Skip to main content

Rob Li

Followers

8

Following

2

Co-author

1

Public Views

Hussam Al-Humadi

University of Babylon

Jose Alberto Suarez Mato

Richard H Finnell

The University of Texas at Austin

Interests

Uploads

Papers by Rob Li

Phosphatidylcholine and choline homeostasis

The Journal of Lipid Research

Phosphatidylcholine (PC) is made in mammalian cells from choline via the CDP-choline pathway. Ani... more Phosphatidylcholine (PC) is made in mammalian cells from choline via the CDP-choline pathway. Animals obtain choline primarily from the diet or from the conversion of phosphatidylethanolamine (PE) to PC followed by catabolism to choline. The main fate of choline is the synthesis of PC. In addition, choline is oxidized to betaine in kidney and liver and converted to acetylcholine in the nervous system. Mice that lack choline kinase (CK) alpha die during embryogenesis, whereas mice that lack CKbeta unexpectedly develop muscular dystrophy. Mice that lack CTP:phosphocholine cytidylyltransferase (CT) alpha also die during early embryogenesis, whereas mice that lack CTbeta exhibit gonadal dysfunction. The cytidylyltransferase beta isoform also plays a role in the branching of axons of neurons. An alternative PC biosynthetic pathway in the liver uses phosphatidylethanolamine N-methyltransferase to catalyze the formation of PC from PE. Mice that lack the methyltransferase survive but die fr...

A framework for ordering composite beliefs in belief networks

IEEE Transactions on Systems, Man, and Cybernetics, 1995

ABSTRACT Given a belief network with evidence, the task of finding the l most probable explanatio... more ABSTRACT Given a belief network with evidence, the task of finding the l most probable explanations (MPE) in the belief network is that of identifying and ordering the l most probable instantiations of the nonevidence nodes. Although many approaches have been proposed for solving this problem, most work only for restricted topologies (e.g., singly connected belief networks). In this paper we will present a framework, optimal factoring, for finding the l MPEs in arbitrary belief networks. Under this framework, efficiently finding the MPE in a belief network can be considered as the problem of finding an ordering of the distributions of the belief network and efficiently combining them. We will discuss the essence of the problem of finding the MPE, and present an optimal algorithm for singly connected belief networks and an efficient algorithm for multiply connected belief networks. We will also discuss the problem of finding the MPE for a subset of variables of a belief network under this framework

A novel chalcone derivative attenuates the diabetes-induced renal injury via inhibition of high glucose-mediated inflammatory response and macrophage infiltration

Toxicology and applied pharmacology, Jan 15, 2015

Inflammation plays a central role in the development and progression of diabetic nephropathy (DN)... more Inflammation plays a central role in the development and progression of diabetic nephropathy (DN). Researches on novel anti-inflammatory agents may offer new opportunities for the treatment of DN. We previously found a chalcone derivative L6H21 could inhibit LPS-induced cytokine release from macrophages. The aim of this study was to investigate whether L6H21 could ameliorate the high glucose-mediated inflammation in NRK-52E cells and attenuate the inflammation-mediated renal injury. According to the results, L6H21 showed a great inhibitory effect on the expression of pro-inflammatory cytokines, cell adhesion molecules, chemokines, and macrophage adhesion via down-regulation of NF-κB/MAPKs activity in high glucose-stimulated renal NRK-52E cells. Further, in vivo oral administration with L6H21 at a dosage of 20 mg/kg/2 days showed a decreased expression of pro-inflammatory cytokines, cell adhesion molecules, which subsequently contributed to the inhibition on renal macrophage infiltra...

An efficient approach for finding the MPE in belief networks

Uncertainty in Artificial Intelligence, 1993

Given a belief network with evidence, the task of finding the l most probable ex planations (MPE)... more Given a belief network with evidence, the task of finding the l most probable ex planations (MPE) in the belief network is that of identifying and ordering the l most probable instantiations of the non-evidence nodes of the belief network. Although many approaches have been proposed for solving this problem, most work only for restricted topologies (i.e., singly connected belief net works). In this paper, we will present a new approach for finding l MPEs in an arbitrary belief network. First, we will present an al gorithm for finding the MPE in a belief net work. Then, we will present a linear time al gorithm for finding the next MPE after find ing the first MPE. And finally, we will discuss the problem of fi nding the MPE for a subset of variables of a belief network, and show that the problem can be efficiently solved by this approach.

Protein tyrosine phosphatase of liver regeneration-1 is required for normal timing of cell cycle progression during liver regeneration

American Journal of Physiology - Gastrointestinal and Liver Physiology, 2014

Protein tyrosine phosphatase of liver regeneration-1 (Prl-1) is an immediate-early gene that is s... more Protein tyrosine phosphatase of liver regeneration-1 (Prl-1) is an immediate-early gene that is significantly induced during liver regeneration. Several in vitro studies have suggested that Prl-1 is important for the regulation of cell cycle progression. To evaluate its function in liver regeneration, we ablated the Prl-1 gene specifically in mouse hepatocytes using the Cre-loxP system. Prl-1 mutant mice (Prl-1(loxP/loxP);AlfpCre) appeared normal and fertile. Liver size and metabolic function in Prl-1 mutants were comparable to controls, indicating that Prl-1 is dispensable for liver development, postnatal growth, and hepatocyte differentiation. Mutant mice demonstrated a delay in DNA synthesis after 70% partial hepatectomy, although ultimate liver mass restoration was not affected. At 40 h posthepatectomy, reduced protein levels of the cell cycle regulators cyclin E, cyclin A2, cyclin B1, and cyclin-dependent kinase 1 were observed in Prl-1 mutant liver. Investigation of the major signaling pathways involved in liver regeneration demonstrated that phosphorylation of protein kinase B (AKT) and signal transducer and activator of transcription (STAT) 3 were significantly reduced at 40 h posthepatectomy in Prl-1 mutants. Taken together, this study provides evidence that Prl-1 is required for proper timing of liver regeneration after partial hepatectomy. Prl-1 promotes G1/S progression via modulating expression of several cell cycle regulators through activation of the AKT and STAT3 signaling pathway.

Cloning, expression, and protective immunity in mice of a gene encoding the diagnostic antigen P-29 of Echinococcus granulosus

Acta biochimica et biophysica Sinica, 2009

Taeniid tapeworm Echinococcus granulosus is the causative agent of Echinococcosis, an important z... more Taeniid tapeworm Echinococcus granulosus is the causative agent of Echinococcosis, an important zoonosis with worldwide distribution. In this study, a diagnostic antigen P-29 was cloned from E. granulosus and expressed in Escherichia coli. Sequence analysis showed that EgP-29 contains 717-bp open reading frame and encodes a protein of 238 amino acid residues with a predicted molecular weight of 27.1 kDa. The recombinant EgP-29 (rEgP-29) could be recognized with antimice sera in Western blotting. The specific antibody was detected by enzyme-linked immunosorbent assay. Mice vaccinated with rEgP-29 and challenged intraperitoneally with E. granulosus protoscoleces revealed significant protective immunity of 96.6% (P<0.05), compared with the control group. Thus, rEgP-29 protein is a promising candidate for an effective vaccine to prevent secondary echinococcosis.

The nucleosome map of the mammalian liver

Nature Structural & Molecular Biology, 2011

Binding to nucleosomal DNA is critical for 'pioneer' transcription factors such as the winged-hel... more Binding to nucleosomal DNA is critical for 'pioneer' transcription factors such as the winged-helix transcription factors Foxa1 and Foxa2 to regulate chromatin structure and gene activation. Here we report the genome-wide map of nucleosome positions in the mouse liver, with emphasis on transcriptional start sites, CpG islands, Foxa2 binding sites and their correlation with gene expression. Despite the heterogeneity of liver tissue, we could clearly discern the nucleosome pattern of the predominant liver cell, the hepatocyte. By analyzing nucleosome occupancy and the distributions of heterochromatin protein 1 (Hp1), CBP (also known as Crebbp) and p300 (Ep300) in Foxa1-and Foxa2-deficient livers, we find that the maintenance of nucleosome position and chromatin structure surrounding Foxa2 binding sites is independent of Foxa1 and Foxa2.

Parallelizing Probabilistic Inference Some Early Explorations

by Tony Fountain and Rob Li

Uncertainty in Artificial Intelligence, 1992

We report on an experimental investigation into opportunities for parallelism in belief net infer... more We report on an experimental investigation into opportunities for parallelism in belief net inference. Specifically, we report on a study performed of the available parallelism, on hypercube style machines, of a set of ran domly generated belief nets, using factoring (SPI) style inference algorithms. Our results indicate that substantial speedup is available, but that it is available only through paral lelization of individual conformal product op erations, and depends critically on finding an appropriate factoring. We find negligible op portunity for parallelism at the topological, or clustering tree, level.

Echinococcus granulosus: Immunoprotection accompanyied by humoral and cytokine response against secondary hydatidosis in mice immunized with rEg.myophilin

Veterinary Research Communications, 2011

Objects: This study aimed to investigate the immunoprotection of the recombinant Eg. myophilin (r... more Objects: This study aimed to investigate the immunoprotection of the recombinant Eg. myophilin (rEg.myophilin) and tentatively analyze mechanism of this protection. Materials and Method: Three groups of female mice were immunized subcutaneously with rEg.myophilin and contrasts, after two boosters, mice were challenged with Eg protoscoleces (PSCs) intraperitoneally, and then analyzed the humoral immune response with specific IgG, IgG1, IgG2a, IgG2b, IgG3 and IgE, and also evaluated the cellular immune with IFN-γ, IL-4, IL-10. Results: Mice immunized with rEg.myophilin produced effective immunity protection (reductions in cyst load more than 86.11%). Mice immunized with rEg.myophilin showed specific IgG, IgG1, IgG2a and IgE accompanied by IFN-γand IL-4 significantly increased after one or more times of immunization, but neither IgG2b nor IgG3 increased. Nevertheless, IL-10 significantly increased in the control groups but a decline trend in rEg.myophilin group.

Dissecting a central flip-flop circuit that integrates contradictory sensory cues in C. elegans feeding regulation

Nature Communications, 2012

Feeding behaviour is modulated by both environmental cues and internal physiological states. Appe... more Feeding behaviour is modulated by both environmental cues and internal physiological states. Appetite is commonly boosted by the pleasant smell (or appearance) of food and destroyed by a bad taste. In reality, animals sense multiple environmental cues at the same time and it is not clear how these sensory inputs are integrated and a decision is made to regulate feeding behaviour accordingly. Here we show that feeding behaviour in Caenorhabditis elegans can be either facilitated by attractive odours or suppressed by repellents. By identifying mutants that are defective for sensory-mediated feeding regulation, we dissected a central flip-flop circuit that integrates two contradictory sensory inputs and generates bistable hormone output to regulate feeding behaviour. As feeding regulation is fundamental to animal survival, we speculate that the basic organizational logic identified here in C. elegans is likely convergent throughout different phyla.

Species-Specific Strategies Underlying Conserved Functions of Metabolic Transcription Factors

Molecular Endocrinology, 2011

The winged helix protein FOXA2 and the nuclear receptor peroxisome proliferator-activated recepto... more The winged helix protein FOXA2 and the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) are highly conserved, regionally expressed transcription factors (TFs) that regulate networks of genes controlling complex metabolic functions. Cistrome analysis for Foxa2 in mouse liver and PPARγ in mouse adipocytes has previously produced consensus-binding sites that are nearly identical to those used by the corresponding TFs in human cells. We report here that, despite the conservation of the canonical binding motif, the great majority of binding regions for FOXA2 in human liver and for PPARγ in human adipocytes are not in the orthologous locations corresponding to the mouse genome, and vice versa. Of note, TF binding can be absent in one species despite sequence conservation, including motifs that do support binding in the other species, demonstrating a major limitation of in silico binding site prediction. Whereas only approximately 10% of binding sites are conserved, gene-centric analysis reveals that about 50% of genes with nearby TF occupancy are shared across species for both hepatic FOXA2 and adipocyte PPARγ. Remarkably, for both TFs, many of the shared genes function in tissue-specific metabolic pathways, whereas species-unique genes fail to show enrichment for these pathways. Nonetheless, the species-unique genes, like the shared genes, showed the expected transcriptional regulation by the TFs in loss-of-function experiments. Thus, species-specific strategies underlie the biological functions of metabolic TFs that are highly conserved across mammalian species. Analysis of factor binding in multiple species may be necessary to distinguish apparent species-unique noise and reveal functionally relevant information.

Thematic Review Series: Glycerolipids. Phosphatidylcholine and choline homeostasis

The Journal of Lipid Research, 2008

Phosphatidylcholine (PC) is made in mammalian cells from choline via the CDP-choline pathway. Ani... more Phosphatidylcholine (PC) is made in mammalian cells from choline via the CDP-choline pathway. Animals obtain choline primarily from the diet or from the conversion of phosphatidylethanolamine (PE) to PC followed by catabolism to choline. The main fate of choline is the synthesis of PC. In addition, choline is oxidized to betaine in kidney and liver and converted to acetylcholine in the nervous system. Mice that lack choline kinase (CK) alpha die during embryogenesis, whereas mice that lack CKbeta unexpectedly develop muscular dystrophy. Mice that lack CTP:phosphocholine cytidylyltransferase (CT) alpha also die during early embryogenesis, whereas mice that lack CTbeta exhibit gonadal dysfunction. The cytidylyltransferase beta isoform also plays a role in the branching of axons of neurons. An alternative PC biosynthetic pathway in the liver uses phosphatidylethanolamine N-methyltransferase to catalyze the formation of PC from PE. Mice that lack the methyltransferase survive but die from steatohepatitis and liver failure when placed on a choline-deficient diet. Hence, choline is an essential nutrient. PC biosynthesis is required for normal very low density lipoprotein secretion from hepatocytes. Recent studies indicate that choline is recycled in the liver and redistributed from kidney, lung, and intestine to liver and brain when choline supply is attenuated.

Foxa1 and Foxa2 regulate bile duct development in mice

Journal of Clinical Investigation, 2009

The forkhead box proteins A1 and A2 (Foxa1 and Foxa2) are transcription factors with critical rol... more The forkhead box proteins A1 and A2 (Foxa1 and Foxa2) are transcription factors with critical roles in establishing the developmental competence of the foregut endoderm and in initiating liver specification. Using conditional gene ablation during a later phase of liver development, we show here that deletion of both Foxa1 and Foxa2 (Foxa1/2) in the embryonic liver caused hyperplasia of the biliary tree. Abnormal bile duct formation in Foxa1/2-deficient liver was due, at least in part, to activation of IL-6 expression, a proliferative signal for cholangiocytes. The glucocorticoid receptor is a negative regulator of IL-6 transcription; in the absence of Foxa1/2, the glucocorticoid receptor failed to bind to the IL-6 promoter, causing enhanced IL-6 expression. Thus, after liver specification, Foxa1/2 are required for normal bile duct development through prevention of excess cholangiocyte proliferation. Our data suggest that Foxa1/2 function as terminators of bile duct expansion in the adult liver through inhibition of IL-6 expression.

Choline Redistribution during Adaptation to Choline Deprivation

Journal of Biological Chemistry, 2007

Choline is an important nutrient for mammals. Choline can also be generated by the catabolism of ... more Choline is an important nutrient for mammals. Choline can also be generated by the catabolism of phosphatidylcholine synthesized in the liver by the methylation of phosphatidylethanolamine by phosphatidylethanolamine N-methyltransferase (PEMT). Complete choline deprivation is achieved by feeding Pemt ؊/؊ mice a choline-deficient diet and is lethal due to liver failure. Mice that lack both PEMT and MDR2 (multiple drugresistant protein 2) successfully adapt to choline deprivation via hepatic choline recycling. We now report another mechanism involved in this adaptation, choline redistribution. Normal levels of choline-containing metabolites were maintained in the brains of choline-deficient Mdr2 ؊/؊ /Pemt ؊/؊ mice for 90 days despite continued choline consumption via oxidation. Choline oxidase activity had not been previously detected in the brain. Plasma levels of choline were also maintained for 90 days, whereas plasma phosphatidylcholine levels decreased by >60%.

Phosphatidylcholine Homeostasis and Liver Failure

Journal of Biological Chemistry, 2005

In mammals, the only endogenous pathway for choline biosynthesis is the methylation of phosphatid... more In mammals, the only endogenous pathway for choline biosynthesis is the methylation of phosphatidylethanolamine to phosphatidylcholine (PC) by phosphatidylethanolamine N-methyltransferase (PEMT) coupled to PC degradation. Complete choline deprivation in mice by feeding Pemt(-/-) mice a choline-deficient (CD) diet decreases hepatic PC by 50% and is lethal within 5 days. PC secretion into bile is mediated by a PC-specific flippase, multiple drug-resistant protein 2 (MDR2). Here, we report that mice that lack both PEMT and MDR2 and are fed a CD diet survive for &amp;amp;amp;amp;amp;amp;amp;amp;gt;90 days. Unexpectedly, the amount of PC also decreases by 50% in the livers of Mdr2(-/-)/Pemt(-/-) mice. The Mdr2(-/-)/Pemt(-/-) mice adapt to the severe choline deprivation via choline recycling by induction of phospholipase A(2), choline kinase, and CTP:phosphocholine cytidylyltransferase activities and by a strikingly decreased expression of choline oxidase. The ability of Mdr2(-/-)/Pemt(-/-) mice to survive complete choline deprivation suggests that acute lethality in CD-Pemt(-/-) mice results from rapid depletion of hepatic PC via biliary secretion.

Glial Expression of the Caenorhabditis elegans Gene swip-10 Supports Glutamate Dependent Control of Extrasynaptic Dopamine Signaling

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 24, 2015

Glial cells play a critical role in shaping neuronal development, structure, and function. In a s... more Glial cells play a critical role in shaping neuronal development, structure, and function. In a screen for Caenorhabditis elegans mutants that display dopamine (DA)-dependent, Swimming-Induced Paralysis (Swip), we identified a novel gene, swip-10, the expression of which in glia is required to support normal swimming behavior. swip-10 mutants display reduced locomotion rates on plates, consistent with our findings of elevated rates of presynaptic DA vesicle fusion using fluorescence recovery after photobleaching. In addition, swip-10 mutants exhibit elevated DA neuron excitability upon contact with food, as detected by in vivo Ca(2+) monitoring, that can be rescued by glial expression of swip-10. Mammalian glia exert powerful control of neuronal excitability via transporter-dependent buffering of extracellular glutamate (Glu). Consistent with this idea, swip-10 paralysis was blunted in mutants deficient in either vesicular Glu release or Glu receptor expression and could be phenocop...

Hepatic Phosphatidylethanolamine N-Methyltransferase, Unexpected Roles in Animal Biochemistry and Physiology

Journal of Biological Chemistry, 2007

Phosphatidylcholine is an essential phospholipid that is synthesized by 2 different pathways, the... more Phosphatidylcholine is an essential phospholipid that is synthesized by 2 different pathways, the CDP-choline pathway and the methylation of phosphatidylethanolamine by phosphatidylethanolamine N-methyltransferase (PEMT). Recent studies have suggested that PEMT is an important consumer of methyl groups from S-adenosylmethionine (SAM) and is a major determinant of homocysteine pools. Diabetes and all-trans-retinoic acid (ATRA) have been shown to alter the activities of several enzymes involved in methyl group metabolism. Thus, we investigated how diabetes and ATRA, individually and together, affect SAM-dependent phospholipid methylation. Rats received a single injection of streptozotocin (60 mg/kg body wt) or vehicle followed by administration of ATRA (30 mmol/kg body wt) or vehicle for 5 d. The hepatic activity of PEMT increased 50% in both diabetic rat groups, whereas administration of ATRA was without effect. In diabetic rats, plasma total homocysteine decreased 30-35% in all treatment groups as compared with the control group. Thus, alterations in the activity of PEMT were not directly correlated to changes in homocysteine concentrations. Moreover, treatment of diabetic rats with insulin prevented the increase in PEMT activity and abundance. Because these observations support an increased need for SAM-dependent phosphatidylcholine synthesis, this may also indicate an increased choline requirement in diabetes.

Interplay of estrogen receptors and FOXA factors in the liver cancer

Molecular and Cellular Endocrinology, 2015

Liver cancer is the fifth most common cancer in human with male dominance. Sexual dimorphism of l... more Liver cancer is the fifth most common cancer in human with male dominance. Sexual dimorphism of liver cancer is conserved from rodents to humans, which was firstly found in mice in late 1930s and female mice were resistant to liver cancer. Sex hormones were found to affect the incidence of liver cancer in rodents. Estrogen receptor alpha (ERα)-mediated estrogen signaling or androgen receptor-mediated androgen signaling prevents or promotes the growth of rodent liver tumors, respectively. Forkhead box protein A (Foxa) factors, Foxa1 and Foxa2, also known as pioneer transcription factors in liver specification, are essential for both estrogen and androgen signaling by acting as central regulators of sexual dimorphism in liver cancer. This review mainly focuses on the interplay between ERα and FOXA factors in liver cancer, and summarizes recent breakthrough studies in elucidating the mechanisms of sexual dimorphism in liver cancer.

Efficient inference in Bayes networks as a combinatorial optimization problem

International Journal of Approximate Reasoning, 1994

A number of exact algorithms have been developed to perform probabilistic inference in Bayesian b... more A number of exact algorithms have been developed to perform probabilistic inference in Bayesian belief networks in recent years. The techniques used in these algorithms are closely related to network structures and some of them are not easy to understand and implement. In this paper, we consider the problem from the combinatorial optimization point of view and state that ecient probabilistic inference i n a b elief network is a problem of nding an optimal factoring given a set of probability distributions. From this viewpoint, previously developed algorithms can be seen as alternate factoring strategies. In this paper, we dene a combinatorial optimization problem, the optimal factoring problem, and discuss application of this problem in belief networks. We show that optimal factoring provides insight into the key elements of ecient probabilistic inference, and demonstrate simple, easily implemented algorithms with excellent performance.

Encoding of both analog- and digital-like behavioral outputs by one C. elegans interneuron

Cell, Jan 6, 2014

Model organisms usually possess a small nervous system but nevertheless execute a large array of ... more Model organisms usually possess a small nervous system but nevertheless execute a large array of complex behaviors, suggesting that some neurons are likely multifunctional and may encode multiple behavioral outputs. Here, we show that the C. elegans interneuron AIY regulates two distinct behavioral outputs: locomotion speed and direction-switch by recruiting two different circuits. The "speed" circuit is excitatory with a wide dynamic range, which is well suited to encode speed, an analog-like output. The "direction-switch" circuit is inhibitory with a narrow dynamic range, which is ideal for encoding direction-switch, a digital-like output. Both circuits employ the neurotransmitter ACh but utilize distinct postsynaptic ACh receptors, whose distinct biophysical properties contribute to the distinct dynamic ranges of the two circuits. This mechanism enables graded C. elegans synapses to encode both analog- and digital-like outputs. Our studies illustrate how an in...

Phosphatidylcholine and choline homeostasis

The Journal of Lipid Research

Phosphatidylcholine (PC) is made in mammalian cells from choline via the CDP-choline pathway. Ani... more Phosphatidylcholine (PC) is made in mammalian cells from choline via the CDP-choline pathway. Animals obtain choline primarily from the diet or from the conversion of phosphatidylethanolamine (PE) to PC followed by catabolism to choline. The main fate of choline is the synthesis of PC. In addition, choline is oxidized to betaine in kidney and liver and converted to acetylcholine in the nervous system. Mice that lack choline kinase (CK) alpha die during embryogenesis, whereas mice that lack CKbeta unexpectedly develop muscular dystrophy. Mice that lack CTP:phosphocholine cytidylyltransferase (CT) alpha also die during early embryogenesis, whereas mice that lack CTbeta exhibit gonadal dysfunction. The cytidylyltransferase beta isoform also plays a role in the branching of axons of neurons. An alternative PC biosynthetic pathway in the liver uses phosphatidylethanolamine N-methyltransferase to catalyze the formation of PC from PE. Mice that lack the methyltransferase survive but die fr...

A framework for ordering composite beliefs in belief networks

IEEE Transactions on Systems, Man, and Cybernetics, 1995

ABSTRACT Given a belief network with evidence, the task of finding the l most probable explanatio... more ABSTRACT Given a belief network with evidence, the task of finding the l most probable explanations (MPE) in the belief network is that of identifying and ordering the l most probable instantiations of the nonevidence nodes. Although many approaches have been proposed for solving this problem, most work only for restricted topologies (e.g., singly connected belief networks). In this paper we will present a framework, optimal factoring, for finding the l MPEs in arbitrary belief networks. Under this framework, efficiently finding the MPE in a belief network can be considered as the problem of finding an ordering of the distributions of the belief network and efficiently combining them. We will discuss the essence of the problem of finding the MPE, and present an optimal algorithm for singly connected belief networks and an efficient algorithm for multiply connected belief networks. We will also discuss the problem of finding the MPE for a subset of variables of a belief network under this framework

A novel chalcone derivative attenuates the diabetes-induced renal injury via inhibition of high glucose-mediated inflammatory response and macrophage infiltration

Toxicology and applied pharmacology, Jan 15, 2015

Inflammation plays a central role in the development and progression of diabetic nephropathy (DN)... more Inflammation plays a central role in the development and progression of diabetic nephropathy (DN). Researches on novel anti-inflammatory agents may offer new opportunities for the treatment of DN. We previously found a chalcone derivative L6H21 could inhibit LPS-induced cytokine release from macrophages. The aim of this study was to investigate whether L6H21 could ameliorate the high glucose-mediated inflammation in NRK-52E cells and attenuate the inflammation-mediated renal injury. According to the results, L6H21 showed a great inhibitory effect on the expression of pro-inflammatory cytokines, cell adhesion molecules, chemokines, and macrophage adhesion via down-regulation of NF-κB/MAPKs activity in high glucose-stimulated renal NRK-52E cells. Further, in vivo oral administration with L6H21 at a dosage of 20 mg/kg/2 days showed a decreased expression of pro-inflammatory cytokines, cell adhesion molecules, which subsequently contributed to the inhibition on renal macrophage infiltra...

An efficient approach for finding the MPE in belief networks

Uncertainty in Artificial Intelligence, 1993

Given a belief network with evidence, the task of finding the l most probable ex planations (MPE)... more Given a belief network with evidence, the task of finding the l most probable ex planations (MPE) in the belief network is that of identifying and ordering the l most probable instantiations of the non-evidence nodes of the belief network. Although many approaches have been proposed for solving this problem, most work only for restricted topologies (i.e., singly connected belief net works). In this paper, we will present a new approach for finding l MPEs in an arbitrary belief network. First, we will present an al gorithm for finding the MPE in a belief net work. Then, we will present a linear time al gorithm for finding the next MPE after find ing the first MPE. And finally, we will discuss the problem of fi nding the MPE for a subset of variables of a belief network, and show that the problem can be efficiently solved by this approach.

Protein tyrosine phosphatase of liver regeneration-1 is required for normal timing of cell cycle progression during liver regeneration

American Journal of Physiology - Gastrointestinal and Liver Physiology, 2014

Protein tyrosine phosphatase of liver regeneration-1 (Prl-1) is an immediate-early gene that is s... more Protein tyrosine phosphatase of liver regeneration-1 (Prl-1) is an immediate-early gene that is significantly induced during liver regeneration. Several in vitro studies have suggested that Prl-1 is important for the regulation of cell cycle progression. To evaluate its function in liver regeneration, we ablated the Prl-1 gene specifically in mouse hepatocytes using the Cre-loxP system. Prl-1 mutant mice (Prl-1(loxP/loxP);AlfpCre) appeared normal and fertile. Liver size and metabolic function in Prl-1 mutants were comparable to controls, indicating that Prl-1 is dispensable for liver development, postnatal growth, and hepatocyte differentiation. Mutant mice demonstrated a delay in DNA synthesis after 70% partial hepatectomy, although ultimate liver mass restoration was not affected. At 40 h posthepatectomy, reduced protein levels of the cell cycle regulators cyclin E, cyclin A2, cyclin B1, and cyclin-dependent kinase 1 were observed in Prl-1 mutant liver. Investigation of the major signaling pathways involved in liver regeneration demonstrated that phosphorylation of protein kinase B (AKT) and signal transducer and activator of transcription (STAT) 3 were significantly reduced at 40 h posthepatectomy in Prl-1 mutants. Taken together, this study provides evidence that Prl-1 is required for proper timing of liver regeneration after partial hepatectomy. Prl-1 promotes G1/S progression via modulating expression of several cell cycle regulators through activation of the AKT and STAT3 signaling pathway.

Cloning, expression, and protective immunity in mice of a gene encoding the diagnostic antigen P-29 of Echinococcus granulosus

Acta biochimica et biophysica Sinica, 2009

Taeniid tapeworm Echinococcus granulosus is the causative agent of Echinococcosis, an important z... more Taeniid tapeworm Echinococcus granulosus is the causative agent of Echinococcosis, an important zoonosis with worldwide distribution. In this study, a diagnostic antigen P-29 was cloned from E. granulosus and expressed in Escherichia coli. Sequence analysis showed that EgP-29 contains 717-bp open reading frame and encodes a protein of 238 amino acid residues with a predicted molecular weight of 27.1 kDa. The recombinant EgP-29 (rEgP-29) could be recognized with antimice sera in Western blotting. The specific antibody was detected by enzyme-linked immunosorbent assay. Mice vaccinated with rEgP-29 and challenged intraperitoneally with E. granulosus protoscoleces revealed significant protective immunity of 96.6% (P<0.05), compared with the control group. Thus, rEgP-29 protein is a promising candidate for an effective vaccine to prevent secondary echinococcosis.

The nucleosome map of the mammalian liver

Nature Structural & Molecular Biology, 2011

Binding to nucleosomal DNA is critical for 'pioneer' transcription factors such as the winged-hel... more Binding to nucleosomal DNA is critical for 'pioneer' transcription factors such as the winged-helix transcription factors Foxa1 and Foxa2 to regulate chromatin structure and gene activation. Here we report the genome-wide map of nucleosome positions in the mouse liver, with emphasis on transcriptional start sites, CpG islands, Foxa2 binding sites and their correlation with gene expression. Despite the heterogeneity of liver tissue, we could clearly discern the nucleosome pattern of the predominant liver cell, the hepatocyte. By analyzing nucleosome occupancy and the distributions of heterochromatin protein 1 (Hp1), CBP (also known as Crebbp) and p300 (Ep300) in Foxa1-and Foxa2-deficient livers, we find that the maintenance of nucleosome position and chromatin structure surrounding Foxa2 binding sites is independent of Foxa1 and Foxa2.

Parallelizing Probabilistic Inference Some Early Explorations

by Tony Fountain and Rob Li

Uncertainty in Artificial Intelligence, 1992

We report on an experimental investigation into opportunities for parallelism in belief net infer... more We report on an experimental investigation into opportunities for parallelism in belief net inference. Specifically, we report on a study performed of the available parallelism, on hypercube style machines, of a set of ran domly generated belief nets, using factoring (SPI) style inference algorithms. Our results indicate that substantial speedup is available, but that it is available only through paral lelization of individual conformal product op erations, and depends critically on finding an appropriate factoring. We find negligible op portunity for parallelism at the topological, or clustering tree, level.

Echinococcus granulosus: Immunoprotection accompanyied by humoral and cytokine response against secondary hydatidosis in mice immunized with rEg.myophilin

Veterinary Research Communications, 2011

Objects: This study aimed to investigate the immunoprotection of the recombinant Eg. myophilin (r... more Objects: This study aimed to investigate the immunoprotection of the recombinant Eg. myophilin (rEg.myophilin) and tentatively analyze mechanism of this protection. Materials and Method: Three groups of female mice were immunized subcutaneously with rEg.myophilin and contrasts, after two boosters, mice were challenged with Eg protoscoleces (PSCs) intraperitoneally, and then analyzed the humoral immune response with specific IgG, IgG1, IgG2a, IgG2b, IgG3 and IgE, and also evaluated the cellular immune with IFN-γ, IL-4, IL-10. Results: Mice immunized with rEg.myophilin produced effective immunity protection (reductions in cyst load more than 86.11%). Mice immunized with rEg.myophilin showed specific IgG, IgG1, IgG2a and IgE accompanied by IFN-γand IL-4 significantly increased after one or more times of immunization, but neither IgG2b nor IgG3 increased. Nevertheless, IL-10 significantly increased in the control groups but a decline trend in rEg.myophilin group.

Dissecting a central flip-flop circuit that integrates contradictory sensory cues in C. elegans feeding regulation

Nature Communications, 2012

Feeding behaviour is modulated by both environmental cues and internal physiological states. Appe... more Feeding behaviour is modulated by both environmental cues and internal physiological states. Appetite is commonly boosted by the pleasant smell (or appearance) of food and destroyed by a bad taste. In reality, animals sense multiple environmental cues at the same time and it is not clear how these sensory inputs are integrated and a decision is made to regulate feeding behaviour accordingly. Here we show that feeding behaviour in Caenorhabditis elegans can be either facilitated by attractive odours or suppressed by repellents. By identifying mutants that are defective for sensory-mediated feeding regulation, we dissected a central flip-flop circuit that integrates two contradictory sensory inputs and generates bistable hormone output to regulate feeding behaviour. As feeding regulation is fundamental to animal survival, we speculate that the basic organizational logic identified here in C. elegans is likely convergent throughout different phyla.

Species-Specific Strategies Underlying Conserved Functions of Metabolic Transcription Factors

Molecular Endocrinology, 2011

The winged helix protein FOXA2 and the nuclear receptor peroxisome proliferator-activated recepto... more The winged helix protein FOXA2 and the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) are highly conserved, regionally expressed transcription factors (TFs) that regulate networks of genes controlling complex metabolic functions. Cistrome analysis for Foxa2 in mouse liver and PPARγ in mouse adipocytes has previously produced consensus-binding sites that are nearly identical to those used by the corresponding TFs in human cells. We report here that, despite the conservation of the canonical binding motif, the great majority of binding regions for FOXA2 in human liver and for PPARγ in human adipocytes are not in the orthologous locations corresponding to the mouse genome, and vice versa. Of note, TF binding can be absent in one species despite sequence conservation, including motifs that do support binding in the other species, demonstrating a major limitation of in silico binding site prediction. Whereas only approximately 10% of binding sites are conserved, gene-centric analysis reveals that about 50% of genes with nearby TF occupancy are shared across species for both hepatic FOXA2 and adipocyte PPARγ. Remarkably, for both TFs, many of the shared genes function in tissue-specific metabolic pathways, whereas species-unique genes fail to show enrichment for these pathways. Nonetheless, the species-unique genes, like the shared genes, showed the expected transcriptional regulation by the TFs in loss-of-function experiments. Thus, species-specific strategies underlie the biological functions of metabolic TFs that are highly conserved across mammalian species. Analysis of factor binding in multiple species may be necessary to distinguish apparent species-unique noise and reveal functionally relevant information.

Thematic Review Series: Glycerolipids. Phosphatidylcholine and choline homeostasis

The Journal of Lipid Research, 2008

Phosphatidylcholine (PC) is made in mammalian cells from choline via the CDP-choline pathway. Ani... more Phosphatidylcholine (PC) is made in mammalian cells from choline via the CDP-choline pathway. Animals obtain choline primarily from the diet or from the conversion of phosphatidylethanolamine (PE) to PC followed by catabolism to choline. The main fate of choline is the synthesis of PC. In addition, choline is oxidized to betaine in kidney and liver and converted to acetylcholine in the nervous system. Mice that lack choline kinase (CK) alpha die during embryogenesis, whereas mice that lack CKbeta unexpectedly develop muscular dystrophy. Mice that lack CTP:phosphocholine cytidylyltransferase (CT) alpha also die during early embryogenesis, whereas mice that lack CTbeta exhibit gonadal dysfunction. The cytidylyltransferase beta isoform also plays a role in the branching of axons of neurons. An alternative PC biosynthetic pathway in the liver uses phosphatidylethanolamine N-methyltransferase to catalyze the formation of PC from PE. Mice that lack the methyltransferase survive but die from steatohepatitis and liver failure when placed on a choline-deficient diet. Hence, choline is an essential nutrient. PC biosynthesis is required for normal very low density lipoprotein secretion from hepatocytes. Recent studies indicate that choline is recycled in the liver and redistributed from kidney, lung, and intestine to liver and brain when choline supply is attenuated.

Foxa1 and Foxa2 regulate bile duct development in mice

Journal of Clinical Investigation, 2009

The forkhead box proteins A1 and A2 (Foxa1 and Foxa2) are transcription factors with critical rol... more The forkhead box proteins A1 and A2 (Foxa1 and Foxa2) are transcription factors with critical roles in establishing the developmental competence of the foregut endoderm and in initiating liver specification. Using conditional gene ablation during a later phase of liver development, we show here that deletion of both Foxa1 and Foxa2 (Foxa1/2) in the embryonic liver caused hyperplasia of the biliary tree. Abnormal bile duct formation in Foxa1/2-deficient liver was due, at least in part, to activation of IL-6 expression, a proliferative signal for cholangiocytes. The glucocorticoid receptor is a negative regulator of IL-6 transcription; in the absence of Foxa1/2, the glucocorticoid receptor failed to bind to the IL-6 promoter, causing enhanced IL-6 expression. Thus, after liver specification, Foxa1/2 are required for normal bile duct development through prevention of excess cholangiocyte proliferation. Our data suggest that Foxa1/2 function as terminators of bile duct expansion in the adult liver through inhibition of IL-6 expression.

Choline Redistribution during Adaptation to Choline Deprivation

Journal of Biological Chemistry, 2007

Choline is an important nutrient for mammals. Choline can also be generated by the catabolism of ... more Choline is an important nutrient for mammals. Choline can also be generated by the catabolism of phosphatidylcholine synthesized in the liver by the methylation of phosphatidylethanolamine by phosphatidylethanolamine N-methyltransferase (PEMT). Complete choline deprivation is achieved by feeding Pemt ؊/؊ mice a choline-deficient diet and is lethal due to liver failure. Mice that lack both PEMT and MDR2 (multiple drugresistant protein 2) successfully adapt to choline deprivation via hepatic choline recycling. We now report another mechanism involved in this adaptation, choline redistribution. Normal levels of choline-containing metabolites were maintained in the brains of choline-deficient Mdr2 ؊/؊ /Pemt ؊/؊ mice for 90 days despite continued choline consumption via oxidation. Choline oxidase activity had not been previously detected in the brain. Plasma levels of choline were also maintained for 90 days, whereas plasma phosphatidylcholine levels decreased by >60%.

Phosphatidylcholine Homeostasis and Liver Failure

Journal of Biological Chemistry, 2005

In mammals, the only endogenous pathway for choline biosynthesis is the methylation of phosphatid... more In mammals, the only endogenous pathway for choline biosynthesis is the methylation of phosphatidylethanolamine to phosphatidylcholine (PC) by phosphatidylethanolamine N-methyltransferase (PEMT) coupled to PC degradation. Complete choline deprivation in mice by feeding Pemt(-/-) mice a choline-deficient (CD) diet decreases hepatic PC by 50% and is lethal within 5 days. PC secretion into bile is mediated by a PC-specific flippase, multiple drug-resistant protein 2 (MDR2). Here, we report that mice that lack both PEMT and MDR2 and are fed a CD diet survive for &amp;amp;amp;amp;amp;amp;amp;amp;gt;90 days. Unexpectedly, the amount of PC also decreases by 50% in the livers of Mdr2(-/-)/Pemt(-/-) mice. The Mdr2(-/-)/Pemt(-/-) mice adapt to the severe choline deprivation via choline recycling by induction of phospholipase A(2), choline kinase, and CTP:phosphocholine cytidylyltransferase activities and by a strikingly decreased expression of choline oxidase. The ability of Mdr2(-/-)/Pemt(-/-) mice to survive complete choline deprivation suggests that acute lethality in CD-Pemt(-/-) mice results from rapid depletion of hepatic PC via biliary secretion.

Glial Expression of the Caenorhabditis elegans Gene swip-10 Supports Glutamate Dependent Control of Extrasynaptic Dopamine Signaling

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 24, 2015

Glial cells play a critical role in shaping neuronal development, structure, and function. In a s... more Glial cells play a critical role in shaping neuronal development, structure, and function. In a screen for Caenorhabditis elegans mutants that display dopamine (DA)-dependent, Swimming-Induced Paralysis (Swip), we identified a novel gene, swip-10, the expression of which in glia is required to support normal swimming behavior. swip-10 mutants display reduced locomotion rates on plates, consistent with our findings of elevated rates of presynaptic DA vesicle fusion using fluorescence recovery after photobleaching. In addition, swip-10 mutants exhibit elevated DA neuron excitability upon contact with food, as detected by in vivo Ca(2+) monitoring, that can be rescued by glial expression of swip-10. Mammalian glia exert powerful control of neuronal excitability via transporter-dependent buffering of extracellular glutamate (Glu). Consistent with this idea, swip-10 paralysis was blunted in mutants deficient in either vesicular Glu release or Glu receptor expression and could be phenocop...

Hepatic Phosphatidylethanolamine N-Methyltransferase, Unexpected Roles in Animal Biochemistry and Physiology

Journal of Biological Chemistry, 2007

Phosphatidylcholine is an essential phospholipid that is synthesized by 2 different pathways, the... more Phosphatidylcholine is an essential phospholipid that is synthesized by 2 different pathways, the CDP-choline pathway and the methylation of phosphatidylethanolamine by phosphatidylethanolamine N-methyltransferase (PEMT). Recent studies have suggested that PEMT is an important consumer of methyl groups from S-adenosylmethionine (SAM) and is a major determinant of homocysteine pools. Diabetes and all-trans-retinoic acid (ATRA) have been shown to alter the activities of several enzymes involved in methyl group metabolism. Thus, we investigated how diabetes and ATRA, individually and together, affect SAM-dependent phospholipid methylation. Rats received a single injection of streptozotocin (60 mg/kg body wt) or vehicle followed by administration of ATRA (30 mmol/kg body wt) or vehicle for 5 d. The hepatic activity of PEMT increased 50% in both diabetic rat groups, whereas administration of ATRA was without effect. In diabetic rats, plasma total homocysteine decreased 30-35% in all treatment groups as compared with the control group. Thus, alterations in the activity of PEMT were not directly correlated to changes in homocysteine concentrations. Moreover, treatment of diabetic rats with insulin prevented the increase in PEMT activity and abundance. Because these observations support an increased need for SAM-dependent phosphatidylcholine synthesis, this may also indicate an increased choline requirement in diabetes.

Interplay of estrogen receptors and FOXA factors in the liver cancer

Molecular and Cellular Endocrinology, 2015

Liver cancer is the fifth most common cancer in human with male dominance. Sexual dimorphism of l... more Liver cancer is the fifth most common cancer in human with male dominance. Sexual dimorphism of liver cancer is conserved from rodents to humans, which was firstly found in mice in late 1930s and female mice were resistant to liver cancer. Sex hormones were found to affect the incidence of liver cancer in rodents. Estrogen receptor alpha (ERα)-mediated estrogen signaling or androgen receptor-mediated androgen signaling prevents or promotes the growth of rodent liver tumors, respectively. Forkhead box protein A (Foxa) factors, Foxa1 and Foxa2, also known as pioneer transcription factors in liver specification, are essential for both estrogen and androgen signaling by acting as central regulators of sexual dimorphism in liver cancer. This review mainly focuses on the interplay between ERα and FOXA factors in liver cancer, and summarizes recent breakthrough studies in elucidating the mechanisms of sexual dimorphism in liver cancer.

Efficient inference in Bayes networks as a combinatorial optimization problem

International Journal of Approximate Reasoning, 1994

A number of exact algorithms have been developed to perform probabilistic inference in Bayesian b... more A number of exact algorithms have been developed to perform probabilistic inference in Bayesian belief networks in recent years. The techniques used in these algorithms are closely related to network structures and some of them are not easy to understand and implement. In this paper, we consider the problem from the combinatorial optimization point of view and state that ecient probabilistic inference i n a b elief network is a problem of nding an optimal factoring given a set of probability distributions. From this viewpoint, previously developed algorithms can be seen as alternate factoring strategies. In this paper, we dene a combinatorial optimization problem, the optimal factoring problem, and discuss application of this problem in belief networks. We show that optimal factoring provides insight into the key elements of ecient probabilistic inference, and demonstrate simple, easily implemented algorithms with excellent performance.

Encoding of both analog- and digital-like behavioral outputs by one C. elegans interneuron

Cell, Jan 6, 2014

Model organisms usually possess a small nervous system but nevertheless execute a large array of ... more Model organisms usually possess a small nervous system but nevertheless execute a large array of complex behaviors, suggesting that some neurons are likely multifunctional and may encode multiple behavioral outputs. Here, we show that the C. elegans interneuron AIY regulates two distinct behavioral outputs: locomotion speed and direction-switch by recruiting two different circuits. The "speed" circuit is excitatory with a wide dynamic range, which is well suited to encode speed, an analog-like output. The "direction-switch" circuit is inhibitory with a narrow dynamic range, which is ideal for encoding direction-switch, a digital-like output. Both circuits employ the neurotransmitter ACh but utilize distinct postsynaptic ACh receptors, whose distinct biophysical properties contribute to the distinct dynamic ranges of the two circuits. This mechanism enables graded C. elegans synapses to encode both analog- and digital-like outputs. Our studies illustrate how an in...