Search

Cell adhesion mediated by adhesion molecules is of central importance in the maintenance of tissue homeostasis. Therefore, altered expression of adhesion molecules leads to the development of various tissue disorders involving cell activation, degeneration, and apoptosis. Nevertheless, it still remains unclear what initiates the altered expression of adhesion molecules and how the subsequent pathological cascades proceed. In this regard, cell adhesion molecule 1 (CADM1) is one of the candidates that is involved in the development of pathological lesions; it is an intercellular adhesion molecule that is expressed in various types of cells such as pulmonary cells, neurons, and mast cells. Recent studies have revealed that alterations in the transcriptional or post-transcriptional expressions of CADM1 correlate with the pathogenesis of pulmonary diseases and allergic diseases. In this review, we specifically focus on how CADM1 is involved in the development of pathological lesions in pulmonary emphysema and atopic dermatitis.

Background and Aims: Type 2 diabetes (T2D) and chronic hepatitis B infection (CHB) are risk factors of HCC. Sodium glucose co-transporter 2 inhibitors (SGLT2i) inhibit HCC oncogenesis in preclinical studies. However, clinical studies are lacking. This study aimed to evaluate the impact of SGLT2i use on incident HCC using a territory-wide cohort of exclusively patients with co-existing T2D and CHB., Approach and Results: Patients with co-existing T2D and CHB between 2015 and 2020 were identified from the representative electronic database of the Hong Kong Hospital Authority. Patients with and without SGLT2i use were 1:1 matched by propensity score for their demographics, biochemistry results, liver-related characteristics, and background medications. Cox proportional hazards regression model was used to assess the association between SGLT2i use and incident HCC. A total of 2,000 patients with co-existing T2D and CHB (1,000 in each SGLT2i and non-SGLT2i group; 79.7% on anti-HBV therapy at baseline) were included after propensity-score matching. Over a follow-up of 3,704 person-years, the incidence rates of HCC were 1.39 and 2.52 cases per 100 person-year in SGLT2i and non-SGLT2i groups, respectively. SGLT2i use was associated with a significantly lower risk of incident HCC (HR 0.54, 95%CI: 0.33-0.88, p =0.013). The association remained similar regardless of sex, age, glycemic control, diabetes duration, presence of cirrhosis and hepatic steatosis, timing of anti-HBV therapy, and background antidiabetic agents including dipeptidyl peptidase-4 inhibitors, insulin, or glitazones (all p interaction>0.05)., Conclusions: Among patients with co-existing T2D and CHB, SGLT2i use was associated with a lower risk of incident HCC., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Schizophrenia (SCZ) has long been recognized as a highly heterogeneous disorder. Patients differed in their clinical manifestations, prognosis, and underlying pathophysiologies. Here we presented and applied a framework for finding subtypes of SCZ utilizing genome-wide association study (GWAS) and clinical data. We postulated that genetic information may help stratify patient into useful subgroups, and incorporation of other clinical information and cognitive profiles will further improve patient subtyping. We conducted cluster analysis in 387 Hong Kong Chinese with SCZ. First we performed 'single-view' clustering using genetic or clinical data alone, then proceeded to 'multi-view' clustering (MVC) accounting for both types of information. We validated clustering results by assessing subgroup differences in various outcomes. We found significant differences in outcomes including treatment response, disease course and symptom severity (Simes overall p-value using MVC = 1.64E-9). Overall speaking, we identified three subgroups with good, intermediate and poor prognosis respectively. MVC generally out-performed single-view methods. The analysis was repeated for different sets of input SNPs, and stratified analysis of male and female patients, and the results remained largely robust. We also found significant enrichment for SCZ loci among the SNPs selected by the cluster algorithm. Numerous selected genes (e.g. NRG1, ERBB4, NRXN1, ANK3) and pathways (e.g. neuregulin-ErbB4 and calcium signaling) were implicated in SCZ or related pathophysiological processes. This is first study to combine both genetic and clinical data for subtyping SCZ, and to employ genome-wide SNP data in cluster analysis of a complex disease. This work points to a new way of GWAS analysis of translational potential., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background & Aims: Biliary atresia (BA) is a rare and most severe cholestatic disease in neonates, but the pathogenic mechanisms are unknown. Through a previous genome wide association study (GWAS) on Han Chinese, we discovered association of the 10q24.2 region encompassing ADD3 and XPNPEP1 genes, which was replicated in Chinese and Thai populations. This study aims to fully characterize the genetic architecture at 10q24.2 and to reveal the link between the genetic variants and BA., Methods: We genotyped 107 single nucleotide polymorphisms (SNPs) in 10q24.2 in 339 Han Chinese patients and 401 matched controls using Sequenom. Exhaustive follow-up studies of the association signals were performed., Results: The combined BA-association p-value of the GWAS SNP (rs17095355) achieved 6.06×10(-10). Further, we revealed the common risk haplotype encompassing 5 tagging-SNPs, capturing the risk-predisposing alleles in 10q24.2 [p=5.32×10(-11); odds ratio, OR: 2.38; confidence interval, CI: (2.14-2.62)]. Through Sanger sequencing, no deleterious rare variants (RVs) residing in the risk haplotype were found, dismissing the theory of "synthetic" association. Moreover, in bioinformatics and in vivo genotype-expression investigations, the BA-associated potentially regulatory SNPs correlated with ADD3 gene expression (n=36; p=0.0030). Remarkably, the risk haplotype frequency coincides with BA incidences in the population, and, positive selection (favoring the derived alleles that arose from mutations) was evident at the ADD3 locus, suggesting a possible role for the BA-associated common variants in shaping the general population diversity., Conclusions: Common genetic variants in 10q24.2 can alter BA risk by regulating ADD3 expression levels in the liver, and may exert an effect on disease epidemiology and on the general population., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

We present the genetic analyses conducted on a three-generation family (14 individuals) with three members affected with isolated-Hirschsprung disease (HSCR) and one with HSCR and heterochromia iridum (syndromic-HSCR), a phenotype reminiscent of Waardenburg-Shah syndrome (WS4). WS4 is characterized by pigmentary abnormalities of the skin, eyes and/or hair, sensorineural deafness and HSCR. None of the members had sensorineural deafness. The family was screened for copy number variations (CNVs) using Illumina-HumanOmni2.5-Beadchip and for coding sequence mutations in WS4 genes (EDN3, EDNRB, or SOX10) and in the main HSCR gene (RET). Confocal microscopy and immunoblotting were used to assess the functional impact of the mutations. A heterozygous A/G transition in EDNRB was identified in 4 affected and 3 unaffected individuals. While in EDNRB isoforms 1 and 2 (cellular receptor) the transition results in the abolishment of translation initiation (M1V), in isoform 3 (only in the cytosol) the replacement occurs at Met91 (M91V) and is predicted benign. Another heterozygous transition (c.-248G/A; -predicted to affect translation efficiency-) in the 5'-untranslated region of EDN3 (EDNRB ligand) was detected in all affected individuals but not in healthy carriers of the EDNRB mutation. Also, a de novo CNVs encompassing DACH1 was identified in the patient with heterochromia iridum and HSCR Since the EDNRB and EDN3 variants only coexist in affected individuals, HSCR could be due to the joint effect of mutations in genes of the same pathway. Iris heterochromia could be due to an independent genetic event and would account for the additional phenotype within the family.

Hirschsprung disease (HSCR) is a congenital disorder characterized by aganglionosis of the distal intestine. To assess the contribution of copy number variants (CNVs) to HSCR, we analysed the data generated from our previous genome-wide association study on HSCR patients, whereby we identified NRG1 as a new HSCR susceptibility locus. Analysis of 129 Chinese patients and 331 ethnically matched controls showed that HSCR patients have a greater burden of rare CNVs (p = 1.50 × 10(-5)), particularly for those encompassing genes (p = 5.00 × 10(-6)). Our study identified 246 rare-genic CNVs exclusive to patients. Among those, we detected a NRG3 deletion (p = 1.64 × 10(-3)). Subsequent follow-up (96 additional patients and 220 controls) on NRG3 revealed 9 deletions (combined p = 3.36 × 10(-5)) and 2 de novo duplications among patients and two deletions among controls. Importantly, NRG3 is a paralog of NRG1. Stratification of patients by presence/absence of HSCR-associated syndromes showed that while syndromic-HSCR patients carried significantly longer CNVs than the non-syndromic or controls (p = 1.50 × 10(-5)), non-syndromic patients were enriched in CNV number when compared to controls (p = 4.00 × 10(-6)) or the syndromic counterpart. Our results suggest a role for NRG3 in HSCR etiology and provide insights into the relative contribution of structural variants in both syndromic and non-syndromic HSCR. This would be the first genome-wide catalog of copy number variants identified in HSCR., Competing Interests: The authors have declared that no competing interests exist.

Over 50 years ago Kögl and Erxleben reported that tumor proteins contain appreciable amounts of D-amino acids. This postulate remained highly controversial for several years, during which time several researchers either supported or refuted the hypothesis. We have analyzed several sets of tumors and normal control tissues for the presence of D-aspartate (D-Asp) and D-glutamate (D-Glu). Most tumors contain less D-Asp than the control tissues, whereas nearly half of the tumors contain 1.6 to 5.4 times more D-Glu than the controls. The tumors averaged 0.72% D-Asp and 0.61% D-Glu compared to 0.94% D-Asp and 0.35% D-Glu in the control tissues. However, within the limits of experimental error, there is no significant difference in the level of these D-amino acids between the tumors and normal tissues.

Normal protein-bound L-aspartyl/L-asparaginyl residues may undergo post-translational modification by racemization to D-aspartate, or by isomerization to the L-isoaspartyl form in which the peptide chain links through the beta carboxyl group of the residue. Based on preliminary results reported here, proteins associated with Alzheimer neurofibrillary tangle preparations contain a significantly greater number of these modified aspartyl residues than the unaffected proteins from the surrounding gray matter or in comparable preparations from normal brains.

Normal protein-bound L-aspartyl/L-asparaginyl residues may undergo posttranslational modification by racemization to D-aspartate. Based on preliminary results reported here, proteins associated with Alzheimer neurofibrillary tangle preparations contain a greater number of these racemized D-aspartyl residues than the unaffected proteins from the surrounding gray matter or in comparable preparations from normal brains.

In this report we present evidence for the presence of free D-aspartic acid (D-Asp) and D-alanine (D-Ala) in the white and gray matter of normal human brains and brains of individuals with Alzheimer's disease. D-Asp occurs at about the same concentration in the gray matter of both normal (18.6 nmol/g) and Alzheimer (14.8 nmol/g) brains, whereas in white matter its concentration is more than two times higher in normal than Alzheimer brains (22.4 and 10.5 nmol/g, respectively). D-Ala occurs in white matter at approximately the same concentration in both normal and Alzheimer brains (12.3 and 13.8 nmol/g, respectively), whereas in Alzheimer gray matter the D-Ala concentration is more than twice that found in normal gray matter (20.8 and 9.5 nmol/g, respectively). However, when the results are expressed as a percentage of D-amino acid/D+L, only small differences occur in all tissues examined.

The present studies were undertaken to examine how the substitution of racemized forms of selected amino acids in synthetic peptides of guinea pig myelin basic protein (GPMBP) would alter the host's immunological ability to recognize such molecules. Using peptides from the 69-84 sequence of GPMBP containing a D-serine at position 70 or 75 (69-84[D-ser70 or D-ser75]) or D-aspartate at position 82 (69-84[D-asp82]), the findings demonstrated that the position of the diastereomer substitution on these neuropeptides was critical with respect to the ability of the immune system to recognize the molecule. Thus substitution of D-asp at position 82 or D-ser at position 75 abrogated the ability of these peptides to induce experimental autoimmune encephalitis and proliferation of host T cells. In contrast, a peptide containing a D-ser70 residue was capable of inducing clinical disease in rats, as well as stimulating T lymphocytes from 69-84-(D-ser70)-injected animals. Moreover, although this D-peptide was shown to share at least some determinant(s) with the 69-84 peptide, the use of 69-84(D-ser70)-stimulated cell lines demonstrated that some epitope(s) unique to this molecule could stimulate CD4+ syngeneic T cells.

The presence of the biologically uncommon D-isomer of aspartic acid in the white matter of human brains has been reported previously from this laboratory (1). We now report that the level of D-aspartate in human brains is higher in purified myelin than in white matter and is even higher in the myelin basic protein fraction. There also appears to be a difference in the level of D-aspartate found in human brain as compared to bovine brain, possibly a species or age-related difference.

A previously described procedure for determining the enantiomeric ratios of amino acids has produced inconsistent results when determining relatively low (less than or equal to 0.110) D/L ratios. The method involves synthesis of diastereomeric N-trifluoroacetyl-L-prolyl-D/L-amino acid ester dipeptides which are resolved by gas chromatography (GC). We have found that triethylamine, which is added to maintain a basic pH during the coupling reaction, racemizes the chiral reagent N-trifluoroacetyl-L-prolyl chloride (TPC). Coupling of partially racemized TPC to D/L-amino acid esters results in the formation of four dipeptides (two pairs of enantiomers) instead of the expected two diastereomeric dipeptides. The enantiomeric dipeptides coelute on an achiral GC column, resulting in erroneous D/L ratios. More accurate D/L ratios are obtained by preparing the volatile N-trifluoroacetyl-D/L-amino acid isopropyl ester derivative which can be separated into its enantiomers on a chiral GC column such as the Chirasil-Val III (registered trademark of Applied Science Laboratories).

The presence of the biologically uncommon D-aspartic acid (D-aspartate) in human brain white matter has been previously reported. The earlier study has now been expanded to include D/L-aspartate ratios from 67 normal brains. The data show that the D-aspartate content increases rapidly from 1 year to approximately 35 years of age, levels off in middle age, and then appears to decrease somewhat. The D-aspartate content in gray matter remains at a consistently low level (half of that found in white matter) throughout the human life span. Within the limitations of current analytical methods, there was no detectable difference in D/L-aspartate ratios in white and gray matter of brains with Alzheimer's disease and several other pathologies when compared with brains of normal subjects. However, the presence of a significant D-aspartate level in white matter during the adult life span may lead to changes in protein configuration related to dysfunctions associated with the aging brain.

An age-related accumulation of D-aspartic acid was detected in the white matter of ten normal brains from individuals aged 30 to 80 years. Gray matter showed no systematic increase in D-aspartic acid. The rate constant for D-aspartate formation in the brain is equal to the predicted value calculated for 37 degrees C. Accumulation of the uncommon D-aspartate isomer in myelinated white matter implies that there is little or no turnover of this tissue, and this may have a bearing on dysfunction of the aging brain or on other diseases of myelin.