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  1. Fulltext Transcriptome analysis of Rafflesia cantleyi flower stages reveals insights into the regulation of senescence
    Mohd-Elias NA, Rosli K, Alias H, Juhari MA, Abu-Bakar MF, Md-Isa N, et al.
    Sci Rep, 2021 Dec 08;11(1):23661.
    PMID: 34880337 DOI: 10.1038/s41598-021-03028-x
    Rafflesia is a unique plant species existing as a single flower and produces the largest flower in the world. While Rafflesia buds take up to 21 months to develop, its flowers bloom and wither within about a week. In this study, transcriptome analysis was carried out to shed light on the molecular mechanism of senescence in Rafflesia. A total of 53.3 million high quality reads were obtained from two Rafflesia cantleyi flower developmental stages and assembled to generate 64,152 unigenes. Analysis of this dataset showed that 5,166 unigenes were differentially expressed, in which 1,073 unigenes were identified as genes involved in flower senescence. Results revealed that as the flowers progress to senescence, more genes related to flower senescence were significantly over-represented compared to those related to plant growth and development. Senescence of the R. cantleyi flower activates senescence-associated genes in the transcription activity (members of the transcription factor families MYB, bHLH, NAC, and WRKY), nutrient remobilization (autophagy-related protein and transporter genes), and redox regulation (CATALASE). Most of the senescence-related genes were found to be differentially regulated, perhaps for the fine-tuning of various responses in the senescing R. cantleyi flower. Additionally, pathway analysis showed the activation of genes such as ETHYLENE RECEPTOR, ETHYLENE-INSENSITIVE 2, ETHYLENE-INSENSITIVE 3, and ETHYLENE-RESPONSIVE TRANSCRIPTION FACTOR, indicating the possible involvement of the ethylene hormone response pathway in the regulation of R. cantleyi senescence. Our results provide a model of the molecular mechanism underlying R. cantleyi flower senescence, and contribute essential information towards further understanding the biology of the Rafflesiaceae family.
    Matched MeSH terms: Flowers/genetics*
  2. Environmental surveillance of SARS-CoV-2 in municipal wastewater to monitor COVID-19 status in urban clusters in Malaysia
    Aziz MA, Norman S, Mohamed Zaid S, Simarani K, Sulaiman R, Mohd Aris A, et al.
    Arch Microbiol, 2023 Jan 28;205(2):76.
    PMID: 36708390 DOI: 10.1007/s00203-023-03417-y
    Wastewater monitoring for SARS-CoV-2 has attracted considerable attention worldwide to complement the existing clinical-based surveillance system. In this study, we report our first successful attempt to prove the circulation of SARS-CoV-2 genes in Malaysian urban wastewater. A total of 18 wastewater samples were obtained from a regional sewage treatment plant that received municipal sewage between February 2021 and May 2021. Using the quantitative PCR assay targeting the E and RdRp genes of SARS-CoV-2, we confirmed that both genes were detected in the raw sewage, while no viral RNA was found in the treated sewage. We were also able to show that the trend of COVID-19 cases in Kuala Lumpur and Selangor was related to the changes in SARS-CoV-2 RNA levels in the wastewater samples. Overall, our study highlights that monitoring wastewater for SARS-CoV-2 should help local health professionals to obtain additional information on the rapid and silent circulation of infectious agents in communities at the regional level.
    Matched MeSH terms: RNA, Viral/genetics
  3. Thermo-Responsive Polymer-siRNA Conjugates Enabling Artificial Control of Gene Silencing around Body Temperature
    Honda Y, Onodera S, Takemoto H, Harun NFC, Nomoto T, Matsui M, et al.
    Pharm Res, 2023 Jan;40(1):157-165.
    PMID: 36307662 DOI: 10.1007/s11095-022-03414-8
    PURPOSE: Controlling small interfering RNA (siRNA) activity by external stimuli is useful to exert a selective therapeutic effect at the target site. This study aims to develop a technology to control siRNA activity in a thermo-responsive manner, which can be utilized even at temperatures close to body temperature.

    METHODS: siRNA was conjugated with a thermo-responsive copolymer that was synthesized by copolymerization of N-isopropylacrylamide (NIPAAm) and hydrophilic N,N-dimethylacrylamide (DMAA) to permit thermally controlled interaction between siRNA and an intracellular gene silencing-related protein by utilizing the coil-to-globule phase transition of the copolymer. The composition of the copolymer was fine-tuned to obtain lower critical solution temperature (LCST) around body temperature, and the phase transition behavior was evaluated. The cellular uptake and gene silencing efficiency of the copolymer-siRNA conjugates were then investigated in cultured cells.

    RESULTS: The siRNA conjugated with the copolymer with LCST of 38.0°C exhibited ~ 11.5 nm of the hydrodynamic diameter at 37°C and ~ 9.8 nm of the diameter at 41°C, indicating the coil-globule transition above the LCST. In line with this LCST behavior, its cellular uptake and gene silencing efficiency were enhanced when the temperature was increased from 37°C to 41°C.

    CONCLUSION: By fine-tuning the LCST behavior of the copolymer that was conjugated with siRNA, siRNA activity could be controlled in a thermo-responsive manner around the body temperature. This technique may offer a promising approach to induce therapeutic effects of siRNA selectively in the target site even in the in vivo conditions.

    Matched MeSH terms: RNA, Small Interfering/genetics
  4. DNA methylation of ITGB2 contributes to allopurinol hypersensitivity
    Liu Y, Wang CW, Chen CB, Yu KH, Wu YJ, Choon SE, et al.
    Clin Immunol, 2023 Mar;248:109250.
    PMID: 36738816 DOI: 10.1016/j.clim.2023.109250
    BACKGROUNDS: HLA-B*58:01 allele was strongly associated with allopurinol induced severe cutaneous adverse drug reaction (SCAR). However, HLA-B genotype is not sufficient to predict the occurrence of allopurinol-induced SCAR.

    OBJECTIVE: To discover DNA methylation markers for allopurinol-induced SCAR which may improve the prediction accuracy of genetic testing.

    STUDY DESIGN: The study was designed as a retrospective case-control clinical study in multicenter hospitals across Taiwan, Mainland China, Malaysia and Canada. 125 cases of allopurinol-induced SCAR patients and 139 cases of allopurinol tolerant controls were enrolled in this study during 2005 to 2021.

    RESULTS: The results of genome-wide DNA methylation assay of 62 patients revealed that ITGB2 showed strong discriminative ability of allopurinol-induced SCAR in both HLA-B*58:01 positive and negative patients with AUC value of 0.9364 (95% CI 0.8682-1.000). In validation study, significant hypermethylation of ITGB2 were further validated in allopurinol-induced SCAR patients compared to tolerant controls, especially in those without HLA-B*58:01(AUC value of 0.8814 (95% CI 0.7121-1.000)). Additionally, the methylation levels of 2 sites on ITGB2 were associated with SCAR phenotypes. Combination of HLA-B*58:01 genotyping and ITGB2 methylation status could improve the prediction accuracy of allopurinol-induced SCAR with the AUC value up to 0.9387 (95% CI 0.9089-0.9684), while the AUC value of HLA-B*58:01 genotyping alone was 0.8557 (95% CI 0.8030-0.9083).

    CONCLUSIONS: Our study uncovers differentially methylated genes between allopurinol-induced SCAR patients and tolerant controls with positive or negative HLA-B*58:01 allele and provides the novel epigenetic marker that improves the prediction accuracy of genetic testing for prevention of allopurinol-induced SCAR.

    Matched MeSH terms: HLA-B Antigens/genetics
  5. Regulation of adipogenesis by exosomal milk miRNA
    Abbas MA, Al-Saigh NN, Saqallah FG
    Rev Endocr Metab Disord, 2023 Apr;24(2):297-316.
    PMID: 36692804 DOI: 10.1007/s11154-023-09788-3
    Milk is a rich source of miRNA packaged in exosomes. Evidence for the systemic uptake and tissue distribution of milk exosomes was reported in newborn and adult humans and animals. Breastfeeding in infants was associated with a reduced risk of obesity. Numerous adipogenesis-related miRNAs have been detected in human milk exosomes. It has been demonstrated that ingested exosomal milk miRNAs may alter gene expression in offspring to regulate their metabolism and growth. In humans, consumption of other species' milk, such as cows and goats, is continued through adulthood. Since miRNAs are conserved, the concern of cross-species transfer of adipogenic miRNA has been raised in recent years, and the increase in obesity worldwide was attributed partially to dairy milk consumption by humans. However, evidence is still weak. Research emphasizes the need for an adequate number of exosomal milk's miRNAs to reach the target cell for biological action to be achieved. It was reported that obese women's milk had less miRNA-148a and miRNA-30b, which may affect the fat acquisition of their babies. Some exosomal milk miRNAs, such as miRNA-29, miRNA-148, miRNA-30b and miRNA-125b, may have epigenetic effects on milk recipients. Moreover, the ability of milk exosomes to cross the gastrointestinal barrier makes them a promising oral drug delivery tool. Yet, exosomes may also be tagged with specific ligands which target certain tissues. Thus, milk exosomes can be engineered and loaded with certain miRNAs responsible for adipocyte differentiation, conversion, or browning. Modifications in the miRNA cargo of exosomes can benefit human health and be an alternative to traditional drugs.
    Matched MeSH terms: Adipogenesis/genetics
  6. In silico analysis prediction of HepTH1-5 as a potential therapeutic agent by targeting tumour suppressor protein networks
    Azemin WA, Alias N, Ali AM, Shamsir MS
    J Biomol Struct Dyn, 2023 Mar;41(4):1141-1167.
    PMID: 34935583 DOI: 10.1080/07391102.2021.2017349
    Many studies reported that the activation of tumour suppressor protein, p53 induced the human hepcidin expression. However, its expression decreased when p53 was silenced in human hepatoma cells. Contrary to Tilapia hepcidin TH1-5, HepTH1-5 was previously reported to trigger the p53 activation through the molecular docking approach. The INhibitor of Growth (ING) family members are also shown to directly interact with p53 and promote cell cycle arrest, senescence, apoptosis and participate in DNA replication and DNA damage responses to suppress the tumour initiation and progression. However, the interrelation between INGs and HepTH1-5 remains unknown. Therefore, this study aims to identify the mechanism and their protein interactions using in silico approaches. The finding revealed that HepTH1-5 and its ligands had interacted mostly on hotspot residues of ING proteins which involved in histone modifications via acetylation, phosphorylation, and methylation. This proves that HepTH1-5 might implicate in an apoptosis signalling pathway and preserve the protein structure and function of INGs by reducing the perturbation of histone binding upon oxidative stress response. This study would provide theoretical guidance for the design and experimental studies to decipher the role of HepTH1-5 as a potential therapeutic agent for cancer therapy. Communicated by Ramaswamy H. Sarma.
    Matched MeSH terms: Tumor Suppressor Proteins/genetics
  7. LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes
    Alfattal R, Alfarhan M, Algaith AM, Albash B, Elshafie RM, Alshammari A, et al.
    Am J Med Genet A, 2023 May;191(5):1401-1411.
    PMID: 36757047 DOI: 10.1002/ajmg.a.63143
    Defects of respiratory chain complex III (CIII) result in characteristic but rare mitochondrial disorders associated with distinct neuroradiological findings. The underlying molecular defects affecting mitochondrial CIII assembly factors are few and yet to be identified. LYRM7 assembly factor is required for proper CIII assembly where it acts as a chaperone for the Rieske iron-sulfur (UQCRFS1) protein in the mitochondrial matrix and stabilizing it. We present here the seventeenth individual with LYRM7-associated mitochondrial leukoencephalopathy harboring a previously reported rare pathogenic homozygous LYRM 7 variant, c.2T>C, (p.Met1?). Like previously reported individuals, our 5-year-old male proband presented with recurrent metabolic and lactic acidosis, encephalopathy, and fatigue. Further, he has additional, previously unreported features, including an acute stroke like episode with bilateral central blindness and optic neuropathy, recurrent hyperglycemia and hypertension associated with metabolic crisis. However, he has no signs of psychomotor regression. He has been stable clinically with residual left-sided reduced visual acuity and amblyopia, and no more metabolic crises for 2-year-period while on the mitochondrial cocktail. Although the reported brain MRI findings in other affected individuals are homogenous, it is slightly different in our index, revealing evidence of bilateral almost symmetric multifocal periventricular T2 hyperintensities with hyperintensities of the optic nerves, optic chiasm, and corona radiata but with no cavitation or cystic changes. This report describes new clinical and radiological findings of LYRM7-associated disease. The report also summarizes the clinical and molecular data of previously reported individuals describing the full phenotypic spectrum.
    Matched MeSH terms: Mitochondrial Proteins/genetics
  8. Fulltext Endometrial microbiota composition is associated with reproductive outcome in infertile patients
    Moreno I, Garcia-Grau I, Perez-Villaroya D, Gonzalez-Monfort M, Bahçeci M, Barrionuevo MJ, et al.
    Microbiome, 2022 Jan 04;10(1):1.
    PMID: 34980280 DOI: 10.1186/s40168-021-01184-w
    BACKGROUND: Previous evidence indicates associations between the female reproductive tract microbiome composition and reproductive outcome in infertile patients undergoing assisted reproduction. We aimed to determine whether the endometrial microbiota composition is associated with reproductive outcomes of live birth, biochemical pregnancy, clinical miscarriage or no pregnancy.

    METHODS: Here, we present a multicentre prospective observational study using 16S rRNA gene sequencing to analyse endometrial fluid and biopsy samples before embryo transfer in a cohort of 342 infertile patients asymptomatic for infection undergoing assisted reproductive treatments.

    RESULTS: A dysbiotic endometrial microbiota profile composed of Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus and Streptococcus was associated with unsuccessful outcomes. In contrast, Lactobacillus was consistently enriched in patients with live birth outcomes.

    CONCLUSIONS: Our findings indicate that endometrial microbiota composition before embryo transfer is a useful biomarker to predict reproductive outcome, offering an opportunity to further improve diagnosis and treatment strategies. Video Abstract.

    Matched MeSH terms: RNA, Ribosomal, 16S/genetics
  9. Fulltext Studies on the genetic variation of the green unicellular alga Haematococcus pluvialis (Chlorophyceae) obtained from different geographical locations using ISSR and RAPD molecular marker
    Mostafa N, Omar H, Tan SG, Napis S
    Molecules, 2011 Mar 22;16(3):2599-608.
    PMID: 21441863 DOI: 10.3390/molecules16032599
    Haematococcus pluvialis (Flotow) is a unicellular green alga, which is considered to be the best astaxanthin-producing organism. Molecular markers are suitable tools for the purpose of finding out genetic variations in organisms; however there have been no studies conducted on ISSR or RAPD molecular markers for this organism. The DNA of 10 different strains of H. pluvialis (four strains from Iran, two strains from Finland, one strain from Switzerland and three strains from the USA) was extracted. A genetic similarity study was carried out using 14 ISSR and 12 RAPD primers. Moreover, the molecular weights of the bands produced ranged from 0.14 to 3.4 Kb. The PCA and dendrogram clustered the H. pluvialis strains into various groups according to their geographical origin. The lowest genetic similarity was between the Iran2 and USA2 strains (0.08) and the highest genetic similarity was between Finland1 and Finland2 (0.64). The maximum numbers of bands produced by the ISSR and RAPD primers were 35 and 6 bands, respectively. The results showed that ISSR and RAPD markers are useful for genetic diversity studies of Haematococcus as they showed geographical discrimination.
    Matched MeSH terms: Chlorophyta/genetics*
  10. Shifting the pH profiles of Staphylococcus epidermidis lipase (SEL) and Staphylococcus hyicus lipase (SHL) through generating chimeric lipases by DNA shuffling strategy
    Hasan WANBW, Nezhad NG, Yaacob MA, Salleh AB, Rahman RNZRA, Leow TC
    World J Microbiol Biotechnol, 2024 Feb 22;40(4):106.
    PMID: 38386107 DOI: 10.1007/s11274-024-03927-x
    Enzymes are often required to function in a particular reaction condition by the industrial procedure. In order to identify critical residues affecting the optimum pH of Staphylococcal lipases, chimeric lipases from homologous lipases were generated via a DNA shuffling strategy. Chimeric 1 included mutations of G166S, K212E, T243A, H271Y. Chimeric 2 consisted of substitutions of K212E, T243A, H271Y. Chimeric 3 contained substitutions of K212E, R359L. From the screening results, the pH profiles for chimeric 1 and 2 lipases were shifted from pH 7 to 6. While the pH of chimeric 3 was shifted to 8. It seems the mutation of K212E in chimeric 1 and 2 decreased the pH to 6 by changing the electrostatic potential surface. Furthermore, chimeric 3 showed 10 ˚C improvement in the optimum temperature due to the rigidification of the catalytic loop through the hydrophobic interaction network. Moreover, the substrate specificity of chimeric 1 and 2 was increased towards the longer carbon length chains due to the mutation of T243A adjacent to the lid region through increasing the flexibility of the lid. Current study illustrated that directed evolution successfully modified lipase properties including optimum pH, temperature and substrate specificity through mutations, especially near catalytic and lid regions.
    Matched MeSH terms: Lipase/genetics
  11. Management of classical Philadelphia chromosome-negative myeloproliferative neoplasms in Asia: consensus of the Asian Myeloid Working Group
    Gill H, Leung GMK, Ooi MGM, Teo WZY, Wong CL, Choi CW, et al.
    Clin Exp Med, 2023 Dec;23(8):4199-4217.
    PMID: 37747591 DOI: 10.1007/s10238-023-01189-9
    Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized clinically by the proliferation of one or more hematopoietic lineage(s). The classical Philadelphia-chromosome (Ph)-negative MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The Asian Myeloid Working Group (AMWG) comprises representatives from fifteen Asian centers experienced in the management of MPN. This consensus from the AMWG aims to review the current evidence in the risk stratification and treatment of Ph-negative MPN, to identify management gaps for future improvement, and to offer pragmatic approaches for treatment commensurate with different levels of resources, drug availabilities and reimbursement policies in its constituent regions. The management of MPN should be patient-specific and based on accurate diagnostic and prognostic tools. In patients with PV, ET and early/prefibrotic PMF, symptoms and risk stratification will guide the need for early cytoreduction. In younger patients requiring cytoreduction and in those experiencing resistance or intolerance to hydroxyurea, recombinant interferon-α preparations (pegylated interferon-α 2A or ropeginterferon-α 2b) should be considered. In myelofibrosis, continuous risk assessment and symptom burden assessment are essential in guiding treatment selection. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in MF should always be based on accurate risk stratification for disease-risk and post-HSCT outcome. Management of classical Ph-negative MPN entails accurate diagnosis, cytogenetic and molecular evaluation, risk stratification, and treatment strategies that are outcome-oriented (curative, disease modification, improvement of quality-of-life).
    Matched MeSH terms: Interferon-alpha/genetics
  12. Antibiotic Susceptibility of Staphylococcus Aureus with VanA and MecA Genes
    Ghimire L, Banjara MR, Abdulla AM
    J Nepal Health Res Counc, 2024 Mar 31;21(4):616-622.
    PMID: 38616592 DOI: 10.33314/jnhrc.v21i4.4861
    BACKGROUND: Staphylococcus aureus (S.aureus) is an emerging antibiotic resistant bacterium responsible for various infections in human. Resistance to methicillin and vancomycin are of prime concern in S. aureus. The study aims to determine the minimum inhibitory concentration (MIC) of Vancomycin and evaluate the existence of mecA and vanA genes, associated with antibiotic resistance.

    METHODS: Clinical specimens from three Kathmandu hospitals were processed and S. aureus was identified using conventional microbiological procedures. MRSA was phenotypically identified with cefoxitin (30µg) disc diffusion, while vancomycin susceptibility was assessed using the Ezy MICTM stripes. The mecA and vanA genes were detected by polymerase chain reaction (PCR).

    RESULTS: Out of 266 S. aureus samples from various clinical specimen subjected for analysis, 77 (28.9%) were found methicillin-resistant (MRSA) and 10 (3.8%) were observed vancomycin-resistant (VRSA). Vancomycin resistant isolates showed a significant correlation between resistance to ampicillin, chloramphenicol, and cefoxitin. The mecA gene was found in 39 of the MRSA isolates, having 50.64% of MRSA cases, while the vanA gene was detected in 4 of the VRSA cases, constituting 40% of VRSA occurrences.

    CONCLUSIONS: The strains with higher vancomycin minimum inhibitory concentration values (≥ 1.5 μg/ml) displayed increased resistance rates to various antibiotics compared to strains with lower minimum inhibitory concentration values (< 1.5 μg/ml). The presence of vanA genes was strongly associated (100%) with vancomycin resistance, while the 10.3% mecA gene was identified from MRSA having resistance towards vancomycin also.

    Matched MeSH terms: Staphylococcus aureus/genetics
  13. Characterisation of the mitochondrial genome and phylogenetic analysis of Toxocara apodemi (Nematoda: Ascarididae)
    Gao Y, Hu Y, Xu S, Liang H, Lin H, Yin TH, et al.
    J Helminthol, 2024 Apr 15;98:e33.
    PMID: 38618902 DOI: 10.1017/S0022149X24000221
    We first sequenced and characterised the complete mitochondrial genome of Toxocara apodeme, then studied the evolutionary relationship of the species within Toxocaridae. The complete mitochondrial genome was amplified using PCR with 14 specific primers. The mitogenome length was 14303 bp in size, including 12 PCGs (encoding 3,423 amino acids), 22 tRNAs, 2 rRNAs, and 2 NCRs, with 68.38% A+T contents. The mt genomes of T. apodemi had relatively compact structures with 11 intergenic spacers and 5 overlaps. Comparative analyses of the nucleotide sequences of complete mt genomes showed that T. apodemi had higher identities with T. canis than other congeners. A sliding window analysis of 12 PCGs among 5 Toxocara species indicated that nad4 had the highest sequence divergence, and cox1 was the least variable gene. Relative synonymous codon usage showed that UUG, ACU, CCU, CGU, and UCU most frequently occurred in the complete genomes of T. apodemi. The Ka/Ks ratio showed that all Toxocara mt genes were subject to purification selection. The largest genetic distance between T. apodemi and the other 4 congeneric species was found in nad2, and the smallest was found in cox2. Phylogenetic analyses based on the concatenated amino acid sequences of 12 PCGs demonstrated that T. apodemi formed a distinct branch and was always a sister taxon to other congeneric species. The present study determined the complete mt genome sequences of T. apodemi, which provide novel genetic markers for further studies of the taxonomy, population genetics, and systematics of the Toxocaridae nematodes.
    Matched MeSH terms: Toxocara/genetics
  14. Deletion in erythrocyte band 3 gene in malaria-resistant Southeast Asian ovalocytosis
    Jarolim P, Palek J, Amato D, Hassan K, Sapak P, Nurse GT, et al.
    Proc Natl Acad Sci U S A, 1991 Dec 15;88(24):11022-6.
    PMID: 1722314
    Southeast Asian ovalocytosis (SAO) is a hereditary condition that is widespread in parts of Southeast Asia. The ovalocytic erythrocytes are rigid and resistant to invasion by various malarial parasites. We have previously found that the underlying defect in SAO involves band 3 protein, the major transmembrane protein, which has abnormal structure and function. We now report two linked mutations in the erythrocyte band 3 gene in SAO: (i) a deletion of codons 400-408 and (ii) a substitution, A----G, in the first base of codon 56 leading to substitution of Lys-56 by Glu-56. The first defect leads to a deletion of nine amino acids in the boundary of cytoplasmic and membrane domains of band 3. This defect has been detected in all 30 ovalocytic subjects from Malaysia, the Philippines, and two unrelated coastal regions of Papua New Guinea, whereas it was absent in all 30 controls from Southeast Asia and 20 subjects of different ethnic origin from the United States. The Lys-56----Glu substitution has likewise been found in all SAO subjects. However, it has also been detected in 5 of the 50 control subjects, suggesting that it represents a linked polymorphism. We conclude that the deletion of codons 400-408 in the band 3 gene constitutes the underlying molecular defect in SAO.
    Matched MeSH terms: Anion Exchange Protein 1, Erythrocyte/genetics*; Codon/genetics; DNA/genetics; Elliptocytosis, Hereditary/genetics*; Immunity, Innate/genetics; Malaria/genetics*; RNA/genetics
  15. Unraveling the genetic variations underlying virulence disparities among SARS-CoV-2 strains across global regions: insights from Pakistan
    Jabeen M, Shoukat S, Shireen H, Bao Y, Khan A, Abbasi AA
    Virol J, 2024 Mar 06;21(1):55.
    PMID: 38449001 DOI: 10.1186/s12985-024-02328-8
    Over the course of the COVID-19 pandemic, several SARS-CoV-2 variants have emerged that may exhibit different etiological effects such as enhanced transmissibility and infectivity. However, genetic variations that reduce virulence and deteriorate viral fitness have not yet been thoroughly investigated. The present study sought to evaluate the effects of viral genetic makeup on COVID-19 epidemiology in Pakistan, where the infectivity and mortality rate was comparatively lower than other countries during the first pandemic wave. For this purpose, we focused on the comparative analyses of 7096 amino-acid long polyprotein pp1ab. Comparative sequence analysis of 203 SARS-CoV-2 genomes, sampled from Pakistan during the first wave of the pandemic revealed 179 amino acid substitutions in pp1ab. Within this set, 38 substitutions were identified within the Nsp3 region of the pp1ab polyprotein. Structural and biophysical analysis of proteins revealed that amino acid variations within Nsp3's macrodomains induced conformational changes and modified protein-ligand interactions, consequently diminishing the virulence and fitness of SARS-CoV-2. Additionally, the epistatic effects resulting from evolutionary substitutions in SARS-CoV-2 proteins may have unnoticed implications for reducing disease burden. In light of these findings, further characterization of such deleterious SARS-CoV-2 mutations will not only aid in identifying potential therapeutic targets but will also provide a roadmap for maintaining vigilance against the genetic variability of diverse SARS-CoV-2 strains circulating globally. Furthermore, these insights empower us to more effectively manage and respond to potential viral-based pandemic outbreaks of a similar nature in the future.
    Matched MeSH terms: Virulence/genetics
  16. Fulltext Ancient proteins resolve controversy over the identity of Genyornis eggshell
    Demarchi B, Stiller J, Grealy A, Mackie M, Deng Y, Gilbert T, et al.
    Proc Natl Acad Sci U S A, 2022 Oct 25;119(43):e2109326119.
    PMID: 35609205 DOI: 10.1073/pnas.2109326119
    The realization that ancient biomolecules are preserved in "fossil" samples has revolutionized archaeological science. Protein sequences survive longer than DNA, but their phylogenetic resolution is inferior; therefore, careful assessment of the research questions is required. Here, we show the potential of ancient proteins preserved in Pleistocene eggshell in addressing a longstanding controversy in human and animal evolution: the identity of the extinct bird that laid large eggs which were exploited by Australia's indigenous people. The eggs had been originally attributed to the iconic extinct flightless bird Genyornis newtoni (†Dromornithidae, Galloanseres) and were subsequently dated to before 50 ± 5 ka by Miller et al. [Nat. Commun. 7, 10496 (2016)]. This was taken to represent the likely extinction date for this endemic megafaunal species and thus implied a role of humans in its demise. A contrasting hypothesis, according to which the eggs were laid by a large mound-builder megapode (Megapodiidae, Galliformes), would therefore acquit humans of their responsibility in the extinction of Genyornis. Ancient protein sequences were reconstructed and used to assess the evolutionary proximity of the undetermined eggshell to extant birds, rejecting the megapode hypothesis. Authentic ancient DNA could not be confirmed from these highly degraded samples, but morphometric data also support the attribution of the eggshell to Genyornis. When used in triangulation to address well-defined hypotheses, paleoproteomics is a powerful tool for reconstructing the evolutionary history in ancient samples. In addition to the clarification of phylogenetic placement, these data provide a more nuanced understanding of the modes of interactions between humans and their environment.
    Matched MeSH terms: DNA/genetics
  17. Fulltext Coordination of apicoplast transcription in a malaria parasite by internal and host cues
    Kobayashi Y, Komatsuya K, Imamura S, Nozaki T, Watanabe YI, Sato S, et al.
    Proc Natl Acad Sci U S A, 2023 Jul 11;120(28):e2214765120.
    PMID: 37406097 DOI: 10.1073/pnas.2214765120
    The malaria parasite Plasmodium falciparum has a nonphotosynthetic plastid called the apicoplast, which contains its own genome. Regulatory mechanisms for apicoplast gene expression remain poorly understood, despite this organelle being crucial for the parasite life cycle. Here, we identify a nuclear-encoded apicoplast RNA polymerase σ subunit (sigma factor) which, along with the α subunit, appears to mediate apicoplast transcript accumulation. This has a periodicity reminiscent of parasite circadian or developmental control. Expression of the apicoplast subunit gene, apSig, together with apicoplast transcripts, increased in the presence of the blood circadian signaling hormone melatonin. Our data suggest that the host circadian rhythm is integrated with intrinsic parasite cues to coordinate apicoplast genome transcription. This evolutionarily conserved regulatory system might be a future target for malaria treatment.
    Matched MeSH terms: Plasmodium falciparum/genetics
  18. Fulltext Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP
    Qian M, Zhang H, Kham SK, Liu S, Jiang C, Zhao X, et al.
    Genome Res, 2017 02;27(2):185-195.
    PMID: 27903646 DOI: 10.1101/gr.209163.116
    Chromosomal translocations are a genomic hallmark of many hematologic malignancies. Often as initiating events, these structural abnormalities result in fusion proteins involving transcription factors important for hematopoietic differentiation and/or signaling molecules regulating cell proliferation and cell cycle. In contrast, epigenetic regulator genes are more frequently targeted by somatic sequence mutations, possibly as secondary events to further potentiate leukemogenesis. Through comprehensive whole-transcriptome sequencing of 231 children with acute lymphoblastic leukemia (ALL), we identified 58 putative functional and predominant fusion genes in 54.1% of patients (n = 125), 31 of which have not been reported previously. In particular, we described a distinct ALL subtype with a characteristic gene expression signature predominantly driven by chromosomal rearrangements of the ZNF384 gene with histone acetyltransferases EP300 and CREBBP ZNF384-rearranged ALL showed significant up-regulation of CLCF1 and BTLA expression, and ZNF384 fusion proteins consistently showed higher activity to promote transcription of these target genes relative to wild-type ZNF384 in vitro. Ectopic expression of EP300-ZNF384 and CREBBP-ZNF384 fusion altered differentiation of mouse hematopoietic stem and progenitor cells and also potentiated oncogenic transformation in vitro. EP300- and CREBBP-ZNF384 fusions resulted in loss of histone lysine acetyltransferase activity in a dominant-negative fashion, with concomitant global reduction of histone acetylation and increased sensitivity of leukemia cells to histone deacetylase inhibitors. In conclusion, our results indicate that gene fusion is a common class of genomic abnormalities in childhood ALL and that recurrent translocations involving EP300 and CREBBP may cause epigenetic deregulation with potential for therapeutic targeting.
    Matched MeSH terms: Translocation, Genetic/genetics; Oncogene Proteins, Fusion/genetics; Trans-Activators/genetics*; E1A-Associated p300 Protein/genetics*; CREB-Binding Protein/genetics*; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics*; Transcriptome/genetics
  19. Harnessing the potential of mutation breeding, CRISPR genome editing, and beyond for sustainable agriculture
    Nor A'azizam NM, Chopra S, Guleria P, Kumar V, Abd Rahim MH, Yaacob JS
    Funct Integr Genomics, 2024 Feb 29;24(2):44.
    PMID: 38421529 DOI: 10.1007/s10142-024-01325-y
    By 2050, the global population is projected to exceed 9.5 billion, posing a formidable challenge to ensure food security worldwide. To address this pressing issue, mutation breeding in horticultural crops, utilizing physical or chemical methods, has emerged as a promising biotechnological strategy. However, the efficacy of these mutagens can be influenced by various factors, including biological and environmental variables, as well as targeted plant materials. This review highlights the global challenges related to food security and explores the potential of mutation breeding as an indispensable biotechnological tool in overcoming food insecurity. This review also covers the emergence of CRISPR-Cas9, a breakthrough technology offering precise genome editing for the development of high-yield, stress-tolerant crops. Together, mutation breeding and CRISPR can potentially address future food demands. This review focuses into these biotechnological advancements, emphasizing their combined potential to fortify global food security in the face of a booming population.
    Matched MeSH terms: Crops, Agricultural/genetics
  20. Integrative transcriptomic and metabolomic analyses reveals the toxicity and mechanistic insights of bioformulated chitosan nanoparticles against Magnaporthe oryzae
    Hafeez R, Guo J, Ahmed T, Ibrahim E, Ali MA, Rizwan M, et al.
    Chemosphere, 2024 May;356:141904.
    PMID: 38582174 DOI: 10.1016/j.chemosphere.2024.141904
    Rice blast, an extremely destructive disease caused by the filamentous fungal pathogen Magnaporthe oryzae, poses a global threat to the production of rice (Oryza sativa L.). The emerging trend of reducing dependence on chemical fungicides for crop protection has increased interest in exploring bioformulated nanomaterials as a sustainable alternative antimicrobial strategy for effectively managing plant diseases. Herein, we used physiomorphological, transcriptomic, and metabolomic methods to investigate the toxicity and molecular action mechanisms of moringa-chitosan nanoparticles (M-CNPs) against M. oryzae. Our results demonstrate that M-CNPs exhibit direct antifungal properties by impeding the growth and conidia formation of M. oryzae in a concentration-dependent manner. Propidium iodide staining indicated concentration-dependent significant apoptosis (91.33%) in the fungus. Ultrastructural observations revealed complete structural damage in fungal cells treated with 200 mg/L M-CNPs, including disruption of the cell wall and destruction of internal organelles. Transcriptomic and metabolomic analyses revealed the intricate mechanism underlying the toxicity of M-CNPs against M. oryzae. The transcriptomics data indicated that exposure to M-CNPs disrupted various processes integral to cell membrane biosynthesis, aflatoxin biosynthesis, transcriptional regulation, and nuclear integrity in M. oryzae., emphasizing the interaction between M-CNPs and fungal cells. Similarly, metabolomic profiling demonstrated that exposure to M-CNPs significantly altered the levels of several key metabolites involved in the integral components of metabolic pathways, microbial metabolism, histidine metabolism, citrate cycle, and lipid and protein metabolism in M. oryzae. Overall, these findings demonstrated the potent antifungal action of M-CNPs, with a remarkable impact at the physiological and molecular level, culminating in substantial apoptotic-like fungal cell death. This research provides a novel perspective on investigating bioformulated nanomaterials as antifungal agents for plant disease control.
    Matched MeSH terms: Ascomycota/genetics
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