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Comparative analysis of viral genomes from acute and chronic hepatitis B reveals novel variants associated with a lower rate of chronicity

Chook JB, Ngeow YF, Khang TF, Ng KP, Tiang YP, Mohamed R

J Med Virol, 2013 Mar;85(3):419-24.
PMID: 23297244 DOI: 10.1002/jmv.23500

Infection with the hepatitis B virus (HBV) may lead to an acute or chronic infection. It is generally accepted that the clinical outcome of infection depends on the balance between host immunity and viral survival strategies. In order to persist, the virus needs to have a high rate of replication and some immune-escape capabilities. Hence, HBVs lacking these properties are likely to be eliminated more rapidly by the host, leading to a lower rate of chronicity. To test this hypothesis, 177 HBV genomes from acute non-fulminant cases and 1,149 from chronic cases were retrieved from GenBank for comparative analysis. Selection of candidate nucleotides associated with the disease state was done using random guess cut-off and the Bonferroni correction. Five significant nucleotides were detected using this filtering step. Their predictive values were assessed using the support vector machine classification with five-fold cross-validation. The average prediction accuracy was 61% ± 1%, with a sensitivity of 24% ± 1%, specificity of 98% ± 1%, positive predictive value of 92% ± 4% and negative predictive value of 56% ± 1%. BCP/X, enhancer I and surface/polymerase variants were found to be associated almost exclusively with acute hepatitis. These HBV variants are novel potential markers for non-progression to chronic hepatitis.
Fulltext Susceptibility and gene interaction study of the angiotensin II type 1 receptor (AGTR1) gene polymorphisms with non-alcoholic fatty liver disease in a multi-ethnic population

Zain SM, Mohamed Z, Mahadeva S, Rampal S, Basu RC, Cheah PL, et al.

PLoS One, 2013;8(3):e58538.
PMID: 23484035 DOI: 10.1371/journal.pone.0058538

Angiotensin II type 1 receptor (AGTR1) has been reported to play a fibrogenic role in non-alcoholic fatty liver disease (NAFLD). In this study, five variants of the AGTR1 gene (rs3772622, rs3772627, rs3772630, rs3772633, and rs2276736) were examined for their association with susceptibility to NAFLD. Subjects made up of 144 biopsy-proven NAFLD patients and 198 controls were genotyped using TaqMan assays. The liver biopsy specimens were histologically graded and scored according to the method of Brunt. Single locus analysis in pooled subjects revealed no association between each of the five variants with susceptibility to NAFLD. In the Indian ethnic group, the rs2276736, rs3772630 and rs3772627 appear to be protective against NAFLD (p = 0.010, p = 0.016 and p = 0.026, respectively). Haplotype ACGCA is shown to be protective against NAFLD for the Indian ethnic subgroup (p = 0.03). Gene-gene interaction between the AGTR1 gene and the patatin-like phospholipase domain-containing 3 (PNPLA3) gene, which we previously reported as associated with NAFLD in this sample, showed a strong interaction between AGTR1 (rs3772627), AGTRI (rs3772630) and PNPLA3 (rs738409) polymorphisms on NAFLD susceptibility (p = 0.007). Further analysis of the NAFLD patients revealed that the G allele of the AGTR1 rs3772622 is associated with increased fibrosis score (p = 0.003). This is the first study that replicates an association between AGTR1 polymorphism and NAFLD, with further details in histological features of NAFLD. There is lack of evidence to suggest an association between any of the five variants of the AGTR1 gene and NAFLD in the Malays and Chinese. In the Indians, the rs2276736, rs3772630 and rs3772627 appear to protect against NAFLD. We report novel findings of an association between the G allele of the rs3772622 with occurrence of fibrosis and of the gene-gene interaction between AGTR1gene and the much-studied PNPLA3 gene.
Fulltext Helicobacter pylori cagA gene variants in Malaysians of different ethnicity

Mohamed R, Hanafiah A, Rose IM, Manaf MR, Abdullah SA, Sagap I, et al.

Eur J Clin Microbiol Infect Dis, 2009 Jul;28(7):865-9.
PMID: 19247698 DOI: 10.1007/s10096-009-0712-x

We have defined DNA repeat variability in the 3'-terminus of the cagA gene of Helicobacter pylori strains from Malaysian patients of different ethnicities. We identified different alleles based on the EPIYA repeats. cagA types A-B-D and A-B-B-D are more similar to the sequence of Japanese strains, whereas cagA types A-B-C, A-B-C-C, A-B and A-C displayed similarity to strain 26695 sequences. A significant association was found between cagA genotypes and patients' ethnicity, with cagA type A-B-D being predominantly isolated from Chinese patients and cagA type A-B-C from Malays and Indians. Our data further corroborate the possibility that variant biological activity of CagA may affect the host specificity and/or pathogenicity of H. pylori.
All-optical generation of a 21 GHz microwave carrier by incorporating a double-Brillouin frequency shifter

Shee YG, Mahdi MA, Al-Mansoori MH, Yaakob S, Mohamed R, Zamzuri AK, et al.

Opt Lett, 2010 May 1;35(9):1461-3.
PMID: 20436603 DOI: 10.1364/OL.35.001461

An all-optical generation of a microwave carrier at 21 GHz that incorporates a double-Brillouin frequency shifter is presented. The frequency shift of approximately 21 GHz is achieved by generating the second-order Brillouin Stokes signal from the Brillouin pump. This is accomplished through the circulation and isolation of its first-order Stokes signal in the optical fiber. The Brillouin pump signal is heterodyned with its second-order Brillouin Stokes signal at a high-speed photodetector, and the output beating frequency is equal to the offset between these two signals. The generated microwave carrier is measured at 21.3968 GHz, and the carrier phase noise as low as -58.67 dBc/Hz is achieved.
Burkholderia pseudomallei animal and human isolates from Malaysia exhibit different phenotypic characteristics

Lee SH, Chong CE, Lim BS, Chai SJ, Sam KK, Mohamed R, et al.

Diagn Microbiol Infect Dis, 2007 Jul;58(3):263-70.
PMID: 17350202

Burkholderia pseudomallei is a Gram-negative saprophytic soil bacterium, which is the etiologic agent of melioidosis, a severe and fatal infectious disease occurring in human and animals. Distinct clinical and animal isolates have been shown to exhibit differences in phenotypic trait such as growth rate, colony morphology, antimicrobial resistance, and virulence. This study was carried out to gain insight into the intrinsic differences between 4 clinical and 6 animal B. pseudomallei isolates from Malaysia. The 16S rRNA-encoding genes from these 10 isolates of B. pseudomallei were sequenced to confirm the identity of these isolates along with the avirulent Burkholderia thailandensis. The nucleotide sequences indicated that the 16S rRNA-encoding genes among the 10 B. pseudomallei isolates were identical to each other. However, the nucleotide sequence differences in the 16S rRNA-encoding genes appeared to be B. pseudomallei and B. thailandensis specific. The growth rate of all B. pseudomallei isolates was determined by generating growth curves at 37 degrees C for 72 h. The isolates were found to differ in growth rates with doubling time varying from 1.5 to 2.3 h. In addition, the B. pseudomallei isolates exhibited considerable variation in colony morphology when grown on Ashdown media, brain-heart infusion agar, and Luria-Bertani agar over 9 days of observation. Antimicrobial susceptibility tests indicated that 80% of the isolates examined were Amp(R) Cb(R) Kn(R) Gm(R) Chl(S) Te(S). Virulence of the B. pseudomallei clinical and animal isolates was evaluated in B. pseudomallei-susceptible BALB/c mice. Most of the clinical isolates were highly virulent. However, virulence did not correlate with isolate origin since 2 of the animal isolates were also highly virulent.
Combined use of wild-type HBV precore and high serum iron marker as a potential tool for the prediction of cirrhosis in chronic hepatitis B infection

Chook JB, Ngeow YF, Yap SF, Tan TC, Mohamed R

J Med Virol, 2011 Apr;83(4):594-601.
PMID: 21328372 DOI: 10.1002/jmv.22016

Hepatitis B virus (HBV) and high liver iron deposits have both been associated with the development of cirrhosis. Among HBV factors, genotype and mutations in the basal core promoter (BCP) and precore regions have been most frequently studied but the evidence for a positive association with cirrhosis has been inconsistent. In this study, sera from persons with chronic HBV infection with and without cirrhosis were used for whole HBV genome analysis and for the estimation of serum iron marker (serum iron or ferritin) levels. Single codon analysis showed that the precore wild-type, TGG (nt 1,895-1,897), gave the highest accuracy (77.5%) for the identification of cirrhosis compared to other codons. When TGG was analyzed together with the precore start codon wild-type, ATG (nt 1,814-1,816), the accuracy was improved to 80.0% (odds ratio=35.29; 95% confidence interval=3.87-321.93; Phi=0.629; P<0.001). When the serum iron marker was included for analysis, it was clear that a combination of a precore wild-type and high serum iron marker gave a better accuracy (90.0%) (odds ratio=107.67; 95% confidence interval=10.21-1,135.59; Phi=0.804; P<0.001) for the identification of cirrhosis than either biomarker alone. It appeared that a combined use of both these biomarkers might help to predict the development of cirrhosis in a person with chronic HBV infection, but longitudinal studies are required to test this hypothesis.
Fulltext Cellular transcripts regulated during infections with Highly Pathogenic H5N1 Avian Influenza virus in 3 host systems

Balasubramaniam VR, Hassan SS, Omar AR, Mohamed M, Noor SM, Mohamed R, et al.

Virol J, 2011;8:196.
PMID: 21529348 DOI: 10.1186/1743-422X-8-196

Highly pathogenic Avian Influenza (HPAI) virus is able to infect many hosts and the virus replicates in high levels in the respiratory tract inducing severe lung lesions. The pathogenesis of the disease is actually the outcome of the infection as determined by complex host-virus interactions involving the functional kinetics of large numbers of participating genes. Understanding the genes and proteins involved in host cellular responses are therefore, critical for the elucidation of the mechanisms of infection.
Uncovering the experiences and needs of patients with chronic hepatitis B infection at diagnosis: a qualitative study

Ng CJ, Low WY, Wong LP, Sudin MR, Mohamed R

Asia Pac J Public Health, 2013 Jan;25(1):32-40.
PMID: 21807630 DOI: 10.1177/1010539511413258

Patients with hepatitis B face uncertainty at diagnosis. Information and support they receive at the early stage of the disease determine their adherence to follow up and treatment. This study aimed to explore the experiences and needs of patients with hepatitis B at diagnosis. A qualitative methodology was used. Nine focus groups (n = 44) were conducted to explore patients' feelings and reaction to the diagnosis, encounters with health care professionals, and their needs. The transcribed data were analyzed using a thematic approach. Most patients were not prepared for the diagnosis and many felt anxious and distressed. This was attributed to poor patients' knowledge, doctor's emphasis on disease complications, and associated stigma. Information about the disease was lacking and patients wanted to know more about the mode of transmission, natural progression of the disease, complications, and treatment options. There was a feeling of "passivity" among patients because there was often no active treatment available at diagnosis. This resulted in patients defaulting surveillance visits and missing the opportunity to start antiviral treatment. Therefore, there is an urgent need to provide sufficient information and education about hepatitis B to newly diagnosed patients, break "bad news" to patients with sensitivity, address their emotional needs, and emphasize on the rationale and importance of surveillance and treatment. This may entail public awareness campaign, implementation of pretest and posttest counseling, and educating doctors on how to communicate the diagnosis and management to patients accurately and sensitively.
ProLysED: an integrated database and meta-server of bacterial protease systems

Firdaus Raih M, Ahmad HA, Sharum MY, Azizi N, Mohamed R

Appl. Bioinformatics, 2005;4(2):147-50.
PMID: 16128617

Bacterial proteases are an important group of enzymes that have very diverse biochemical and cellular functions. Proteases from prokaryotic sources also have a wide range of uses, either in medicine as pathogenic factors or in industry and therapeutics. ProLysED (Prokaryotic Lysis Enzymes Database), our meta-server integrated database of bacterial proteases, is a useful, albeit very niche, resource. The features include protease classification browsing and searching, organism-specific protease browsing, molecular information and visualisation of protease structures from the Protein Data Bank (PDB) as well as predicted protease structures.
In silico identification and characterization of a putative phosphatidylinositol 4-phosphate 5-kinase (PIP5K) gene in Eimeria tenella

Ling KH, Loo SS, Rosli R, Shamsudin MN, Mohamed R, Wan KL

In Silico Biol. (Gedrukt), 2007;7(1):115-21.
PMID: 17688436

Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) play diverse roles in the cellular biology of many organisms, including signal transduction, secretion and vesicular trafficking, and regulation of cytoskeleton assembly. Discovery of the PIP5K gene in Eimeria tenella may shed light on its role in the biology of this avian protozoan, and afford further understanding of the cell-host interaction, particularly during the invasion process. In this study, we report the identification of the PIP5K coding region in the genome sequence of Eimeria tenella using in silico gene prediction approaches. Prediction of the PIP5K coding sequence was confirmed by mapping the full-length cDNA sequence, generated via the Rapid Amplification of cDNA Ends (RACE) method, to the genomic sequence. The putative PIP5K gene of Eimeria tenella is located on the complementary strand of the E1080B12.b1 contig, and comprises 12 exons. Further analysis showed that the coding region spans from exon 1 to exon 7, with all exons obeying the adopted 'gt...ag' splicing rule of intronic sequences. Consensus of the hexameric 5' donor-splice site was deduced as GTRDBB... and the consensus for the 3' acceptor-splice sites as ...BHDYAG. The gene encodes a 252-amino acid residue protein. Domain search and protein fold recognition analyses provide compelling evidences that the deduced protein is a PIP5K.
Fulltext Crystallization and preliminary crystallographic studies of the hypothetical protein BPSL1038 from Burkholderia pseudomallei

Shaibullah S, Mohd-Sharif N, Ho KL, Firdaus-Raih M, Nathan S, Mohamed R, et al.

Acta Crystallogr F Struct Biol Commun, 2014 Dec 01;70(Pt 12):1697-700.
PMID: 25484229 DOI: 10.1107/S2053230X14025278

Melioidosis is an infectious disease caused by the pathogenic bacterium Burkholderia pseudomallei. Whole-genome sequencing revealed that the B. pseudomallei genome includes 5855 coding DNA sequences (CDSs), of which ∼25% encode hypothetical proteins. A pathogen-associated hypothetical protein, BPSL1038, was overexpressed in Escherichia coli, purified and crystallized using vapour-diffusion methods. A BPSL1038 protein crystal that grew using sodium formate as precipitant diffracted to 1.55 Å resolution. It belonged to space group C2221, with unit-cell parameters a = 85.36, b = 115.63, c = 46.73 Å. The calculated Matthews coefficient (VM) suggests that there are two molecules per asymmetric unit, with a solvent content of 48.8%.
Fulltext Projections of the current and future disease burden of hepatitis C virus infection in Malaysia

McDonald SA, Dahlui M, Mohamed R, Naning H, Shabaruddin FH, Kamarulzaman A

PLoS One, 2015;10(6):e0128091.
PMID: 26042425 DOI: 10.1371/journal.pone.0128091

BACKGROUND: The prevalence of hepatitis C virus (HCV) infection in Malaysia has been estimated at 2.5% of the adult population. Our objective, satisfying one of the directives of the WHO Framework for Global Action on Viral Hepatitis, was to forecast the HCV disease burden in Malaysia using modelling methods.
METHODS: An age-structured multi-state Markov model was developed to simulate the natural history of HCV infection. We tested three historical incidence scenarios that would give rise to the estimated prevalence in 2009, and calculated the incidence of cirrhosis, end-stage liver disease, and death, and disability-adjusted life-years (DALYs) under each scenario, to the year 2039. In the baseline scenario, current antiviral treatment levels were extended from 2014 to the end of the simulation period. To estimate the disease burden averted under current sustained virological response rates and treatment levels, the baseline scenario was compared to a counterfactual scenario in which no past or future treatment is assumed.
RESULTS: In the baseline scenario, the projected disease burden for the year 2039 is 94,900 DALYs/year (95% credible interval (CrI): 77,100 to 124,500), with 2,002 (95% CrI: 1340 to 3040) and 540 (95% CrI: 251 to 1,030) individuals predicted to develop decompensated cirrhosis and hepatocellular carcinoma, respectively, in that year. Although current treatment practice is estimated to avert a cumulative total of 2,200 deaths from DC or HCC, a cumulative total of 63,900 HCV-related deaths is projected by 2039.
CONCLUSIONS: The HCV-related disease burden is already high and is forecast to rise steeply over the coming decades under current levels of antiviral treatment. Increased governmental resources to improve HCV screening and treatment rates and to reduce transmission are essential to address the high projected HCV disease burden in Malaysia.
Fulltext Universal Primers for Detection and Sequencing of Hepatitis B Virus Genomes across Genotypes A to G

Chook JB, Teo WL, Ngeow YF, Tee KK, Ng KP, Mohamed R

J Clin Microbiol, 2015 Jun;53(6):1831-5.
PMID: 25788548 DOI: 10.1128/JCM.03449-14

Hepatitis B virus (HBV) has been divided into 10 genotypes, A to J, based on an 8% nucleotide sequence divergence between genotypes. The conventional practice of using a single set of primers to amplify a near-complete HBV genome is hampered by its low analytical sensitivity. The current practice of using overlapping conserved primer sets to amplify a complete HBV genome in a clinical sample is limited by the lack of pan-primers to detect all HBV genotypes. In this study, we designed six highly conserved, overlapping primer sets to cover the complete HBV genome. We based our design on the sequences of 5,154 HBV genomes of genotypes A to I downloaded from the GenBank nucleotide database. These primer sets were tested on 126 plasma samples from Malaysia, containing genotypes A to D and with viral loads ranging from 20 to >79,780,000 IU/ml. The overall success rates for PCR amplification and sequencing were >96% and >94%, respectively. Similarly, there was 100% amplification and sequencing success when the primer sets were tested on an HBV reference panel of genotypes A to G. Thus, we have established primer sets that gave a high analytical sensitivity for PCR-based detection of HBV and a high rate of sequencing success for HBV genomes in most of the viral genotypes, if not all, without prior known sequence data for the particular genotype/genome.
Reduction of microbial risk associated with greywater by disinfection processes for irrigation

Al-Gheethi AA, Radin Mohamed RM, Efaq AN, Amir Hashim MK

J Water Health, 2016 Jun;14(3):379-98.
PMID: 27280605 DOI: 10.2166/wh.2015.220

Greywater is one of the most important alternative sources for irrigation in arid and semi-arid countries. However, the health risk associated with the microbial contents of these waters limits their utilization. Many techniques have been developed and used to generate a high microbiological quality of greywater. The main problem in the treatment of greywater lies in the nature of pathogenic bacteria in terms of their ability to survive during/after the treatment process. The present review focused on the health risk associated with the presence of pathogenic bacteria in greywater and the treatment technologies used for the disinfection processes.
Fulltext DNA Barcoding of the Endangered Aquilaria (Thymelaeaceae) and Its Application in Species Authentication of Agarwood Products Traded in the Market

Lee SY, Ng WL, Mahat MN, Nazre M, Mohamed R

PLoS One, 2016;11(4):e0154631.
PMID: 27128309 DOI: 10.1371/journal.pone.0154631

The identification of Aquilaria species from their resinous non-wood product, the agarwood, is challenging as conventional techniques alone are unable to ascertain the species origin. Aquilaria is a highly protected species due to the excessive exploitation of its precious agarwood. Here, we applied the DNA barcoding technique to generate barcode sequences for Aquilaria species and later applied the barcodes to identify the source species of agarwood found in the market. We developed a reference DNA barcode library using eight candidate barcode loci (matK, rbcL, rpoB, rpoC1, psbA-trnH, trnL-trnF, ITS, and ITS2) amplified from 24 leaf accessions of seven Aquilaria species obtained from living trees. Our results indicated that all single barcodes can be easily amplified and sequenced with the selected primers. The combination of trnL-trnF+ITS and trnL-trnF+ITS2 yielded the greatest species resolution using the least number of loci combination, while matK+trnL-trnF+ITS showed potential in detecting the geographical origins of Aquilaria species. We propose trnL-trnF+ITS2 as the best candidate barcode for Aquilaria as ITS2 has a shorter sequence length compared to ITS, which eases PCR amplification especially when using degraded DNA samples such as those extracted from processed agarwood products. A blind test conducted on eight agarwood samples in different forms using the proposed barcode combination proved successful in their identification up to the species level. Such potential of DNA barcoding in identifying the source species of agarwood will contribute to the international timber trade control, by providing an effective method for species identification and product authentication.
Fulltext Characterization of Burkholderia pseudomallei protein BPSL1375 validates the Putative hemolytic activity of the COG3176 N-Acyltransferase family

Ahmad L, Hung TL, Mat Akhir NA, Mohamed R, Nathan S, Firdaus-Raih M

BMC Microbiol, 2015;15:270.
PMID: 26597807 DOI: 10.1186/s12866-015-0604-4

There are still numerous protein subfamilies within families and superfamilies that do not yet have conclusive empirical experimental evidence providing a specific function. These proteins persist in databases with the annotation of a specific 'putative' function made by association with discernible features in the protein sequence.
Fulltext Development of repeatable arrays of proteins using immobilized DNA microplate (RAPID-M) technology

Ashaari NS, Ramarad S, Khairuddin D, Akhir NA, Hara Y, Mahadi NM, et al.

BMC Res Notes, 2015;8:669.
PMID: 26563904 DOI: 10.1186/s13104-015-1637-3

Protein microarrays have enormous potential as in vitro diagnostic tools stemming from the ability to miniaturize whilst generating maximum evaluation of diagnostically relevant information from minute amounts of sample. In this report, we present a method known as repeatable arrays of proteins using immobilized DNA microplates (RAPID-M) for high-throughput in situ protein microarray fabrication. The RAPID-M technology comprises of cell-free expression using immobilized DNA templates and in situ protein purification onto standard microarray slides.
Fulltext Budget impact analysis of two treatment approaches for hepatitis C in Malaysia through the use of voluntary and compulsory licensing options

Azzeri A, Dahlui M, Mohamed R, McDonald SA, Jaafar H, Shabaruddin FH

Front Public Health, 2023;11:1114560.
PMID: 36935675 DOI: 10.3389/fpubh.2023.1114560

INTRODUCTION: A scaled-up treatment cascade with direct-acting antiviral (DAA) therapy is necessary to achieve global WHO targets for hepatitis C virus (HCV) elimination in Malaysia. Recently, limited access to sofosbuvir/daclatasvir (SOF/DAC) is available through compulsory licensing, with access to sofosbuvir/velpatasvir (SOF/VEL) expected through voluntary licensing due to recent agreements. SOF/VEL has superior clinical outcomes but has higher drug acquisition costs compared to SOF/DAC. A stratified treatment cascade might be the most cost-efficient approach for Malaysia whereby all HCV patients are treated with SOF/DAC except for patients with cirrhosis who are treated with SOF/VEL.
METHODS: This study aimed to conduct a 5-year budget impact analysis of the proposed stratified treatment cascade for HCV treatment in Malaysia. A disease progression model that was developed based on model-predicted HCV epidemiology data was used for the analysis, where all HCV patients in scenario A were treated with SOF/DAC for all disease stages while in scenario B, SOF/DAC was used only for non-cirrhotic patients and SOF/VEL was used for the cirrhotic patients. Healthcare costs associated with DAA therapy and disease stage monitoring were included to estimate the downstream cost implications.
RESULTS: The stratified treatment cascade with 109 in Scenario B was found to be cost-saving compared to Scenario A. The cumulative savings for the stratified treatment cascade was USD 1.4 million over 5 years.
DISCUSSION: A stratified treatment cascade with SOF/VEL was expected to be cost-saving and can result in a budget impact reduction in overall healthcare expenditure in Malaysia.
Highly divergent regions in the complete plastome sequences of Aquilaria are suitable for DNA barcoding applications including identifying species origin of agarwood products

Hishamuddin MS, Lee SY, Syazwan SA, Ramlee SI, Lamasudin DU, Mohamed R

3 Biotech, 2023 Mar;13(3):78.
PMID: 36761338 DOI: 10.1007/s13205-023-03479-1

Members of Aquilaria Lam. (Thymelaeaceae) are evergreen trees that are widely distributed in the Indomalesia region. Aquilaria is highly prized for its unique scented resin, agarwood, which is often the subject of unlawful trade activities. Survival of the tree is heavily threatened by destructive harvesting and agarwood poaching, leading to its protection under the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). Unfortunately, an efficient species identification method, which is crucial to aid in the conservation efforts of Aquilaria is lacking. Here, we described our search for a suitable specific DNA barcode for Aquilaria species using eight complete plastome sequences. We identified five highly variable regions (HVR) (matK-rps16, ndhF-rpl32, psbJ-petA, trnD, and trnT-trnL) in the plastomes. These regions were further analyzed using the neighbor-joining (NJ) method to assess their ability at discriminating the eight species. Coupled with in silico primer design, two potential barcoding regions, psbJ-petA and trnT-trnL, were identified. Their strengths in species delimitation were evaluated individually and in combination, via DNA barcoding analysis. Our findings showed that the combined dataset, psbJ-petA + trnT-trnL, effectively resolved members of the genus Aquilaria by clustering all species into their respective clades. In addition, we demonstrated that the newly proposed DNA barcode was capable at identifying the species of origin of six commercial agarwood samples that were included as unknown samples. Such achievement offers a new technical advancement, useful in the combat against illicit agarwood trades and in assisting the conservation of these valuable species in natural populations.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-023-03479-1.
Architectural Regulation of T-Lymphocyte Function in Hepatocellular Carcinoma: Current Evidence and Translational Opportunities

Abdullah MH, Zulkifle N, Suhaimi SA, Aziz MY, Mohamed R

FASEB J, 2026 Oct 31;40(20).
PMID: 42910499 DOI: 10.1096/fj.202603114R

Hepatocellular carcinoma (HCC) develops within a chronically injured liver in which anti-tumor immunity is governed not only by immune-cell abundance and checkpoint signaling, but also by the spatial, mechanical, and multicellular organization of T lymphocytes. This review reframes T-cell architecture as a regulatory layer operating across molecular, cellular, and tissue scales. Cytoskeletal remodeling, immunological synapse geometry, mechanotransduction, vascular positioning, stromal exclusion, and tertiary lymphoid structure (TLS) organization collectively influence T-cell activation thresholds, effector competence, exhaustion trajectories, and therapeutic responsiveness. We synthesize HCC-specific evidence from spatial transcriptomics, multiplex imaging, digital pathology, and clinical cohorts, while clearly distinguishing direct HCC observations from mechanisms extrapolated from other solid tumors or foundational T-cell biology. Current evidence supports the prognostic relevance of intratumoral CD8+ localisation, perivascular immune rims, fibrotic exclusion niches, and mature intratumoral TLS, but causal links between architecture and T-cell fate remain incompletely defined. We propose an architecture-guided framework in which spatial immune states serve as both biomarkers and modifiable therapeutic targets. Spatially informed checkpoint blockade, engineered T-cell therapy, stromal and vascular remodeling, AI-assisted pathology, and organoid or liver-on-chip models may enable more precise immunotherapy strategies for HCC.

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