phosphorylation

ABSTRACT The Mpk1 mitogen-activated protein kinase (MAPK) of the cell wall integrity signaling pathway uses a noncatalytic mechanism to activate the SBF (Swi4/Swi6) transcription factor. Active Mpk1 forms a complex with Swi4, the DNA-binding subunit of SBF, conferring the ability to bind DNA. Because SBF activation is independent of Mpk1 catalytic activity but requires Mpk1 to be in an active conformation, we sought to understand how Mpk1 interacts with Swi4. Mutational analysis revealed that binding and activation of Swi4 by Mpk1 requires an intact D-motif-binding site, a docking surface common to MAPKs that resides distal to the phosphorylation loop but does not require the substrate-binding site, revealing a novel mechanism for MAPK target regulation. Additionally, we found that Mpk1 binds near the autoinhibitory C terminus of Swi4, suggesting an activation mechanism in which Mpk1 substitutes for Swi6 in promoting Swi4 DNA binding. Finally, we show that caffeine is an atypical activator of cell wall integrity signaling, because it induces phosphorylation of the Mpk1 C-terminal extension at Ser423 and Ser428. These phosphorylations were dependent on the DNA damage checkpoint kinases, Mec1/Tel1 and Rad53. Phosphorylation of Ser423 specifically blocked SBF activation by preventing Mpk1 association with Swi4, revealing a novel mechanism for regulating MAPK target specificity.
Molecular Determinants for Small Maf Protein Control of Platelet Production

ABSTRACT MafG and p45 possess basic region-leucine zipper (bZip) domains and form a heterodimer called NF-E2, a key regulator of megakaryopoiesis. NF-E2 binds to the Maf recognition element (MARE) and activates transcription of many platelet genes. Since the bZip domain, which mediates DNA binding and heterodimerization, is the only functional domain established for MafG, it has been assumed that MafG is required only for p45 binding to MARE and to facilitate p45-mediated transcriptional activation. Analysis of the C-terminal region of MafG, which is distinct from the bZip domain, revealed that this region contains a nuclear matrix-targeting signal. We used a transgenic complementation rescue assay to delineate the function of the MafG C terminus in vivo. Transgenic mice expressing a mutant MafG protein lacking the C terminus (MafGΔC) were crossed into a MafG-null background. The compound mutant mice displayed severe thrombocytopenia and splenomegaly, which phenocopied p45-null mice. The MafG C terminus is essential for proplatelet formation and platelet gene activation but not for p45 binding to MARE. These results demonstrate that the MafG C terminus is required for NF-E2 function and suggest that efficient targeting of NF-E2 to a specific nuclear scaffold is important to achieve high-level activity.
Social Network Aware Device-to-Device Communication in Wireless Networks

Device-to-device (D2D) communication is seen as a major technology to overcome the imminent wireless capacity crunch and to enable new application services. In this paper, a novel social-aware approach for optimizing D2D communication by exploiting two layers, namely the social network layer and the physical wireless network layer, is proposed. In particular, the physical layer D2D network is captured via the users' encounter histories. Subsequently, an approach, based on the so-called Indian Buffet Process, is proposed to model the distribution of contents in the users' online social networks. Given the social relations collected by the base station, a new algorithm for optimizing the traffic offloading process in D2D communications is developed. In addition, the Chernoff bound and approximated cumulative distribution function (cdf) of the offloaded traffic are derived and the validity of the bound and cdf is proven. Simulation results based on real traces demonstrate the effectiveness of our model and show that the proposed approach can offload the network's traffic successfully.
Gastritis — Gastroscopic and Microscopic

We have compared the appearances of the gastric mucosa at gastroscopy with the histological findings in 130 biopsies from 56 patients. There was a fairly consistent correlation be-tween well recognised appearances and the rnicroscopic findings. When the mucosa appeared abnormal this was nearly always confirmed microscopically but one third of apparently normal mucosa showed gastritis. An-tral gastritis which appeared mild on gastro-scopy, was deep and often severe on microscopy. Serial sections are necessary to evaluate gastritis effectively.
Optimal Harvest-Use-Store Strategy for Energy Harvesting Wireless Systems

Energy harvesting (EH) technology has emerged as a promising energy-supplier to unattended wireless systems. In the commonly used harvest-store-use (HSU) scheme, harvested energy is always stored in a battery before its subsequent use. The existence of storage loss in practical battery systems, however, unavoidably reduces the energy efficiency. In this paper, we therefore propose the use of a more efficient harvest-use-store (HUS) architecture for point-to-point data transmission, where the harvested energy is prioritized for use in data transmission while its balance/debt is stored in or extracted from the storage device. We derive the optimal energy polices, under the criterion of throughput maximization, for the HUS architecture on static and block fading channels, and investigate the properties of the resulting power allocation pattern. The optimization is done in the Lagrangian framework, uncovering the special structure of the optimal power pattern and obtaining a closed-form solution conditioned on the knowledge of the block locations for zero battery level. A dynamic programming (DP) based algorithm is developed for locating such blocks in the optimal power patterns. Numerical results are presented to demonstrate the properties of the proposed HUS architecture and its superior performance over the existing schemes.
Neural machine translation research based on the semantic vector of the tri-lingual parallel corpus

RNN Encoder-Decoder and attentional mechanism have lately been used to improve neural machine translation (NMT) on bilingual parallel corpus. In this paper, we propose tri-lingual NMT. Based on the Encoder-Decoder and attentional mechanism, we translate source language to target language, meanwhile translate another parallel source language to target language. We provides two approaches called splicing-model and similarity-model. Both of the approaches are in order to enhance the semantic representation of input sequences. Our experiments on the IWSLT 2012 Chinese to Japanese translation and English to Japanese tasks show that both of the methods provide a comparable or substantial improvement over the bilingual parallel corpus.
Binding of the Extracellular Eight-Cysteine Motif of Opy2 to the Putative Osmosensor Msb2 Is Essential for Activation of the Yeast High-Osmolarity Glycerol Pathway

ABSTRACT To adapt to environmental high osmolarity, the budding yeast Saccharomyces cerevisiae activates the Hog1 mitogen-activated protein kinase, which regulates diverse osmoadaptive responses. Hog1 is activated through the high-osmolarity glycerol (HOG) pathway, which consists of independent upstream signaling routes termed the SLN1 branch and the SHO1 branch. Here, we report that the extracellular cysteine-rich (CR) domain of the transmembrane-anchor protein Opy2 binds to the Hkr1-Msb2 homology (HMH) domain of the putative osmosensor Msb2 and that formation of the Opy2-Msb2 complex is essential for osmotic activation of Hog1 through the MSB2 subbranch of the SHO1 branch. By analyzing the phenotypes of mutants with Opy2 cysteine-to-alanine mutations, we deduced that the CR domain forms four intramolecular disulfide bonds. To probe for the potential induction of conformational changes in the Opy2-Msb2 complex by osmostress, we constructed mutants with a site-specific Cys-to-Ala mutation of the Opy2 CR domain and mutants with a Cys substitution of the Msb2 HMH domain. Each of these mutants had a reduced cysteine. These mutants were then combinatorially cross-linked using chemical cross-linkers of different lengths. Cross-linking between Opy2 Cys48 and Msb2 Cys1023 was sensitive to osmotic changes, suggesting that osmostress induced a conformational change. We therefore propose that the Opy2-Msb2 complex might serve as an osmosensor.
Hepatic Long Intergenic Noncoding RNAs: High Promoter Conservation and Dynamic, Sex-Dependent Transcriptional Regulation by Growth Hormone

ABSTRACT Long intergenic noncoding RNAs (lincRNAs) are increasingly recognized as key chromatin regulators, yet few studies have characterized lincRNAs in a single tissue under diverse conditions. Here, we analyzed 45 mouse liver RNA sequencing (RNA-Seq) data sets collected under diverse conditions to systematically characterize 4,961 liver lincRNAs, 59% of them novel, with regard to gene structures, species conservation, chromatin accessibility, transcription factor binding, and epigenetic states. To investigate the potential for functionality, we focused on the responses of the liver lincRNAs to growth hormone stimulation, which imparts clinically relevant sex differences to hepatic metabolism and liver disease susceptibility. Sex-biased expression characterized 247 liver lincRNAs, with many being nuclear RNA enriched and regulated by growth hormone. The sex-biased lincRNA genes are enriched for nearby and correspondingly sex-biased accessible chromatin regions, as well as sex-biased binding sites for growth hormone-regulated transcriptional activators (STAT5, hepatocyte nuclear factor 6 [HNF6], FOXA1, and FOXA2) and transcriptional repressors (CUX2 and BCL6). Repression of female-specific lincRNAs in male liver, but not that of male-specific lincRNAs in female liver, was associated with enrichment of H3K27me3-associated inactive states and poised (bivalent) enhancer states. Strikingly, we found that liver-specific lincRNA gene promoters are more highly species conserved and have a significantly higher frequency of proximal binding by liver transcription factors than liver-specific protein-coding gene promoters. Orthologs for many liver lincRNAs were identified in one or more supraprimates, including two rat lincRNAs showing the same growth hormone-regulated, sex-biased expression as their mouse counterparts. This integrative analysis of liver lincRNA chromatin states, transcription factor occupancy, and growth hormone regulation provides novel insights into the expression of sex-specific lincRNAs and their potential for regulation of sex differences in liver physiology and disease.
Modeling and Analysis of an Extended Access Barring Algorithm for Machine-Type Communications in LTE-A Networks

Simultaneous channel accesses from mass machine-type communications (MTC) devices may congest the random-access channels (RACHs) of LTE-A networks. Currently, 3GPP selects extended access barring (EAB) mechanism as the baseline solution to relieve the congestion of RACHs by barring low-priority devices. Different settings of EAB parameters may re-shape the arrival process of MTC traffic and thus, lead to unpredictable performance. This paper presents an analytical model to investigate the performance of the EAB algorithm on the RACHs in LTE-A networks. Computer simulations were conducted to verify the accuracy of the analysis. The optimal values of paging cycle and repetition period of system information block type 14 (SIB14) can then be obtained from the analytical model subject to a target quality-of-service (QoS) constraint.
Reciprocal Phosphorylation of Yeast Glycerol-3-Phosphate Dehydrogenases in Adaptation to Distinct Types of Stress

ABSTRACT Eukaryotic cells have evolved mechanisms for ensuring growth and survival in the face of stress caused by a fluctuating environment. Saccharomyces cerevisiae has two homologous glycerol-3-phosphate dehydrogenases, Gpd1 and Gpd2, that are required to endure various stresses, including hyperosmotic shock and hypoxia. These enzymes are only partially redundant, and their unique functions were attributed previously to differential transcriptional regulation and localization. We find that Gpd1 and Gpd2 are negatively regulated through phosphorylation by distinct kinases under reciprocal conditions. Gpd2 is phosphorylated by the AMP-activated protein kinase Snf1 to curtail glycerol production when nutrients are limiting. Gpd1, in contrast, is a target of TORC2-dependent kinases Ypk1 and Ypk2. Inactivation of Ypk1 by hyperosmotic shock results in dephosphorylation and activation of Gpd1, accelerating recovery through increased glycerol production. Gpd1 dephosphorylation acts synergistically with its transcriptional upregulation, enabling long-term growth at high osmolarity. Phosphorylation of Gpd1 and Gpd2 by distinct kinases thereby enables rapid adaptation to specific stress conditions. Introduction of phosphorylation motifs targeted by distinct kinases provides a general mechanism for functional specialization of duplicated genes during evolution.
Spt10 and Swi4 Control the Timing of Histone H2A/H2B Gene Activation in Budding Yeast

ABSTRACT The expression of the histone genes is regulated during the cell cycle to provide histones for nucleosome assembly during DNA replication. In budding yeast, histones H2A and H2B are expressed from divergent promoters at the HTA1-HTB1 and HTA2-HTB2 loci. Here, we show that the major activator of HTA1-HTB1 is Spt10, a sequence-specific DNA binding protein with a putative histone acetyltransferase (HAT) domain. Spt10 binds to two pairs of upstream activation sequence (UAS) elements in the HTA1-HTB1 promoter: UAS1 and UAS2 drive HTA1 expression, and UAS3 and UAS4 drive HTB1 expression. UAS3 and UAS4 also contain binding sites for the cell cycle regulator SBF (an Swi4-Swi6 heterodimer), which overlap the Spt10 binding sites. The binding of Spt10 and binding of SBF to UAS3 and UAS4 are mutually exclusive in vitro. Both SBF and Spt10 are bound in cells arrested with α-factor, apparently awaiting a signal to activate transcription. Soon after the removal of α-factor, SBF initiates a small, early peak of HTA1 and HTB1 transcription, which is followed by a much larger peak due to Spt10. Both activators dissociate from the HTA1-HTB1 promoter after expression has been activated. Thus, SBF and Spt10 cooperate to control the timing of HTA1-HTB1 expression.
Postpartum Doula and Peer Telephone Support for Postpartum Depression

Objectives: This research provides the first test of feasibility of recruiting postpartum doulas and depressed mothers for a peer support intervention study and begins to evaluate the benefit of postpartum doula support and peer telephone support for at-risk mothers. Methods: The authors recruited postpartum doulas from national doula organizations, peer telephone supporters from nursing referrals, and mothers with depressive symptoms from 3 local hospitals, local medical practices, Web sites, and community organizations. Participating mothers were randomized to 3 groups—postpartum doula, peer telephone support, and control group. Surveys were completed at 0, 3, and 6 months postenrollment. Results: Thirty-nine mothers with depressive symptoms, 6 postpartum doulas, and 6 peer telephone supporters participated. The postpartum doula group, compared with the other 2 groups, had a higher proportion of women with a previous history of depression, and similarly, a higher proportion of women who were depressed and receiving depression treatment at the 6-month follow-up. Satisfaction with study-sponsored support was greater in the postpartum doula group than in the telephone support group. Conclusions: It is feasible to recruit postpartum doulas, peer telephone supporters, and mothers with depressive symptoms for a peer support intervention trial. Mothers were more satisfied with postpartum doulas than peer telephone support. The authors recommend further research to assess the benefit of postpartum doula support for postpartum depression as adjunctive or alternative therapy.
PRMT4-Mediated Arginine Methylation Negatively Regulates Retinoblastoma Tumor Suppressor Protein and Promotes E2F-1 Dissociation

ABSTRACT The retinoblastoma protein (pRb/p105) tumor suppressor plays a pivotal role in cell cycle regulation by blockage of the G1-to-S-phase transition. pRb tumor suppressor activity is governed by a variety of posttranslational modifications, most notably phosphorylation by cyclin-dependent kinase (Cdk) complexes. Here we report a novel regulation of pRb through protein arginine methyltransferase 4 (PRMT4)-mediated arginine methylation, which parallels phosphorylation. PRMT4 specifically methylates pRb at the pRb C-terminal domain (pRb Cterm) on arginine (R) residues R775, R787, and R798 in vitro and R787 in vivo. Arginine methylation is important for efficient pRb Cterm phosphorylation, as manifested by the reduced phosphorylation of a methylation-impaired mutant, pRb (R3K). A methylmimetic form of pRb, pRb (R3F), disrupts the formation of the E2F-1/DP1-pRb complex in cells as well as in an isolated system. Finally, studies using a Gal4–E2F-1 reporter system show that pRb (R3F) expression reduces the ability of pRb to repress E2F-1 transcriptional activation, while pRb (R3K) expression further represses E2F-1 transcriptional activation relative to that for cells expressing wild-type pRb. Together, our results suggest that arginine methylation negatively regulates the tumor suppressor function of pRb during cell cycle control, in part by creating a better substrate for Cdk complex phosphorylation and disrupting the interaction of pRb with E2F-1.
Implementing Panel Management for Hypertension in a Low-Income, Urban, Primary Care Setting

Objective: Panel management is a system of care that targets groups of patients with similar needs to improve their quality of care. The purpose of this pilot was to determine whether panel management could improve blood pressure control in patients with previously uncontrolled hypertension and to explore how panel management can be integrated in an urban, low-income, primary care setting. Methods: The practice coach model was used to assist a clinical site in forming a quality improvement team to implement panel management. The team created a patient registry to track hypertensive patients over time and to recall patients with uncontrolled hypertension for planned care visits during which evidence-based interventions for hypertension were delivered. Percent of patients gaining control of blood pressure and change in blood pressure were measured between 6 and 9 months after enrollment. Qualitative interviews of clinic staff were completed to explore strengths and weaknesses of program implementation. Results: Forty patients with uncontrolled hypertension were enrolled in the pilot, and 27.5% gained blood pressure control by 9 months after enrollment (P < .001). The average systolic blood pressure decreased by 16 mm Hg from 156.5 to 140.5 mm Hg (P < .001), and the average diastolic blood pressure decreased by 3.8 mm Hg from 85 to 81.2 mm Hg (P = .03). Staff interviews were generally positive; however, several areas for improvement were identified. Conclusion: Panel management for hypertension can be effective and can be implemented in a low-income, urban, primary care clinic setting given appropriate staffing allocation.