- (DTW)-T-3: Discriminative Differentiable Dynamic Time Warping for Weakly Supervised Action Alignment and Segmentation IEEE COMPUTER SOC. 2019: 3541–50
- Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) AUTOPHAGY 2016; 12 (1): 1-222
- Adaptive Human CDKAL1 Variants Underlie Hormonal Response Variations at the Enteroinsular Axis PLOS ONE 2014; 9 (9)
Roles of CLR/RAMP Receptor Signaling in Reproduction and Development
CURRENT PROTEIN & PEPTIDE SCIENCE
2013; 14 (5): 393-406
Adrenomedullin (ADM), calcitonin gene-related peptides (α- and β-CGRPs), and intermedin/adrenomedullin 2 (IMD/ADM2) are major regulators of vascular tone and cardiovascular development in vertebrates. Recent research into their functions in reproduction has illuminated the role of these peptides and their cognate receptors (calcitonin receptor-like receptor/receptor activity-modifying protein (CLR/RAMP) receptors) in fetal-maternal blood circulation, fetoplacental development, female gamete development, and gamete movement in the oviduct. Although ADM family peptides function in a temporally and spatially specific manner in various reproductive processes, they appear to act via a similar set of second messengers, including nitric oxide, cyclic GMP, cyclic AMP, and calcium-activated potassium channels in different tissues. These discoveries supported the view that CLR/RAMP receptors were recruited to perform a variety of newly evolved reproductive functions during the evolution of internal reproduction in mammals. These advances also provided insight into how CLR/RAMP receptor signaling pathways coordinate with other physiological adaptions to accommodate the extra metabolic needs during pregnancy, and captured some important details as to how fetal-maternal vascular communications are generated in the first place. Furthermore, these findings have revealed novel, promising opportunities for the prevention and treatment of aberrant pregnancies such as pregnancy-induced hypertension, preeclampsia, and tubal ectopic pregnancy. However, significant efforts are still needed to clarify the relationships between certain components of the CLR/RAMP signaling pathway and aberrant pregnancies before CLR/RAMP receptors can become targets for clinical management. With this understanding, this review summarizes recent progresses with particular focus on clinical implications.
View details for Web of Science ID 000324167600005
View details for PubMedID 23745703
Widespread Divergence of the CEACAM/PSG Genes in Vertebrates and Humans Suggests Sensitivity to Selection
2013; 8 (4)
In mammals, carcinoembryonic antigen cell adhesion molecules (CEACAMs) and pregnancy-specific glycoproteins (PSGs) play important roles in the regulation of pathogen transmission, tumorigenesis, insulin signaling turnover, and fetal-maternal interactions. However, how these genes evolved and to what extent they diverged in humans remain to be investigated specifically. Based on syntenic mapping of chordate genomes, we reveal that diverging homologs with a prototypic CEACAM architecture-including an extracellular domain with immunoglobulin variable and constant domain-like regions, and an intracellular domain containing ITAM motif-are present from cartilaginous fish to humans, but are absent in sea lamprey, cephalochordate or urochordate. Interestingly, the CEACAM/PSG gene inventory underwent radical divergence in various vertebrate lineages: from zero in avian species to dozens in therian mammals. In addition, analyses of genetic variations in human populations showed the presence of various types of copy number variations (CNVs) at the CEACAM/PSG locus. These copy number polymorphisms have 3-80% frequency in select populations, and encompass single to more than six PSG genes. Furthermore, we found that CEACAM/PSG genes contain a significantly higher density of nonsynonymous single nucleotide polymorphism (SNP) compared to the chromosome average, and many CEACAM/PSG SNPs exhibit high population differentiation. Taken together, our study suggested that CEACAM/PSG genes have had a more dynamic evolutionary history in vertebrates than previously thought. Given that CEACAM/PSGs play important roles in maternal-fetal interaction and pathogen recognition, these data have laid the groundwork for future analysis of adaptive CEACAM/PSG genotype-phenotypic relationships in normal and complicated pregnancies as well as other etiologies.
View details for DOI 10.1371/journal.pone.0061701
View details for Web of Science ID 000317893400094
View details for PubMedID 23613906
View details for PubMedCentralID PMC3628338
Regulation of Oocyte and Cumulus Cell Interactions by Intermedin/Adrenomedullin 2
JOURNAL OF BIOLOGICAL CHEMISTRY
2011; 286 (50): 43193-43203
Ovarian folliculogenesis has been studied as a model of hormonal regulation of development and differentiation, cell death, and cell-cell communication. In addition to gonadotropins from the pituitary and follicular paracrine factors, oocyte secreted factors have been shown to play critical roles in the regulation of follicular cell functions. Except for the well characterized BMP family proteins, including GDF9 and BMP15, oocytes are known to secrete oocyte secreted factors that are important for the regulation of cumulus cell survival and the maintenance of tertiary structure of cumulus cell-enclosed oocyte complexes (COCs). Based on genomic screening and studies of COCs cultured in vitro, we showed that intermedin (IMD)/adrenomedullin 2 (ADM2) is a novel oocyte-derived ligand important for the regulation of cell interactions in COCs that functions, in part, by suppressing cumulus cell apoptosis. Consistently, we showed that suppression of IMD/ADM2 signaling in growing rat ovaries in vivo leads to oocyte atresia and aberrant cell cycle progression in follicular cells. Together, our studies indicated that mammalian oocytes deploy a G protein-coupled receptor ligand to coordinate normal interactions of oocytes and cumulus cells and provided a better understanding of how the tertiary structure of a COC is maintained as follicles undergo exponential growth during the late stages of folliculogenesis.
View details for DOI 10.1074/jbc.M111.297358
View details for Web of Science ID 000298351300040
View details for PubMedID 22009752
View details for PubMedCentralID PMC3234849
Identification of Metabolic Modifiers That Underlie Phenotypic Variations in Energy-Balance Regulation
2011; 60 (3): 726-734
Although recent studies have shown that human genomes contain hundreds of loci that exhibit signatures of positive selection, variants that are associated with adaptation in energy-balance regulation remain elusive. We reasoned that the difficulty in identifying such variants could be due to heterogeneity in selection pressure and that an integrative approach that incorporated experiment-based evidence and population genetics-based statistical judgments would be needed to reveal important metabolic modifiers in humans.To identify common metabolic modifiers that underlie phenotypic variation in diabetes-associated or obesity-associated traits in humans, or both, we screened 207 candidate loci for regulatory single nucleotide polymorphisms (SNPs) that exhibited evidence of gene-environmental interactions.Three SNPs (rs3895874, rs3848460, and rs937301) at the 5' gene region of human GIP were identified as prime metabolic-modifier candidates at the enteroinsular axis. Functional studies have shown that GIP promoter reporters carrying derived alleles of these three SNPs (haplotype GIP(-1920A)) have significantly lower transcriptional activities than those with ancestral alleles at corresponding positions (haplotype GIP(-1920G)). Consistently, studies of pregnant women who have undergone a screening test for gestational diabetes have shown that patients with a homozygous GIP(-1920A/A) genotype have significantly lower serum concentrations of glucose-dependent insulinotropic polypeptide (GIP) than those carrying an ancestral GIP(-1920G) haplotype. After controlling for a GIPR variation, we showed that serum glucose concentrations of patients carrying GIP(-1920A/A) homozygotes are significantly higher than that of those carrying an ancestral GIP(-1920G) haplotype (odds ratio 3.53).Our proof-of-concept study indicates that common regulatory GIP variants impart a difference in GIP and glucose metabolism. The study also provides a rare example that identified the common variant-common phenotypic variation pattern based on evidence of moderate gene-environmental interactions.
View details for DOI 10.2337/db10-1331
View details for Web of Science ID 000288060300007
View details for PubMedID 21300845
View details for PubMedCentralID PMC3046833
Adaptive selection of an incretin gene in Eurasian populations
2011; 21 (1): 21-32
Diversities in human physiology have been partially shaped by adaptation to natural environments and changing cultures. Recent genomic analyses have revealed single nucleotide polymorphisms (SNPs) that are associated with adaptations in immune responses, obvious changes in human body forms, or adaptations to extreme climates in select human populations. Here, we report that the human GIP locus was differentially selected among human populations based on the analysis of a nonsynonymous SNP (rs2291725). Comparative and functional analyses showed that the human GIP gene encodes a cryptic glucose-dependent insulinotropic polypeptide (GIP) isoform (GIP55S or GIP55G) that encompasses the SNP and is resistant to serum degradation relative to the known mature GIP peptide. Importantly, we found that GIP55G, which is encoded by the derived allele, exhibits a higher bioactivity compared with GIP55S, which is derived from the ancestral allele. Haplotype structure analysis suggests that the derived allele at rs2291725 arose to dominance in East Asians ∼8100 yr ago due to positive selection. The combined results suggested that rs2291725 represents a functional mutation and may contribute to the population genetics observation. Given that GIP signaling plays a critical role in homeostasis regulation at both the enteroinsular and enteroadipocyte axes, our study highlights the importance of understanding adaptations in energy-balance regulation in the face of the emerging diabetes and obesity epidemics.
View details for DOI 10.1101/gr.110593.110
View details for Web of Science ID 000285868300003
View details for PubMedID 20978139
View details for PubMedCentralID PMC3012923
SUCCESSFUL TREATMENT OF METASTATIC BRAIN TUMOR BY CYBERKNIFE: A CASE REPORT
KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
2010; 26 (3): 144-149
Stereotactic radiosurgery plays an important role in management of metastatic brain tumors, especially when the tumor has recurred after treatment with previous whole brain radiotherapy. Most metastatic brain tumors less than 1 cm(3) show a complete response after stereotactic radio-surgery. However, there are few reports of a dramatic change in the complete response of large metastatic brain tumors. Here, we report a case of adenocarcinoma of lung that had metastasized to the brain. Because the recurrence of the metastatic brain tumor measured approximately 3 cm in diameter, the tumor was previously treated with two prior craniotomies followed by whole brain radiation to the resection cavity. The tumor subsequently recurred and was treated with stereotactic radiosurgery (CyberKnife). A dramatic response was noted 3 months after radiosurgery with complete disappearance of the recurrent tumor.
View details for Web of Science ID 000276378800005
View details for PubMedID 20227654
Activation of Calcitonin Receptor and Calcitonin Receptor-like Receptor by Membrane-anchored Ligands
JOURNAL OF BIOLOGICAL CHEMISTRY
2010; 285 (2): 1075-1080
G protein-coupled receptors (GPCRs) are the most important pharmaceutical targets, and more than 40% of drugs in use today modulate GPCR signaling. A major hurdle in the development of therapies targeting GPCRs is the drug candidate's nonselective actions in multiple tissues. The ability to spatially control GPCR signaling would provide a venue for developing therapies that require targeted GPCR signaling. Here, we show that the fusion of a RAMP1 co-receptor with the calcitonin gene-related peptide (CGRP), or calcitonin, transforms the RAMP1 from a co-receptor to bona fide membrane-anchored ligands (CGRP-RAMP1 and CAL-RAMP1). The CAL-RAMP1 selectively activates the calcitonin receptor (CR), whereas, the CGRP-RAMP1 activates both the calcitonin receptor-like receptor (CLR) and CR. Unlike a free peptide, which moves freely in the extracellular space and differentiates targets based on molecular affinity, the anchored CGRP-RAMP1 and CAL-RAMP1 ligands confine their activities to individual cells. In addition, our study showed that a CGRP8-37-RAMP1 chimera, but not RAMP1, functions as an antagonist for CGRP-RAMP1-mediated signaling, suggesting that the activation of CLR by CGRP-RAMP1 shares similar molecular mechanisms with the CGRP-mediated activation of CLR/RAMP1 receptor complexes. Taken together, our finding thus provides a novel class of ligands that activate CR and CLR exclusively in an autocrine manner and a proof-of-concept demonstration for future development of targeted therapies aimed at these receptors in specific cell populations.
View details for DOI 10.1074/jbc.M109.020040
View details for Web of Science ID 000273258200028
View details for PubMedID 19903822
View details for PubMedCentralID PMC2801234
Intermedin/adrenomedullin-2 is a hypoxia-induced endothelial peptide that stabilizes pulmonary microvascular permeability
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
2009; 297 (5): L837-L845
Accumulating evidence suggests a pivotal role of the calcitonin receptor-like receptor (CRLR) signaling pathway in preventing damage of the lung by stabilizing pulmonary barrier function. Intermedin (IMD), also termed adrenomedullin-2, is the most recently identified peptide targeting this receptor. Here we investigated the effect of hypoxia on the expression of IMD in the murine lung and cultured murine pulmonary microvascular endothelial cells (PMEC) as well as the role of IMD in regulating vascular permeability. Monoclonal IMD antibodies were generated, and transcript levels were assayed by quantitative RT-PCR. The promoter region of IMD gene was analyzed, and the effect of hypoxia-inducible factor (HIF)-1alpha on IMD expression was investigated in HEK293T cells. Isolated murine lungs and a human lung microvascular endothelial cell monolayer model were used to study the effect of IMD on vascular permeability. IMD was identified as a pulmonary endothelial peptide by immunohistochemistry and RT-PCR. Hypoxia caused an upregulation of IMD mRNA in the murine lung and PMEC. As shown by these results, HIF-1alpha enhances IMD promoter activity. Our functional studies showed that IMD abolished the increase in pressure-induced endothelial permeability. Moreover, IMD decreased basal and thrombin-induced hyperpermeability of an endothelial cell monolayer in a receptor-dependent manner and activated PKA in these cells. In conclusion, IMD is a novel hypoxia-induced gene and a potential interventional agent for the improvement of endothelial barrier function in systemic inflammatory responses and hypoxia-induced vascular leakage.
View details for DOI 10.1152/ajplung.90608.2008
View details for Web of Science ID 000271141600007
View details for PubMedID 19684198
View details for PubMedCentralID PMC2777497
Regulation of Receptor Signaling by Relaxin A Chain Motifs DERIVATION OF PAN-SPECIFIC AND LGR7-SPECIFIC HUMAN RELAXIN ANALOGS
JOURNAL OF BIOLOGICAL CHEMISTRY
2008; 283 (46): 32099-32109
Relaxin peptides are important hormones for the regulation of reproductive tissue remodeling and the renal cardiovascular system during pregnancy. Recent studies demonstrated that two of the seven human relaxin family peptides, relaxin H2 (RLN2) and INSL3, signal exclusively through leucine-rich repeat-containing G protein-coupled receptors, LGR7 and LGR8. Although it was well characterized that an RXXXRXXI motif at the RLN2 B chain confers receptor activation activity, it is not clear what roles RLN2 A chain plays in receptor interaction. Analyses of relaxin family genes on syntenic regions of model tetrapods showed that the A chain of RLN2 orthologs exhibited a greater sequence divergence as compared with the receptor-binding domain-containing B chain, foreshadowing a potential role in receptor interactions; hence, defining receptor selectivity in this fast evolving peptide hormone. To test our hypothesis that select residues in the human RLN2 A chain play key roles in receptor interaction, we studied mutant peptides with residue substitution(s) in the A chain. Here, we showed that alanine substitution at the A16 and A17 positions enhances LGR8-activation activity of RLN2, whereas mutation at the A22-23 region (RLN2A22-23) ablates LGR8, but not LGR7, activation activity. In addition, we demonstrated that the functional characteristics of the RLN2A22-23 mutant are mainly attributed to modifications at the PheA23 position. Taken together, our studies indicated that ThrA16, LysA17, and PheA23 constitute part of the receptor-binding interface of human RLN2, and that modification of these residues has led to the generation of novel human RLN2 analogs that would allow selective activation of human LGR7, but not LGR8, in vivo.
View details for DOI 10.1074/jbc.M806817200
View details for Web of Science ID 000260760800091
View details for PubMedID 18772127
View details for PubMedCentralID PMC2581550
Origin of INSL3-mediated testicular descent in therian mammals
2008; 18 (6): 974-985
Testicular descent is a unique physiological adaptation found in therian mammals allowing optimal spermatogenesis below core body temperature. Recent studies show that INSL3, produced by Leydig cells, and its receptor LGR8 (RXFP2) are essential for mediating the transabdominal phase of testicular descent during early development. However, the origin and genetic basis for this physiological adaptation is not clear. Using syntenic mapping and the functional characterization of contemporary and resurrected relaxin family hormones, we show that derivation of INSL3-mediated testicular descent involved the duplication of an ancestral RLN3-like gene that encodes an indiscriminate ligand for LGR7 (RXFP1) and LGR8. This event was followed by acquisition of the LGR7-selective characteristics by a daughter gene (RLN3) prior to the evolution of the common ancestor of monotremes, marsupials, and placentals. A subsequent mutation of the other daughter gene (INSL3) occurred before the emergence of therian mammals, which then led to the derivation of the reciprocal LGR8-specific characteristics of INSL3. The stepwise evolution of these independent signaling pathways through gene duplication and subsequent divergence is consistent with Darwinian theory of selection and adaptation, and the temporal proximity suggests an association between these genetic events and the concurrent evolution of testicular descent in ancestral therian mammals.
View details for DOI 10.1101/gr.7119108
View details for Web of Science ID 000256356200015
View details for PubMedID 18463305
View details for PubMedCentralID PMC2413165
GPCR Genes Are Preferentially Retained after Whole Genome Duplication
2008; 3 (4)
One of the most interesting questions in biology is whether certain pathways have been favored during evolution, and if so, what properties could cause such a preference. Due to the lack of experimental evidence, whether select gene families have been preferentially retained over time after duplication in metazoan organisms remains unclear. Here, by syntenic mapping of nonchemosensory G protein-coupled receptor genes (nGPCRs which represent half the receptome for transmembrane signaling) in the vertebrate genomes, we found that, as opposed to the 8-15% retention rate for whole genome duplication (WGD)-derived gene duplicates in the entire genome of pufferfish, greater than 27.8% of WGD-derived nGPCRs which interact with a nonpeptide ligand were retained after WGD in pufferfish Tetraodon nigroviridis. In addition, we show that concurrent duplication of cognate ligand genes by WGD could impose selection of nGPCRs that interact with a polypeptide ligand. Against less than 2.25% probability for parallel retention of a pair of WGD-derived ligands and a pair of cognate receptor duplicates, we found a more than 8.9% retention of WGD-derived ligand-nGPCR pairs--threefold greater than one would surmise. These results demonstrate that gene retention is not uniform after WGD in vertebrates, and suggest a Darwinian selection of GPCR-mediated intercellular communication in metazoan organisms.
View details for DOI 10.1371/journal.pone.0001903
View details for Web of Science ID 000260795400030
View details for PubMedID 18382678
View details for PubMedCentralID PMC2270905
REDUCTION OF NEUTRON-INDUCED BACKGROUND IN NAI GAMMA-RAY SPECTRA
NUCLEAR INSTRUMENTS & METHODS
1973; 109 (3): 585-588
View details for Web of Science ID A1973Q029000027