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The association of mitochondrial DNA 5178 C > a polymorphism with plasma lipid levels among three ethnic groups

Lal S, Madhavan M, Heng CK

Ann. Hum. Genet., 2005 Nov;69(Pt 6):639-44.
PMID: 16266403

Mitochondria are eukaryotic cytoplasmic organelles responsible for oxidative phosphorylation. The C to A nucleotide transversion in the NADH dehydrogenase subunit 2 (MT-ND2) coding region of mitochondrial DNA has been reported to be associated with plasma lipid levels, adult onset diseases and longevity. We have examined the role of this polymorphism in relation to plasma lipid levels and age in a total of 713 healthy individuals belonging to 3 ethnic groups in Singapore. The frequency of the A allele was significantly higher (p < 0.05) among the Chinese (0.15) in comparison to the Malays (0.05) and Indians (0.02). No significant difference in the frequency of the allele was observed between healthy and coronary artery disease subjects, and between age-stratified subjects. We found that the polymorphism is significantly associated in an ethnic- and gender-specific manner with plasma apoB levels in the Chinese males (p < 0.05). This is the first epidemiological report of the mt5178 C > A polymorphism and its association with plasma lipid levels in Asian populations outside Japan.
AML1 protein interacts with influenza A virus neuraminidase and upregulates IFN-β response in infected mammalian cells

Gaur P, Kumar P, Sharma A, Lal SK

Lett Appl Microbiol, 2020 Apr;70(4):252-258.
PMID: 31990997 DOI: 10.1111/lam.13279

Neuraminidase (NA) is an integral membrane protein of influenza A virus (IAV) and primarily aids in the release of progeny virions, following the intracellular viral replication cycle. In an attempt to discover new functions of NA, we conducted a classical yeast two-hybrid screen and found acute myeloid leukaemia marker 1 (AML1) as a novel interacting partner of IAV-NA. The interaction was further validated by co-immunoprecipitation in IAV-infected cells and in an in vitro coupled transcription/translation system. Interestingly, we found an increase in the expression of AML1 upon IAV infection in a dose-dependent manner. As expected, we also observed an increase in the IFN-β levels, the first line of defence against viral infections. Subsequently, when AML1 was downregulated using siRNA, the IFN-β levels were found to be remarkably reduced. Our study also shows that AML1 is induced upon IAV infection and results in the induction of IFN-β. Thus, AML1 is proposed to be an important player in IFN induction and has a role in an antiviral response against IAV infection. SIGNIFICANCE AND IMPACT OF THE STUDY: Influenza epidemics and pandemics are constant threats to human health. Development of antiviral therapeutics has focused on important and major IAV proteins as targets. However, the rate at which this virus mutates makes the task challenging. Thus, next-generation approaches aim at host cellular proteins that aid the virus in its replication. This study reports a new host-virus interaction, of acute myeloid leukaemia marker 1 (AML1) with influenza A neuraminidase (IAV-NA). We have found that this interaction has a direct effect on the upregulation of host IFN-β response. Further studies may lead to a greater understanding of this new innate defence pathway in infected cells.
Fulltext Nucleoprotein of influenza A virus negatively impacts antiapoptotic protein API5 to enhance E2F1-dependent apoptosis and virus replication

Mayank AK, Sharma S, Nailwal H, Lal SK

Cell Death Dis, 2015;6:e2018.
PMID: 26673663 DOI: 10.1038/cddis.2015.360

Apoptosis of host cells profoundly influences virus propagation and dissemination, events that are integral to influenza A virus (IAV) pathogenesis. The trigger for activation of apoptosis is regulated by an intricate interplay between cellular and viral proteins, with a strong bearing on IAV replication. Though the knowledge of viral proteins and mechanisms employed by IAV to induce apoptosis has advanced considerably of late, we know relatively little about the repertoire of host factors targeted by viral proteins. Thus, identification of cellular proteins that are hijacked by the virus will help us not only to understand the molecular underpinnings of IAV-induced apoptosis, but also to design future antiviral therapies. Here we show that the nucleoprotein (NP) of IAV directly interacts with and suppresses the expression of API5, a host antiapoptotic protein that antagonizes E2F1-dependent apoptosis. siRNA-mediated depletion of API5, in NP-overexpressed as well as IAV-infected cells, leads to upregulation of apoptotic protease activating factor 1 (APAF1), a downstream modulator of E2F1-mediated apoptosis, and cleavage of caspases 9 and 3, although a reciprocal pattern of these events was observed on ectopic overexpression of API5. In concordance with these observations, annexin V and 7AAD staining assays exhibit downregulation of early and late apoptosis in IAV-infected or NP-transfected cells on overexpression of API5. Most significantly, while overexpression of API5 decreases viral titers, cellular NP protein as well as mRNA levels in IAV-infected A549 cells, silencing of API5 expression causes a steep rise in the same parameters. From the data reported in this manuscript, we propose a proapoptotic role for NP in IAV pathogenesis, whereby it suppresses expression of antiapoptotic factor API5, thus potentiating the E2F1-dependent apoptotic pathway and ensuring viral replication.
Fulltext The nucleoprotein of influenza A virus induces p53 signaling and apoptosis via attenuation of host ubiquitin ligase RNF43

Nailwal H, Sharma S, Mayank AK, Lal SK

Cell Death Dis, 2015 May 21;6:e1768.
PMID: 25996295 DOI: 10.1038/cddis.2015.131

The interplay between influenza virus and host factors to support the viral life cycle is well documented. Influenza A virus (IAV) proteins interact with an array of cellular proteins and hijack host pathways which are at the helm of cellular responses to facilitate virus invasion. The multifaceted nature of the ubiquitination pathway for protein regulation makes it a vulnerable target of many viruses including IAV. To this end we conducted a yeast two-hybrid screen to search for cellular ubiquitin ligases important for influenza virus replication. We identified host protein, RING finger protein 43 (RNF43), a RING-type E3 ubiquitin ligase, as a novel interactor of nucleoprotein (NP) of IAV and an essential partner to induce NP-driven p53-mediated apoptosis in IAV-infected cells. In this study, we demonstrate that IAV leads to attenuation of RNF43 transcripts and hence its respective protein levels in the cellular milieu whereas in RNF43 depleted cells, viral replication was escalated several folds. Moreover, RNF43 polyubiquitinates p53 which further leads to its destabilization resulting in a decrease in induction of the p53 apoptotic pathway, a hitherto unknown process targeted by NP for p53 stabilization and accumulation. Collectively, these results conclude that NP targets RNF43 to modulate p53 ubiquitination levels and hence causes p53 stabilization which is conducive to an enhanced apoptosis level in the host cells. In conclusion, our study unravels a novel strategy adopted by IAV for utilizing the much conserved ubiquitin proteasomal pathway.
Fulltext Editorial: Advances in breeding for waterlogging tolerance in crops

Ramlal A, Lal SK, Sathuvalli V

Front Plant Sci, 2023;14:1284730.
PMID: 37794926 DOI: 10.3389/fpls.2023.1284730
Fulltext Upregulation of miR-101 during Influenza A Virus Infection Abrogates Viral Life Cycle by Targeting mTOR Pathway

Sharma S, Chatterjee A, Kumar P, Lal S, Kondabagil K

Viruses, 2020 04 15;12(4).
PMID: 32326380 DOI: 10.3390/v12040444

Micro RNAs (miRNAs) are a class of small non-coding single-stranded RNA, which play an important role in modulating host-Influenza A virus (IAV) crosstalk. The interplay between influenza and miRNA interaction is defined by a plethora of complex mechanisms, which are not fully understood yet. Here, we demonstrate that in IAV infected A549 cells, a synchronous increase was observed in the expression of mTOR up to 24 hpi and significant downregulation at 48 hpi. Additionally, NP of IAV interacts with mTOR and modulates the levels of mTOR mRNA and protein, thus regulating the translation of host cell. RNA sequencing and qPCR analysis of IAV-infected A549 cells and NP transfected cells revealed that miR-101 downregulates mTOR transcripts at later stages of infection. Ectopic expression of miR-101 mimic led to a decrease in expression of NP, a reduction in IAV titer and replication. Moreover, treatment of the cells with Everolimus, a potent inhibitor of mTOR, resulted in an increase of miR-101 transcript levels, which further suppressed the viral protein synthesis. Collectively, the data suggest a novel mechanism that IAV stimulates mTOR pathway at early stages of infection; however, at a later time-point, positive regulation of miR-101 restrains the mTOR expression, and hence, the viral propagation.
Fulltext Editorial: A wonder legume, soybean: prospects for improvement

Ramlal A, Nautiyal A, Lal SK, Chigeza G

Front Plant Sci, 2023;14:1294185.
PMID: 37964996 DOI: 10.3389/fpls.2023.1294185
Variation of the platelet glycoprotein IIIa PI(A1/A2) allele frequencies in the three ethnic groups of Singapore

Lim J, Lal S, Ng KC, Ng KS, Saha N, Heng CK

Int J Cardiol, 2003 Aug;90(2-3):269-73.
PMID: 12957761

BACKGROUND: Polymorphisms of the glycoprotein IIIa receptor have been shown to be associated with differences in platelet aggregability. The PI(A2) variant of the polymorphism has been reported to be an inherited risk factor for acute coronary events. Although the allele frequency of this polymorphism is well documented in Caucasian populations, studies involving Asian Indians, Malays and Chinese are lacking. We studied 706 random male individuals to determine the genotypic distribution of this polymorphism in Singapore.
METHODS: Male subjects included in this study were drawn from those undergoing routine annual medical examinations offered by their employers. Venous blood was obtained from these patients after an overnight fast and from which genomic DNA was extracted. Genotyping was carried out by polymerase chain reaction (PCR) followed by digestion with restriction enzyme NciI. Personal and family medical history of the subjects were also taken.
RESULTS: The genotype distribution of the individuals studied was in accordance to a population at Hardy Weinberg equilibrium. The frequency of the PI(A2) allele was 0.1, 0.01 and 0.01 in the Indians, Malays and Chinese, respectively. The differences in frequencies of the PI(A2) variant are significant among different ethnic groups (P<0.001 for Indians vs. Chinese and Indians vs. Malays).
CONCLUSIONS: We observed a significantly higher frequency of the PI(A2) allele among Indians relative to the Chinese and Malays in Singapore. The effect of this genotype may partially explain the higher rate of ischaemic heart disease seen among Indians compared to the Chinese and Malay ethnic groups.
Pharmacogenetics of SLCO1B1: haplotypes, htSNPs and hepatic expression in three distinct Asian populations

Jada SR, Xiaochen S, Yan LY, Xiaoqiang X, Lal S, Zhou SF, et al.

Eur J Clin Pharmacol, 2007 Jun;63(6):555-63.
PMID: 17415554

OBJECTIVE: The aim of this study was to characterize the population frequency of SLCO1B1 polymorphic variants in three distinct healthy Asian populations, namely Chinese (n = 100), Malay (n = 100) and Indian (n = 100), and to explore the association between haplotype-tagged single nucleotide polymorphisms (htSNPs) on hepatic SLCO1B1 mRNA expression.
METHODS: The distribution of polymorphic variants in the SLCO1B1 gene at eight loci that spanned approximately 48 kb was investigated in the three different Asian ethnic groups and in 32 non-cancerous liver tissues from Chinese patients.
RESULTS: Of the 26 polymorphisms screened, we found eight polymorphic variants that differed in genotypic and allelic frequencies between the Chinese, Malay and Indian populations. Significant interethnic differences were observed in the genotype frequency distributions across the promoter SNP [g.-11187G>A (P = 0.030)] as well as three coding region SNPs [c.388G>A (P < 0.001); c.571T>C (P < 0.001); c.597C>T (P < 0.001)] in the healthy subjects. Haplotype analysis revealed 12 different haplotypes in both the Chinese and Malay populations and 18 haplotypes in the Indian population. In both the Malay and Indian populations, the htSNPs were c.388A>G, c.571T>C and c.597C>T, whereas in the Chinese population they were g.-11187G>A, c.388A>G and c.597C>T. The c.388A>G and c.597C>T htSNPs accounted for more than 70% of the variations between the three major haplotypes in each Asian ethnic group. In terms of the c.388A>G htSNPs, genotypic-phenotypic association analyses revealed that there was no effect on SLCO1B1 expression in hepatic tissues; in addition, no genotypic-phenotypic associations were evident with regards to the c.597C>T htSNP.
CONCLUSION: Future studies should investigate the phenotypic effects of the c.388A>G htSNP on the disposition of OATP1B1 substrates in Asian populations.
Fulltext Image-based phenotyping of seed architectural traits and prediction of seed weight using machine learning models in soybean

Duc NT, Ramlal A, Rajendran A, Raju D, Lal SK, Kumar S, et al.

Front Plant Sci, 2023;14:1206357.
PMID: 37771485 DOI: 10.3389/fpls.2023.1206357

Among seed attributes, weight is one of the main factors determining the soybean harvest index. Recently, the focus of soybean breeding has shifted to improving seed size and weight for crop optimization in terms of seed and oil yield. With recent technological advancements, there is an increasing application of imaging sensors that provide simple, real-time, non-destructive, and inexpensive image data for rapid image-based prediction of seed traits in plant breeding programs. The present work is related to digital image analysis of seed traits for the prediction of hundred-seed weight (HSW) in soybean. The image-based seed architectural traits (i-traits) measured were area size (AS), perimeter length (PL), length (L), width (W), length-to-width ratio (LWR), intersection of length and width (IS), seed circularity (CS), and distance between IS and CG (DS). The phenotypic investigation revealed significant genetic variability among 164 soybean genotypes for both i-traits and manually measured seed weight. Seven popular machine learning (ML) algorithms, namely Simple Linear Regression (SLR), Multiple Linear Regression (MLR), Random Forest (RF), Support Vector Regression (SVR), LASSO Regression (LR), Ridge Regression (RR), and Elastic Net Regression (EN), were used to create models that can predict the weight of soybean seeds based on the image-based novel features derived from the Red-Green-Blue (RGB)/visual image. Among the models, random forest and multiple linear regression models that use multiple explanatory variables related to seed size traits (AS, L, W, and DS) were identified as the best models for predicting seed weight with the highest prediction accuracy (coefficient of determination, R2=0.98 and 0.94, respectively) and the lowest prediction error, i.e., root mean square error (RMSE) and mean absolute error (MAE). Finally, principal components analysis (PCA) and a hierarchical clustering approach were used to identify IC538070 as a superior genotype with a larger seed size and weight. The identified donors/traits can potentially be used in soybean improvement programs.
Fulltext In silico analysis of angiotensin-converting enzyme inhibitory compounds obtained from soybean [Glycine max (L.) Merr.]

Ramlal A, Bhat I, Nautiyal A, Baweja P, Mehta S, Kumar V, et al.

Front Physiol, 2023;14:1172684.
PMID: 37324400 DOI: 10.3389/fphys.2023.1172684

Cardiovascular diseases (CVDs) are one of the major reasons for deaths globally. The renin-angiotensin-aldosterone system (RAAS) regulates body hypertension and fluid balance which causes CVD. Angiotensin-converting enzyme I (ACE I) is the central Zn-metallopeptidase component of the RAAS playing a crucial role in maintaining homeostasis of the cardiovascular system. The available drugs to treat CVD have many side effects, and thus, there is a need to explore phytocompounds and peptides to be utilized as alternative therapies. Soybean is a unique legume cum oilseed crop with an enriched source of proteins. Soybean extracts serve as a primary ingredient in many drug formulations against diabetes, obesity, and spinal cord-related disorders. Soy proteins and their products act against ACE I which may provide a new scope for the identification of potential scaffolds that can help in the design of safer and natural cardiovascular therapies. In this study, the molecular basis for selective inhibition of 34 soy phytomolecules (especially of beta-sitosterol, soyasaponin I, soyasaponin II, soyasaponin II methyl ester, dehydrosoyasaponin I, and phytic acid) was evaluated using in silico molecular docking approaches and dynamic simulations. Our results indicate that amongst the compounds, beta-sitosterol exhibited a potential inhibitory action against ACE I.
Fulltext COVID-19 infection in patients on long-term home parenteral nutrition for chronic intestinal failure

Pironi L, Jezerski D, Sobocki J, Lal S, Vanuytsel T, Theilla M, et al.

Clin Nutr ESPEN, 2023 Jun;55:212-220.
PMID: 37202049 DOI: 10.1016/j.clnesp.2023.03.008

BACKGROUND AND AIMS: To investigate the incidence and the severity of COVID-19 infection in patients enrolled in the database for home parenteral nutrition (HPN) for chronic intestinal failure (CIF) of the European Society for Clinical Nutrition and Metabolism (ESPEN).
METHODS: Period of observation: March 1st, 2020 March 1st, 2021.
INCLUSION CRITERIA: patients included in the database since 2015 and still receiving HPN on March 1st, 2020 as well as new patients included in the database during the period of observation. Data related to the previous 12 months and recorded on March 1st 2021: 1) occurrence of COVID-19 infection since the beginning of the pandemic (yes, no, unknown); 2) infection severity (asymptomatic; mild, no-hospitalization; moderate, hospitalization no-ICU; severe, hospitalization in ICU); 3) vaccinated against COVID-19 (yes, no, unknown); 4) patient outcome on March 1st 2021: still on HPN, weaned off HPN, deceased, lost to follow up.
RESULTS: Sixty-eight centres from 23 countries included 4680 patients. Data on COVID-19 were available for 55.1% of patients. The cumulative incidence of infection was 9.6% in the total group and ranged from 0% to 21.9% in the cohorts of individual countries. Infection severity was reported as: asymptomatic 26.7%, mild 32.0%, moderate 36.0%, severe 5.3%. Vaccination status was unknown in 62.0% of patients, non-vaccinated 25.2%, vaccinated 12.8%. Patient outcome was reported as: still on HPN 78.6%, weaned off HPN 10.6%, deceased 9.7%, lost to follow up 1.1%. A higher incidence of infection (p = 0.04), greater severity of infection (p

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