Miracle-dz/UniFAR-FTUs huggingface dataset:
The role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice

The multidrug resistance 2 knockout (Mdr2–/–) mouse is a well‐established model of cholestatic cholangiopathies. Female Mdr2–/– mice develop more severe hepatobiliary damage than male Mdr2–/– mice, which is correlated with a higher proportion of taurocholate in the bile. Although estrogen has been identified as an important player in intrahepatic cholestasis, the underlying molecular mechanisms of gender‐based disparity of cholestatic injury remain unclear. The long noncoding RNA H19 is an imprinted, maternally expressed, and estrogen‐targeted gene, which is significantly induced in human fibrotic/cirrhotic liver and bile duct–ligated mouse liver. However, whether aberrant expression of H19 accounts for gender‐based disparity of cholestatic injury in Mdr2–/– mice remains unknown. The current study demonstrated that H19 was markedly induced (∼200‐fold) in the livers of female Mdr2–/– mice at advanced stages of cholestasis (100 days old) but not in age‐matched male Mdr2–/– mice. During the early stages of cholestasis, H19 expression was minimal. We further determined that hepatic H19 was mainly expressed in cholangiocytes, not hepatocytes. Both taurocholate and estrogen significantly activated the extracellular signal–regulated kinase 1/2 signaling pathway and induced H19 expression in cholangiocytes. Knocking down H19 not only significantly reduced taurocholate/estrogen‐induced expression of fibrotic genes and sphingosine 1‐phosphate receptor 2 in cholangiocytes but also markedly reduced cholestatic injury in female Mdr2–/– mice. Furthermore, expression of small heterodimer partner was substantially inhibited at advanced stages of liver fibrosis, which was reversed by H19 short hairpin RNA in female Mdr2–/– mice. Similar findings were obtained in human primary sclerosing cholangitis liver samples. Conclusion: H19 plays a critical role in the disease progression of cholestasis and represents a key factor that causes the gender disparity of cholestatic liver injury in Mdr2–/– mice. (Hepatology 2017;66:869–884).
Immune phenotype and function of natural killer and T cells in chronic hepatitis C patients who received a single dose of anti‐MicroRNA‐122, RG‐101

MicroRNA‐122 is an important host factor for the hepatitis C virus (HCV). Treatment with RG‐101, an N‐acetylgalactosamine‐conjugated anti‐microRNA‐122 oligonucleotide, resulted in a significant viral load reduction in patients with chronic HCV infection. Here, we analyzed the effects of RG‐101 therapy on antiviral immunity. Thirty‐two chronic HCV patients infected with HCV genotypes 1, 3, and 4 received a single subcutaneous administration of RG‐101 at 2 mg/kg (n = 14) or 4 mg/kg (n = 14) or received a placebo (n = 2/dosing group). Plasma and peripheral blood mononuclear cells were collected at multiple time points, and comprehensive immunological analyses were performed. Following RG‐101 administration, HCV RNA declined in all patients (mean decline at week 2, 3.27 log10 IU/mL). At week 8 HCV RNA was undetectable in 15/28 patients. Plasma interferon‐γ‐induced protein 10 (IP‐10) levels declined significantly upon dosing with RG‐101. Furthermore, the frequency of natural killer (NK) cells increased, the proportion of NK cells expressing activating receptors normalized, and NK cell interferon‐γ production decreased after RG‐101 dosing. Functional HCV‐specific interferon‐γ T‐cell responses did not significantly change in patients who had undetectable HCV RNA levels by week 8 post–RG‐101 injection. No increase in the magnitude of HCV‐specific T‐cell responses was observed at later time points, including 3 patients who were HCV RNA–negative 76 weeks postdosing. Conclusion: Dosing with RG‐101 is associated with a restoration of NK‐cell proportions and a decrease of NK cells expressing activation receptors; however, the magnitude and functionality of ex vivo HCV‐specific T‐cell responses did not increase following RG‐101 injection, suggesting that NK cells, but not HCV adaptive immunity, may contribute to HCV viral control following RG‐101 therapy. (Hepatology 2017;66:57–68).
Role of Arabidopsis NHL family in ABA and stress response

ABSTRACT Based on their sequence homology to Arabidopsis NDR1 and tobacco (Nicotiana tabacum) HIN1, 45 NHL (NDR1/HIN1-like) family genes are found in Arabidopsis genome. Recently, we reported that overexpression of NHL6, a member of NHL family, modulated seed germination under abiotic stresses through affecting ABA biosynthesis and signaling. We also carried out qPCR and investigated the expression of the other 8 member genes (NHL7a, 16, 17, 21, 25, 26, 41, 43) whose transcriptional data are publicly unavailable, and found that expression of NHL17 was induced more than 2 folds in ABA treated seedlings. Furthermore, in addition to the plasma membrane localization, YFP-NHL6 fusion protein was also observed in the cytosol (as dots) or on the membrane of small vacuoles or vesicles. As a member of the pathogen infection related genes, expression of NHL6 was significantly induced by salicylic acid and NHL6s are evolutionarily conserved among different plant species. A working model of NHL6 in ABA response was proposed.
Partial Blood Recirculation: A New Trial for Prolonging Filter Life During Continuous Hemodiafiltration

Abstract: Although continuous hemodiafiltration (CHDF) has been widely accepted in the management of complicated acute renal failure, the requirement for prolonged continuous systemic anticoagulation appears to be a major drawback. We herein describe the case of a patient who developed postoperative multiple organ failure and received CHDF therapy with partial blood recirculation (PBR). PBR is a mode of extracorporeal circulation used as an anticoagulation modality. The technique accelerates the blood flow rate with the goal of extending filter life, and it was performed because the filter life had been significantly shortened (10.5 ± 5.1 h) during the CHDF process in this case. Despite increasing the dose of the anticoagulant, changing the hemofilter and changing the mode from postdilution to predilution, we did not obtain amelioration of filter life. The filter life was significantly improved (41.5 ± 1.4 h) when we performed PBR. It is difficult to minimize the bleeding risk and maintain filter life during CHDF. Our success in prolonging the filter life during this case therefore suggests that PBR might resolve one of the main problems related to CHDF, although more study is needed to clarify the advantages of this system.
Dose Determination of Cinacalcet Hydrochloride in Japanese Hemodialysis Patients With Secondary Hyperparathyroidism

Abstract: Cinacalcet hydrochloride is a calcimimetic agent that activates the calcium‐sensing receptor on the surface of parathyroid cells and inhibits parathyroid hormone (PTH) secretion. To manage secondary hyperparathyroidism, cinacalcet, which lowers PTH levels without increasing serum calcium, phosphorus and calcium–phosphorus product (Ca × P) levels, may provide a new potential therapy. To identify the optimal starting dose of cinacalcet for Japanese hemodialysis patients with secondary hyperparathyroidism, this double‐blind, placebo‐controlled, parallel, dose‐finding study was conducted. One hundred and twenty Japanese hemodialysis patients with intact PTH levels greater than or equal to 300 pg/mL were randomized into four groups: placebo, and 12.5, 25 and 50 mg of cinacalcet. The treatment period was three weeks followed by a two‐week follow‐up observation period. Cinacalcet decreased serum intact PTH levels in a dose‐dependent manner, and also decreased serum calcium, phosphorus, Ca × P, tartrate‐resistant acid phosphatase and osteocalcin levels. The treatment with cinacalcet was generally well tolerated in this study. However, the incidence of treatment‐related adverse events, such as gastrointestinal disorders and hypocalcemia, and the rate of withdrawal from the study due to treatment‐related adverse events were higher in the 50 mg dose group than in the other groups. On the basis of both efficacy and safety results, 25 mg has been identified as the optimal starting dose of cinacalcet for Japanese hemodialysis patients with secondary hyperparathyroidism.
Current progress in orchid flowering/flower development research

ABSTRACT Genetic pathways relevant to flowering of Arabidopsis are under the control of environmental cues such as day length and temperatures, and endogenous signals including phytohormones and developmental aging. However, genes and even regulatory pathways for flowering identified in crops show divergence from those of Arabidopsis and often do not have functional equivalents to Arabidopsis and/or existing species- or genus-specific regulators and show modified or novel pathways. Orchids are the largest, most highly evolved flowering plants, and form an extremely peculiar group of plants. Here, we briefly summarize the flowering pathways of Arabidopsis, rice and wheat and present them alongside recent discoveries/progress in orchid flowering and flower developmental processes including our transgenic Phalaenopsis orchids for LEAFY overexpression. Potential biotechnological applications in flowering/flower development of orchids with potential target genes are also discussed from an interactional and/or comparative viewpoint.
A Case Report of the Modified Malmö Protocol: An Alternative Therapeutic Approach to Refractory Chronic Idiopathic Thrombocytopenic Purpura

Abstract: Therapy in refractory chronic idiopathic thrombocytopenic purpura is usually a difficult and expensive procedure, with little benefit to the patient, and the results are typically only short‐term improvements. In this case report, we study a patient with refractory chronic idiopathic thrombocytopenic purpura who was initially treated with a first line therapy with only partial and temporary benefit, and in whom none of the experimental therapies tried later on resulted in any long lasting effect. In the case study conducted, among all the second‐line experimental treatment modalities, only the proposed new protocol (the Modified Malmö Protocol) resulted in a major response. Our results suggest that, the Modified Malmö Protocol may be a promising second‐line treatment option for severely refractory idiopathic thrombocytopenic purpura cases.
Criteria for Direct Hemoperfusion With an Immobilized Polymyxin B Fiber Column Based on Oxygen Metabolism

Abstract: The optimum time for commencement of direct hemoperfusion with a polymyxin B immobilized fiber column (DHP‐PMX) in patients with sepsis remains unclear. We retrospectively studied the response to DHP‐PMX in relation to parameters of oxygen metabolism in 48 patients with sepsis who were divided into two groups. In the effective group (N = 36), the mean blood pressure increased by at least 10 mm Hg after DHP‐PMX. Patients who did not show such a blood pressure elevation were assigned to the non‐effective group (N = 12). Before the start of therapy, various parameters (mixed venous oxygen saturation, oxygen delivery index, oxygen consumption index (VO2I), oxygen extraction ratio, gastric mucosal–arterial PCO2 difference, age, systemic vascular resistance index, Acute Physiology and Chronic Health Evaluation II score, and Sequential Organ Failure Assessment score were measured in both groups. These parameters were then compared between the two groups. Only VO2I showed a significant difference between the two groups, and all patients in the effective group had a VO2I of 100 mL/min/m2 or more. Based on these results, DHP‐PMX should be introduced during the period when VO2I is still equal to or greater than 100 mL/min/m2.
The coding sequence of firefly luciferase reporter gene affects specific hyperexpression in Arabidopsis thaliana cpl1 mutant

ABSTRACT Forward genetic screening of mutants using firefly luciferase (LUC) reporter gene became a standard practice in plant research. Such screenings frequently identified alleles of CPL1 (Carboxyl-terminal Phosphatase-Like 1) regardless of promoters or pathways studied. Expression of the corresponding endogenous genes often shows the minimal difference between wild type and cpl1. Here we show that the LUC coding sequence is responsible for the high expression in cpl1, using a classical RD29a-LUC. Deletion of the LUC 3′-UTR did not change hyperactivation of LUC in cpl1. However, a codon-modified LUC (LUC2) produced similar expression levels both in wild type and in cpl1. These results indicate that the coding region of LUC is responsible for the cpl1-specific LUC overexpression uncoupled with the expression of the endogenous counterpart.
Arabidopsis thaliana Acyl-CoA-binding protein ACBP6 interacts with plasmodesmata-located protein PDLP8

ABSTRACT In Arabidopsis thaliana, six acyl-CoA-binding proteins (ACBPs), designated as AtACBP1 to AtACBP6, have been identified to function in various events related to plant stress and development. The 10-kDa AtACBP6 is the smallest in this protein family, and recombinant AtACBP6 interacts with lipids in vitro by binding to acyl-CoA esters and phosphatidylcholine. Using anti-AtACBP6 antibodies in immunoelectron microscopy, we have localized AtACBP6 in the Arabidopsis phloem. The detection of immunogold grains in the plasmodesmata suggested that AtACBP6 could move from the companion cells to the sieve elements via the plasmodesmata. As AtACBP6 has been identified in a membrane-based interactome analysis to be a potential protein partner of Plasmodesmata-Localized Protein, PDLP8, AtACBP6-PDLP8 interaction was investigated herein utilizing isothermal titration calorimetry, as well as pull-down and bimolecular fluorescence complementation assays (BiFC). Notably, BiFC data revealed that AtACBP6-PDLP8 interaction occurred at the plasma membrane, which was unexpected as AtACBP6 has been previously identified in the cytosol. AtACBP6 expression was generally higher than PDLP8 in β-glucuronidase (GUS) assays on transgenic Arabidopsis transformed with AtACBP6 or PDLP8 promoter-driven GUS, consistent with qRT-PCR and microarray results. Furthermore, western blot analysis using anti-AtACBP6 antibodies showed a reduction in AtACBP6 expression in the pdlp8 T-DNA insertional mutant, suggesting that PDLP8 may possibly influence AtACBP6 accumulation in the sieve elements, probably in the plasmodesmata, where PDLP8 is confined and to where AtACBP6 has been immunodetected.
Expression profiling of development related genes in rice plants ectopically expressing AtTOR

ABSTRACT Expression analysis of genes associated with development at different growth stages such as shoot apical meristem (SAM), root apical meristem (RAM), shoot and root tissues 10 DAG, flowers and grains of 2 high expression transgenic lines of rice ectopically expressing AtTOR revealed the involvement of AtTOR in transcriptional regulation of these genes. We have observed that in the SAM of these 2 selected lines, TR-2.24 and TR-15.1, OsFON1 and OsFON4 (orthologs of AtCLV1 and AtCLV3, respectively), OsKNOX2, OsKNOX3 and OsWOX3 became upregulated. The upregulation of OsFON1 and OsFON4 is likely to be involved in the maintenance of effective meristem size of the inflorescence and phyllotaxis. The grains and spikes of transgenic plants exhibited enhanced transcript levels of OsMADS1, OsMADS6, and OsMADS29 further implicating the role of TOR in modulating the expression of the genes in rice grain formation and development. Moreover, the upregulation of auxin transporter, PIN1c in RAM and roots derived from seedlings 10 DAG showed the involvement of TOR in root development. The seeds of 2 high expression lines also showed increased expression of OSE2 and GAMYB transcription factors involved in seed development. In summary, the present study, by heterologous expression of AtTOR in rice, demonstrated the involvement of TOR in regulating genes involved in various growth and developmental stages of rice plant and also in photosynthesis, productivity related functions and water-use efficiency.
Broadband over Power Lines Systems Convergence: Multiple-Input Multiple-Output Communications Analysis of Overhead and Underground Low-Voltage and Medium-Voltage BPL Networks

This review paper reveals the broadband potential of overhead and underground low-voltage (LV) and medium-voltage (MV) broadband over power lines (BPL) networks associated with multiple-input multiple-output (MIMO) technology. The contribution of this review paper is fourfold. First, the unified value decomposition (UVD) modal analysis is introduced. UVD modal analysis is a new technique that unifies eigenvalue decomposition (EVD) and singular value decomposition (SVD) modal analyses achieving the common handling of traditional SISO/BPL and upcoming MIMO/BPL systems. The validity of UVD modal analysis is examined by comparing its simulation results with those of other exact analytical models. Second, based on the proposed UVD modal analysis, the MIMO channels of overhead and underground LV and MV BPL networks (distribution BPL networks) are investigated with regard to their inherent characteristics. Towards that direction, an extended collection of well-validated metrics from the communications literature, such as channel attenuation, average channel gain (ACG), root-mean-square delay spread (RMS-DS), coherence bandwidth (CB), cumulative capacity, capacity complementary cumulative distribution function (CCDF), and capacity gain (GC), is first applied in overhead and underground MIMO/LV and MIMO/MV BPL channels and systems. It is found that the results of the aforementioned metrics portfolio depend drastically on the frequency, the power grid type (either overhead or underground, either LV or MV), the MIMO scheme configuration properties, the MTL configuration, the physical properties of the cables used, the end-to-end distance, and the number, the electrical length, and the terminations of the branches encountered along the end-to-end BPL signal propagation. Third, three interesting findings concerning the statistical properties of MIMO channels of distribution BPL networks are demonstrated, namely, (i) the ACG, RMS-DS, and cumulative capacity lognormal distributions; (ii) the correlation between RMS-DS and ACG; and (iii) the correlation between RMS-DS and CB. By fitting the numerical results, unified regression distributions appropriate for MIMO/BPL channels and systems are proposed. These three fundamental properties can play significant role in the evaluation of recently proposed statistical channel models for various BPL systems. Fourth, the potential of transformation of overhead and underground LV/BPL and MV/BPL distribution grids to an alternative solution to fiber-to-the-building (FTTB) technology is first revealed. By examining the capacity characteristics of various MIMO scheme configurations and by comparing these capacity results against SISO ones, a new promising urban backbone network seems to be born in a smart grid (SG) environment.
A single session of rTMS over the left dorsolateral prefrontal cortex influences attentional control in depressed patients

Depressed patients are impaired in the ability to shift their focus of attention. This attentional control process is related to dysfunctions in the dorsolateral prefrontal cortex (DLPFC). It has been proposed that a dorsal circuit plays an important role in the interaction between emotional and attentional information processing. However, because the different emphasis of fundamental cognitive neuroscience research and clinical research of repetitive transcranial magnetic stimulation (rTMS) over the DLPFC, little research has been done on the effects of rTMS on cognitive functioning after a single stimulation session to explore the neural systems underlying depression. This study was conducted as a double-blind, placebo-controlled, crossover, within subjects design. Sixteen depressed patients performed a modified task switching paradigm, before and after receiving high frequency (HF) versus placebo rTMS over the left DLPFC. One session of HF- rTMS over the left DLPFC had a specific beneficial effect on task-switching performance, whereas mood remained stable. Antidepressant effects of rTMS could be related to the same neurochemical changes that underlie cognitive functioning. Therefore, task switching performance may provide a unique window into the extent of antidepressant effects which can be considered as second-order long-term effects possibly related to primary alternations in cognitive functioning.
A phosphokinome‐based screen uncovers new drug synergies for cancer driven by liver‐specific gain of nononcogenic receptor tyrosine kinases

Genetic mutations leading to oncogenic variants of receptor tyrosine kinases (RTKs) are frequent events during tumorigenesis; however, the cellular vulnerability to nononcogenic RTK fluctuations has not been characterized. Here, we demonstrated genetically that in the liver subtle increases in wild‐type Met RTK levels are sufficient for spontaneous tumors in mice (Alb‐R26Met), conceptually illustrating how the shift from physiological to pathological conditions results from slight perturbations in signaling dosage. By analyzing 96 different genes in a panel of tumor samples, we demonstrated that liver tumorigenesis modeled by Alb‐R26Met mice corresponds to a subset of hepatocellular carcinoma (HCC) patients, thus establishing the clinical relevance of this HCC mouse model. We elucidated the regulatory networks underlying tumorigenesis by combining a phosphokinome screen with bioinformatics analysis. We then used the signaling diversity results obtained from Alb‐R26Met HCC versus control livers to design an “educated guess” drug screen, which led to the identification of new, deleterious synthetic lethal interactions. In particular, we report synergistic effects of mitogen‐activated protein kinase kinase, ribosomal S6 kinase, and cyclin‐dependent kinase 1/2 in combination with Bcl‐XL inhibition on a panel of liver cancer cells. Focusing on mitogen‐activated protein kinase kinase and Bcl‐XL targeting, we mechanistically demonstrated concomitant down‐regulation of phosphorylated extracellular signal–regulated kinase and myeloid cell leukemia 1 levels. Of note, a phosphorylated extracellular signal–regulated kinase+/BCL‐XL+/myeloid cell leukemia 1+ signature, deregulated in Alb‐R26Met tumors, characterizes a subgroup of HCC patients with poor prognosis. Conclusion: Our genetic studies highlight the heightened vulnerability of liver cells to subtle changes in nononcogenic RTK levels, allowing them to acquire a molecular profile that facilitates the full tumorigenic program; furthermore, our outcomes uncover new synthetic lethal interactions as potential therapies for a cluster of HCC patients. (Hepatology 2017;66:1644–1661).