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Fulltext Soy fermentation by indigenous oral probiotic Streptococcus spp. and its antimicrobial activity against oral pathogens

How, Y. H., Ewe, J. A., Song, K. P., Kuan, C. H., Kuan, C. S., Yeo, S. K.

International Food Research Journal, 2020;27(2):357-365.
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The present work aimed to determine the antagonistic effect of probiotic-fermented soy against oral pathogens. Indigenous oral probiotics (Streptococcus salivarius Taylor’s Univer- sity Collection Centre (TUCC) 1251, S. salivarius TUCC 1253, S. salivarius TUCC 1254, S. salivarius TUCC 1255, and S. orisratti TUCC 1253) were incorporated into soy fermentation at 37°C for 24 h. Growth characteristics, β-glucosidase activity, and total isoflavones content of Streptococcus strains following soy fermentation were analysed. Antimicrobial test of Streptococcus-fermented soy was carried out against oral pathogens Enterococcus faecalis American Type Culture Collection (ATCC) 700802, Streptococcus pyogenes ATCC 19615, and Staphylococcus aureus ATCC 25923. Streptococcus strains showed a significant increase in growth following soy fermentation. S. salivarius TUCC 1253-fermented soy showed signif- icantly higher extracellular β-glucosidase activity and amount of aglycones. S. salivarius TUCC 1253-fermented soy showed antimicrobial effect against all oral tested pathogens in both aerobic and anaerobic conditions. These results showed that S. salivarius TUCC 1253-fermented soy could potentially be used as a preventive action or alternative treatment for oral infections.
Early-life citalopram-induced impairments in sexual behavior and the role of androgen receptor

Soga T, Wong DW, Putteeraj M, Song KP, Parhar IS

Neuroscience, 2012 Dec 6;225:172-84.
PMID: 22960312 DOI: 10.1016/j.neuroscience.2012.08.061

Postnatal treatment with selective serotonin reuptake inhibitors (SSRIs) has been found to affect brain development and the regulation of reproduction in rodent models. The normal masculinization process in the brain requires a transient decrease in serotonin (5-HT) levels in the brain during the second postnatal week. Strict regulation of androgen receptor (AR) and gonadotropin-releasing hormone (GnRH) expression is important to control male reproductive activity. Therefore, this study was designed to examine the effects of a potent SSRI (citalopram) on male sexual behavior and expression levels of AR and GnRH in adult male mice receiving either vehicle or citalopram (10mg/kg) daily during postnatal days 8-21. The citalopram-treated male mice showed altered sexual behavior, specifically a significant reduction in the number of intromissions preceding ejaculation compared with the vehicle-treated mice. The citalopram-treated male mice displayed elevated anxiety-like behavior in an open field test and lower locomotor activity in their home cage during the subjective night. Although there was no change in GnRH and AR mRNA levels in the preoptic area (POA), quantified by real-time polymerase chain reaction, immunostained AR cell numbers in the medial POA were decreased in the citalopram-treated male mice. These results suggest that the early-life inhibition of 5-HT transporters alters the regulation of AR expression in the medial POA, likely causing decreased sexual behavior and altered home cage activity in the subjective night.
Fructose promotes pyoluteorin biosynthesis via the CbrAB-CrcZ-Hfq/Crc pathway in the biocontrol strain Pseudomonas PA1201

Cui Y, Song K, Jin ZJ, Lee LH, Thawai C, He YW

Synth Syst Biotechnol, 2023 Dec;8(4):618-628.
PMID: 37823038 DOI: 10.1016/j.synbio.2023.09.004

Biocontrol strain Pseudomonas PA1201 produces pyoluteorin (Plt), which is an antimicrobial secondary metabolite. Plt represents a promising candidate pesticide due to its broad-spectrum antifungal and antibacterial activity. Although PA1201 contains a complete genetic cluster for Plt biosynthesis, it fails to produce detectable level of Plt when grown in media typically used for Pseudomonas strains. In this study, minimum medium (MM) was found to favor Plt biosynthesis. Using the medium M, which contains all the salts of MM medium except for mannitol, as a basal medium, we compared 10 carbon sources for their ability to promote Plt biosynthesis. Fructose, mannitol, and glycerol promoted Plt biosynthesis, with fructose being the most effective carbon source. Glucose or succinic acid had no significant effect on Plt biosynthesis, but effectively antagonized fructose-dependent synthesis of Plt. Promoter-lacZ fusion reporter strains demonstrated that fructose acted through activation of the pltLABCDEFG (pltL) operon but had no effect on other genes of plt gene cluster; glucose or succinic acid antagonized fructose-dependent pltL induction. Mechanistically, fructose-mediated Plt synthesis involved carbon catabolism repression. The two-component system CbrA/CbrB and small RNA catabolite repression control Z (crcZ) were essential for fructose-induced Plt synthesis. The small RNA binding protein Hfq and Crc negatively regulated fructose-induced Plt. Taken together, this study provides a new model of fructose-dependent Plt production in PA1201 that can help improve Plt yield by biosynthetic approaches.
Whole-transcriptome analysis reveals mechanisms underlying antibacterial activity and biofilm inhibition by a malic acid combination (MAC) in Pseudomonas aeruginosa

Song K, Chen L, Suo N, Kong X, Li J, Wang T, et al.

PeerJ, 2023;11:e16476.
PMID: 38084141 DOI: 10.7717/peerj.16476

BACKGROUND: Pseudomonas aeruginosa is a highly prevalent bacterial species known for its ability to cause various infections and its remarkable adaptability and biofilm-forming capabilities. In earlier work, we conducted research involving the screening of 33 metabolites obtained from a commercial source against two prevalent bacterial strains, Escherichia coli and Staphylococcus aureus. Through screening assays, we discovered a novel malic acid combination (MAC) consisting of malic acid, citric acid, glycine, and hippuric acid, which displayed significant inhibitory effects. However, the precise underlying mechanism and the potential impact of the MAC on bacterial biofilm formation remain unknown and warrant further investigation.
METHODS: To determine the antibacterial effectiveness of the MAC against Pseudomonas aeruginosa, we conducted minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) techniques were employed to observe bacterial morphology and biofilm formation. We further performed a biofilm inhibition assay to assess the effect of the MAC on biofilm formation. Whole-transcriptome sequencing and bioinformatics analysis were employed to elucidate the antibacterial mechanism of the MAC. Additionally, the expression levels of differentially expressed genes were validated using the real-time PCR approach.
RESULTS: Our findings demonstrated the antibacterial activity of the MAC against P. aeruginosa. SEM analysis revealed that the MAC can induce morphological changes in bacterial cells. The biofilm assay showed that the MAC could reduce biofilm formation. Whole-transcriptome analysis revealed 1093 differentially expressed genes consisting of 659 upregulated genes and 434 downregulated genes, in response to the MAC treatment. Mechanistically, the MAC inhibited P. aeruginosa growth by targeting metabolic processes, secretion system, signal transduction, and cell membrane functions, thereby potentially compromising the survival of this human pathogen. This study provides valuable insights into the antibacterial and antibiofilm activities of the MAC, a synergistic and cost-effective malic acid combination, which holds promise as a potential therapeutic drug cocktail for treating human infectious diseases in the future.
Evaluation of novel Parkinson's disease candidate genes in the Chinese population

Chew EGY, Liany H, Tan LCS, Au WL, Prakash KM, Annuar AA, et al.

Neurobiol Aging, 2019 02;74:235.e1-235.e4.
PMID: 30337193 DOI: 10.1016/j.neurobiolaging.2018.09.013

Recent whole-exome sequencing studies in European patients with Parkinson's disease (PD) have identified potential risk variants across 33 novel PD candidate genes. We aim to determine if these reported candidate genes are similarly implicated in Asians by assessing common, rare, and novel nonsynonymous coding variants by sequencing all 33 genes in 198 Chinese samples and genotyping coding variants in an independent set of 9756 Chinese samples. We carried out further targeted sequencing of CD36 in an additional 576 Chinese and Korean samples. We found that only 8 of 43 reported risk variants were polymorphic in our Chinese samples. We identified several heterozygotes for rare loss-of-function mutations, including the reported CD36 p.Gln74Ter variant, in both cases and controls. We also observed 2 potential compound heterozygotes among PD cases for rare loss-of-function mutations in CD36 and SSPO. The other reported variants were common in East Asians and not associated with PD, completely absent, or only found in controls. Therefore, the 33 reported candidate genes and associated variants are unlikely to confer significant PD risk in the East Asian population.
Fulltext Genetic diversity and transmission patterns of Burkholderia pseudomallei on Hainan island, China, revealed by a population genomics analysis

Zheng H, Qin J, Chen H, Hu H, Zhang X, Yang C, et al.

Microb Genom, 2021 11;7(11).
PMID: 34762026 DOI: 10.1099/mgen.0.000659

Burkholderia pseudomallei is a Gram-negative soil-dwelling bacillus that causes melioidosis, a frequently fatal infectious disease, in tropical and subtropical regions. Previous studies have identified the overall genetic and evolutionary characteristics of B. pseudomallei on a global scale, including its origin and transmission routes. However, beyond its known hyperendemicity foci in northern Australia and Southeast Asia, the distribution and genetic characteristics of B. pseudomallei in most tropical regions remain poorly understood, including in southern China. Here, we sequenced the genomes of 122 B. pseudomallei strains collected from Hainan, an island in southern China, in 2002-2018, to investigate the population structure, relationships with global strains, local epidemiology, and virulence and antimicrobial-resistance factors. A phylogenetic analysis and hierarchical clustering divided the Hainan strains into nine phylogenic groups (PGs), 80 % of which were concentrated within five major groups (group 1: corresponding to minor sequence types [STs], 12.3 %; group 3: ST46 and ST50, 31.1 %; group 9: ST58, 13.1 %; group 11: ST55, 8.2 %; group 15: mainly ST658, 15.6%). A phylogenetic analysis that included global strains suggested that B. pseudomallei in Hainan originated from Southeast Asian countries, transmitted in multiple historical importation events. We also identified several mutual transmission events between Hainan and Southeast Asian countries in recent years, including three importation events from Thailand and Singapore to Hainan and three exportation events from Hainan to Singapore, Malaysia, and Taiwan island. A statistical analysis of the temporal distribution showed that the Hainan strains of groups 3, 9, and 15 have dominated the disease epidemic locally in the last 5 years. The spatial distribution of the Hainan strains demonstrated that some PGs are distributed in different cities on Hainan island, and by combining phylogenic and geographic distribution information, we detected 21 between-city transmission events, indicating its frequent local transmission. The detection of virulence factor genes showed that 56 % of the Hainan strains in group 1 encode a B. pseudomallei-specific adherence factor, boaB, confirming the specific pathogenic characteristics of the Hainan strains in group 1. An analysis of the antimicrobial-resistance potential of B. pseudomallei showed that various kinds of alterations were identified in clinically relevant antibiotic resistance factors, such as AmrR, PenA and PBP3, etc. Our results clarify the population structure, local epidemiology, and pathogenic characteristics of B. pseudomallei in Hainan, providing further insight into its regional and global transmission networks and improving our knowledge of its global phylogeography.
Fulltext Analysis of non-synonymous-coding variants of Parkinson's disease-related pathogenic and susceptibility genes in East Asian populations

Foo JN, Tan LC, Liany H, Koh TH, Irwan ID, Ng YY, et al.

Hum Mol Genet, 2014 Jul 15;23(14):3891-7.
PMID: 24565865 DOI: 10.1093/hmg/ddu086

To evaluate the contribution of non-synonymous-coding variants of known familial and genome-wide association studies (GWAS)-linked genes for Parkinson's disease (PD) to PD risk in the East Asian population, we sequenced all the coding exons of 39 PD-related disease genes and evaluated the accumulation of rare non-synonymous-coding variants in 375 early-onset PD cases and 399 controls. We also genotyped 782 non-synonymous-coding variants of these genes in 710 late-onset PD cases and 9046 population controls. Significant enrichment of LRRK2 variants was observed in both early- and late-onset PD (odds ratio = 1.58; 95% confidence interval = 1.29-1.93; P = 8.05 × 10(-6)). Moderate enrichment was also observed in FGF20, MCCC1, GBA and ITGA8. Half of the rare variants anticipated to cause loss of function of these genes were present in healthy controls. Overall, non-synonymous-coding variants of known familial and GWAS-linked genes appear to make a limited contribution to PD risk, suggesting that clinical sequencing of these genes will provide limited information for risk prediction and molecular diagnosis.
Fulltext Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome-Wide Association Study

Foo JN, Chew EGY, Chung SJ, Peng R, Blauwendraat C, Nalls MA, et al.

JAMA Neurol, 2020 06 01;77(6):746-754.
PMID: 32310270 DOI: 10.1001/jamaneurol.2020.0428

Importance: Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian).
Objectives: To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts.
Design Setting, and Participants: Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria.
Main Outcomes and Measures: Genotypes of common variants, association with disease status, and polygenic risk scores.
Results: Of 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 10-3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 × 10-12).
Conclusions and Relevance: This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.
Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson's disease risk

Chew EG, Liu Z, Li Z, Chung SJ, Lian MM, Tandiono M, et al.

Nat Aging, 2024 Nov 21.
PMID: 39572736 DOI: 10.1038/s43587-024-00760-7

Parkinson's disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (<44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10-15) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10-8). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease.
Fulltext Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1

Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, et al.

Autophagy, 2021 Jan;17(1):1-382.
PMID: 33634751 DOI: 10.1080/15548627.2020.1797280

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

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