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1.
Int J Biol Macromol ; 270(Pt 1): 132070, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38705313

ABSTRACT

Plastic pots used in horticultural nurseries generate substantial waste, causing environmental pollution. This study aimed to develop biodegradable composites from banana pseudo-stem reinforced with agricultural residues like pineapple leaves, taro and water hyacinth as eco-friendly substitutes. The aim of this study is to develop optimised banana biocomposite formulations with suitable reinforcements that balance mechanical durability, biodegradation, and seedling growth promotion properties to serve as viable eco-friendly alternatives to plastic seedling pots. This study was carried out by fabricating banana fibre mats through pulping, drying and hot pressing. Composite sheets were reinforced with 50 % pineapple, taro or water hyacinth fibres. The mechanical properties (tensile, yield strength, elongation, bursting strength), hydrophilicity (contact angle, water absorption), biodegradability (soil burial test), and seedling growth promotion were evaluated through appropriate testing methods. The results show that banana-taro composites exhibited suitable tensile strength (25 MPa), elongation (27 %), water uptake (41 %) and 82 % biodegradation in 60 days. It was observed that biodegradable seedling trays fabricated from banana-taro composite showed 95 % tomato seed germination and a 125 cm plant height increase in 30 days, superior to plastic trays. The finding shows that the study demonstrates the potential of banana-taro biocomposites as alternatives to plastic nursery pots, enabling healthy seedling growth while eliminating plastic waste pollution through biodegradation.


Subject(s)
Musa , Seedlings , Musa/growth & development , Musa/chemistry , Seedlings/growth & development , Tensile Strength , Biodegradation, Environmental , Germination , Water/chemistry
2.
Beilstein J Org Chem ; 20: 1088-1098, 2024.
Article in English | MEDLINE | ID: mdl-38774272

ABSTRACT

Nucleoside and polynucleotide cytidine deaminases (CDAs), such as CDA and APOBEC3, share a similar mechanism of cytosine to uracil conversion. In 1984, phosphapyrimidine riboside was characterised as the most potent inhibitor of human CDA, but the quick degradation in water limited the applicability as a potential therapeutic. To improve stability in water, we synthesised derivatives of phosphapyrimidine nucleoside having a CH2 group instead of the N3 atom in the nucleobase. A charge-neutral phosphinamide and a negatively charged phosphinic acid derivative had excellent stability in water at pH 7.4, but only the charge-neutral compound inhibited human CDA, similar to previously described 2'-deoxyzebularine (Ki = 8.0 ± 1.9 and 10.7 ± 0.5 µM, respectively). However, under basic conditions, the charge-neutral phosphinamide was unstable, which prevented the incorporation into DNA using conventional DNA chemistry. In contrast, the negatively charged phosphinic acid derivative was incorporated into DNA instead of the target 2'-deoxycytidine using an automated DNA synthesiser, but no inhibition of APOBEC3A was observed for modified DNAs. Although this shows that the negative charge is poorly accommodated in the active site of CDA and APOBEC3, the synthetic route reported here provides opportunities for the synthesis of other derivatives of phosphapyrimidine riboside for potential development of more potent CDA and APOBEC3 inhibitors.

3.
Nat Commun ; 14(1): 6382, 2023 10 11.
Article in English | MEDLINE | ID: mdl-37821454

ABSTRACT

The normally antiviral enzyme APOBEC3A is an endogenous mutagen in human cancer. Its single-stranded DNA C-to-U editing activity results in multiple mutagenic outcomes including signature single-base substitution mutations (isolated and clustered), DNA breakage, and larger-scale chromosomal aberrations. APOBEC3A inhibitors may therefore comprise a unique class of anti-cancer agents that work by blocking mutagenesis, slowing tumor evolvability, and preventing detrimental outcomes such as drug resistance and metastasis. Here we reveal the structural basis of competitive inhibition of wildtype APOBEC3A by hairpin DNA bearing 2'-deoxy-5-fluorozebularine in place of the cytidine in the TC substrate motif that is part of a 3-nucleotide loop. In addition, the structural basis of APOBEC3A's preference for YTCD motifs (Y = T, C; D = A, G, T) is explained. The nuclease-resistant phosphorothioated derivatives of these inhibitors have nanomolar potency in vitro and block APOBEC3A activity in human cells. These inhibitors may be useful probes for studying APOBEC3A activity in cellular systems and leading toward, potentially as conjuvants, next-generation, combinatorial anti-mutator and anti-cancer therapies.


Subject(s)
Neoplasms , Proteins , Humans , Proteins/chemistry , Mutagenesis , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , DNA , Cytidine Deaminase/genetics , Cytidine Deaminase/chemistry
4.
Int J Biol Macromol ; 253(Pt 5): 126888, 2023 Dec 31.
Article in English | MEDLINE | ID: mdl-37709217

ABSTRACT

Limnocharis flava is a noxious aquatic weed that poses a threat to paddy cultivation. The high cellulose and low lignin contents in this plant make it a potential raw material for papermaking. Against this backdrop, this study was taken up to develop Limnocharis flava (LF) based sheets containing natural fibres from Banana (B), Pineapple (P), and Rice Straw (RS) as reinforcing agents. The influence of carboxymethyl cellulose (CMC) as a binder on the LF-based sheets was also studied. To enhance the mechanical and moisture resistance properties, a chitosan coating was provided to the sheets. Analytical tests for mechanical properties, water barrier properties, functional groups, structure and microstructure, thermal properties and biodegradability were performed. Among the samples, LF + B showed the highest tensile strength (34.86 Mpa) and bursting strength (13.055 kg/cm2), while LF + R had higher puncture and tearing strengths. Chitosan coating was found to enhance the sheets and improve the water barrier properties mechanically. The contact angle of LF + B increased from 91.6° to 110.65°, while the water vapour transmission rate of LF reduced from 532.18 to 404.47 on providing chitosan coating. The significant interactions of reinforcing agents were confirmed by the results of FTIR and that of the coating by the SEM micrographs. The LF-based sheets were also found to have decent thermal stability. The high value of the crystallinity index in LF + R samples supported their remarkable mechanical properties. This study proclaims the notable suitability of Limnocharis flava in manufacturing paper for packaging applications.


Subject(s)
Chitosan , Chitosan/chemistry , Wood , Cellulose/chemistry , Lignin , Food Packaging , Tensile Strength
5.
Org Biomol Chem ; 21(24): 5117-5128, 2023 06 21.
Article in English | MEDLINE | ID: mdl-37282621

ABSTRACT

The APOBEC3 (APOBEC3A-H) enzyme family as a part of the human innate immune system deaminates cytosine to uracil in single-stranded DNA (ssDNA) and thereby prevents the spread of pathogenic genetic information. However, APOBEC3-induced mutagenesis promotes viral and cancer evolution, thus enabling the progression of diseases and development of drug resistance. Therefore, APOBEC3 inhibition offers a possibility to complement existing antiviral and anticancer therapies and prevent the emergence of drug resistance, thus making such therapies effective for longer periods of time. Here, we synthesised nucleosides containing seven-membered nucleobases based on azepinone and compared their inhibitory potential against human cytidine deaminase (hCDA) and APOBEC3A with previously described 2'-deoxyzebularine (dZ) and 5-fluoro-2'-deoxyzebularine (FdZ). The nanomolar inhibitor of wild-type APOBEC3A was obtained by the incorporation of 1,3,4,7-tetrahydro-2H-1,3-diazepin-2-one in the TTC loop of a DNA hairpin instead of the target 2'-deoxycytidine providing a Ki of 290 ± 40 nM, which is only slightly weaker than the Ki of the FdZ-containing inhibitor (117 ± 15 nM). A less potent but notably different inhibition of human cytidine deaminase (CDA) and engineered C-terminal domain of APOBEC3B was observed for 2'-deoxyribosides of the S and R isomers of hexahydro-5-hydroxy-azepin-2-one: the S-isomer was more active than the R-isomer. The S-isomer shows resemblance in the position of the OH-group observed recently for the hydrated dZ and FdZ in the crystal structures with APOBEC3G and APOBEC3A, respectively. This shows that 7-membered ring analogues of pyrimidine nucleosides can serve as a platform for further development of modified ssDNAs as powerful A3 inhibitors.


Subject(s)
Neoplasms , Proteins , Humans , Proteins/metabolism , Cytidine Deaminase , Mutagenesis , Neoplasms/genetics , Minor Histocompatibility Antigens
6.
bioRxiv ; 2023 Feb 17.
Article in English | MEDLINE | ID: mdl-36824964

ABSTRACT

The normally antiviral enzyme APOBEC3A1-4 is an endogenous mutagen in many different human cancers5-7, where it becomes hijacked to fuel tumor evolvability. APOBEC3A's single-stranded DNA C-to-U editing activity1,8 results in multiple mutagenic outcomes including signature single-base substitution mutations (isolated and clustered), DNA breakage, and larger-scale chromosomal aberrations5-7. Transgenic expression in mice demonstrates its tumorigenic potential9. APOBEC3A inhibitors may therefore comprise a novel class of anti-cancer agents that work by blocking mutagenesis, preventing tumor evolvability, and lessening detrimental outcomes such as drug resistance and metastasis. Here we reveal the structural basis of competitive inhibition of wildtype APOBEC3A by hairpin DNA bearing 2'-deoxy-5-fluorozebularine in place of the cytidine in the TC recognition motif that is part of a three-nucleotide loop. The nuclease-resistant phosphorothioated derivatives of these inhibitors maintain nanomolar in vitro potency against APOBEC3A, localize to the cell nucleus, and block APOBEC3A activity in human cells. These results combine to suggest roles for these inhibitors to study A3A activity in living cells, potentially as conjuvants, leading toward next-generation, combinatorial anti-mutator and anti-cancer therapies.

7.
Biochemistry ; 61(22): 2568-2578, 2022 11 15.
Article in English | MEDLINE | ID: mdl-36302365

ABSTRACT

Drug resistance is a major problem associated with anticancer chemo- and immunotherapies. Recent advances in the understanding of resistance mechanisms have revealed that enzymes of the APOBEC3 (A3) family contribute to the development of drug resistance in multiple cancers. A3 enzymes are polynucleotide cytidine deaminases that convert cytosine to uracil (C→U) in single-stranded DNA (ssDNA) and in this way protect humans against viruses and mobile retroelements. On the other hand, cancer cells use A3s, especially A3A and A3B, to mutate human DNA, and thus by increasing rates of evolution, cancer cells escape adaptive immune responses and resist drugs. However, as A3A and A3B are non-essential for primary metabolism, their inhibition opens up a strategy to augment existing anticancer therapies and suppress cancer evolution. To test our hypothesis that pre-shaped ssDNA mimicking the U-shape observed in ssDNA-A3 complexes can provide a better binder to A3 enzymes, a Cu(I)-catalyzed azide-alkyne cycloaddition was used to cross-link two distant modified nucleobases in ssDNA. The resultant cytosine-containing substrate, where the cytosine sits at the apex of the loop, was deaminated faster by the engineered C-terminal domain of A3B than a standard, linear substrate. The cross-linked ssDNA was converted into an A3 inhibitor by replacing the 2'-deoxycytidine in the preferred TCA substrate motif by 2'-deoxyzebularine, a known inhibitor of single nucleoside cytidine deaminases. This strategy yielded the first nanomolar inhibitor of engineered A3BCTD and wild-type A3A (Ki = 690 ± 140 and 360 ± 120 nM, respectively), providing a platform for further development of powerful A3 inhibitors.


Subject(s)
Cytidine Deaminase , Oligonucleotides , Humans , Cytidine Deaminase/metabolism , DNA, Single-Stranded , Cytidine/chemistry , Cytosine
8.
Viruses ; 14(9)2022 09 06.
Article in English | MEDLINE | ID: mdl-36146779

ABSTRACT

APOBEC3 enzymes are polynucleotide deaminases, converting cytosine to uracil on single-stranded DNA (ssDNA) and RNA as part of the innate immune response against viruses and retrotransposons. APOBEC3G is a two-domain protein that restricts HIV. Although X-ray single-crystal structures of individual catalytic domains of APOBEC3G with ssDNA as well as full-length APOBEC3G have been solved recently, there is little structural information available about ssDNA interaction with the full-length APOBEC3G or any other two-domain APOBEC3. Here, we investigated the solution-state structures of full-length APOBEC3G with and without a 40-mer modified ssDNA by small-angle X-ray scattering (SAXS), using size-exclusion chromatography (SEC) immediately prior to irradiation to effect partial separation of multi-component mixtures. To prevent cytosine deamination, the target 2'-deoxycytidine embedded in 40-mer ssDNA was replaced by 2'-deoxyzebularine, which is known to inhibit APOBEC3A, APOBEC3B and APOBEC3G when incorporated into short ssDNA oligomers. Full-length APOBEC3G without ssDNA comprised multiple multimeric species, of which tetramer was the most scattering species. The structure of the tetramer was elucidated. Dimeric interfaces significantly occlude the DNA-binding interface, whereas the tetrameric interface does not. This explains why dimers completely disappeared, and monomeric protein species became dominant, when ssDNA was added. Data analysis of the monomeric species revealed a full-length APOBEC3G-ssDNA complex that gives insight into the observed "jumping" behavior revealed in studies of enzyme processivity. This solution-state SAXS study provides the first structural model of ssDNA binding both domains of APOBEC3G and provides data to guide further structural and enzymatic work on APOBEC3-ssDNA complexes.


Subject(s)
DNA, Single-Stranded , Retroelements , APOBEC-3G Deaminase/metabolism , Cytidine Deaminase , Cytosine , Deoxycytidine , Polynucleotides , Protein Binding , Proteins , RNA/metabolism , Scattering, Small Angle , Uracil , X-Ray Diffraction , X-Rays
9.
Viruses ; 13(2)2021 02 12.
Article in English | MEDLINE | ID: mdl-33673243

ABSTRACT

In normal cells APOBEC3 (A3A-A3H) enzymes as part of the innate immune system deaminate cytosine to uracil on single-stranded DNA (ssDNA) to scramble DNA in order to give protection against a range of exogenous retroviruses, DNA-based parasites, and endogenous retroelements. However, some viruses and cancer cells use these enzymes, especially A3A and A3B, to escape the adaptive immune response and thereby lead to the evolution of drug resistance. We have synthesized first-in-class inhibitors featuring modified ssDNA. We present models based on small-angle X-ray scattering (SAXS) data that (1) confirm that the mode of binding of inhibitor to an active A3B C-terminal domain construct in the solution state is the same as the mode of binding substrate to inactive mutants of A3A and A3B revealed in X-ray crystal structures and (2) give insight into the disulfide-linked inactive dimer formed under the oxidizing conditions of purification.


Subject(s)
Cytidine Deaminase/chemistry , Cytidine Deaminase/metabolism , DNA, Single-Stranded/chemistry , Minor Histocompatibility Antigens/chemistry , Minor Histocompatibility Antigens/metabolism , RNA, Viral/chemistry , Retroviridae Infections/enzymology , Retroviridae/genetics , Catalytic Domain , Cytidine Deaminase/genetics , DNA, Single-Stranded/metabolism , Dimerization , Humans , Minor Histocompatibility Antigens/genetics , Mutation , RNA, Viral/genetics , RNA, Viral/metabolism , Retroviridae/metabolism , Retroviridae Infections/genetics , Retroviridae Infections/virology , Scattering, Small Angle
10.
Front Public Health ; 9: 808751, 2021.
Article in English | MEDLINE | ID: mdl-35141190

ABSTRACT

The rapid global rise of COVID-19 from late 2019 caught major manufacturers of RT-qPCR reagents by surprise and threw into sharp focus the heavy reliance of molecular diagnostic providers on a handful of reagent suppliers. In addition, lockdown and transport bans, necessarily imposed to contain disease spread, put pressure on global supply lines with freight volumes severely restricted. These issues were acutely felt in New Zealand, an island nation located at the end of most supply lines. This led New Zealand scientists to pose the hypothetical question: in a doomsday scenario where access to COVID-19 RT-qPCR reagents became unavailable, would New Zealand possess the expertise and infrastructure to make its own reagents onshore? In this work we describe a review of New Zealand's COVID-19 test requirements, bring together local experts and resources to make all reagents for the RT-qPCR process, and create a COVID-19 diagnostic assay referred to as HomeBrew (HB) RT-qPCR from onshore synthesized components. This one-step RT-qPCR assay was evaluated using clinical samples and shown to be comparable to a commercial COVID-19 assay. Through this work we show New Zealand has both the expertise and, with sufficient lead time and forward planning, infrastructure capacity to meet reagent supply challenges if they were ever to emerge.


Subject(s)
COVID-19 Nucleic Acid Testing , COVID-19 , Humans , Indicators and Reagents/supply & distribution , SARS-CoV-2
12.
J Electrocardiol ; 62: 79-85, 2020.
Article in English | MEDLINE | ID: mdl-32835984

ABSTRACT

INTRODUCTION: Although abnormalities of ventricular repolarization are a hallmark of SC, their clinical impact on management remains to be determined. This study sought to evaluate the prognostic value of dispersion of repolarization in stress cardiomyopathy (SC) with regards to major cardiac events (MCE), recovery time, and recurrence. METHODS: This study analyzed data from258 patients with SC, from January 2009 to January 2018. Standard 12 lead ECG recordings during the acute, subacute, and recovery phases were collected for each eligible patient. Logistic regression was used to identify independent predictors of MCE, a composite of 30 day all-cause mortality, cardiogenic shock, life-threatening ventricular arrhythmias, and stroke. RESULTS: Among the 101 eligible patients (80.2% females, mean age 45.8 ± 11.5 years) in the study cohort, MCE occurred in 16 patients (15.8%). Cox regression analysis identified two independent predictors of MCE: increased ΔQT dispersion ≥ 40 ms (HR 1.31, 95% CI 1.05-9.77, p = 0.029) and increased Δnegative T wave amplitude dispersion ≤ -2.0 mV (HR 1.25, 95% CI 1.11-11.93, p = 0.018) during the subacute phase. The final regression model had good accuracy (sensitivity 81.3%, specificity 96.5%) and discriminative power (AUC 0.89, 95% CI 0.83-0.95). Kaplan-Meier analysis revealed that there was increasing MCE in patients with zero, one, or two predictors (log rank p < 0.001). In addition, patients with increased dispersion also had a significantly longer time to achieve complete recovery (21.4 ± 6.8 vs. 8.5 ± 4.3 days, p = 0.012) and a higher incidence of recurrence (31.3% vs. 2.4%, p = 0.011) of SC. CONCLUSION: Evaluation of dynamic changes of dispersion of repolarization is a simple bed-side tool with high predictive accuracy for prognostication of short term adverse outcomes, delayed recovery, and recurrence in patients with SC.


Subject(s)
Takotsubo Cardiomyopathy , Adult , Arrhythmias, Cardiac , Electrocardiography , Female , Humans , Male , Middle Aged , Prognosis , Shock, Cardiogenic
13.
Acta Cardiol ; 75(1): 42-46, 2020 Feb.
Article in English | MEDLINE | ID: mdl-30602338

ABSTRACT

Background: Fragmented QRS (fQRS) and Q waves are ECG findings in patients with myocardial scar. fQRS is more sensitive than pathological Q waves in detecting myocardial fibrosis in patients with coronary artery disease (CAD). Cardiac magnetic resonance (CMR) imaging is used for the diagnosis and for quantifying scar tissue in patients with HCM. Our aim was to correlate ECG parameters like fQRS and Q waves with the presence of late gadolinium enhancement (LGE) assessed by contrast CMR imaging to elucidate ECG markers which might predict scar tissue in HCM.Methods: This study is a retrospective analysis which included 39 patients who were diagnosed/suspected to have HCM on echocardiography and referred for contrast CMR imaging at our centre between 2010 and 2016. Presence of fQRS was correlated with scar demonstrated by LGE on CMR.Results: Twenty four (66.67%) patients had asymmetrical septal hypertrophy, 7 (19.44%) patients had apical involvement while 5 (13.89%) had concentric pattern. Only 4 (11.11%) patients had pathological Q waves in contiguous leads on surface ECG while fQRS in two contiguous leads was present in 23 (63.89%) patients. Presence of fQRS was more in patients with LGE on CMR than those without (84.61 versus 10%, p<.001). When presence of LGE in specific segments (anterior, lateral and inferior) was correlated with corresponding ECG leads, all the three segments showed significant correlation. The overall sensitivity, specificity, PPV and NPV of fQRS for predicting scar tissue were 84.6, 90.0, 95.6 and 69.2%, respectively.Conclusion: fQRS on surface ECG can be used as an indirect marker to predict the presence of fibrosis in HCM.


Subject(s)
Action Potentials , Cardiomyopathy, Hypertrophic/diagnosis , Cicatrix/diagnosis , Electrocardiography , Heart Rate , Myocardium/pathology , Adult , Cardiomyopathy, Hypertrophic/pathology , Cardiomyopathy, Hypertrophic/physiopathology , Cicatrix/pathology , Cicatrix/physiopathology , Echocardiography , Female , Fibrosis , Humans , Magnetic Resonance Imaging, Cine , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , Time Factors
14.
Chembiochem ; 21(7): 1028-1035, 2020 04 01.
Article in English | MEDLINE | ID: mdl-31633265

ABSTRACT

The APOBEC3 (APOBEC3A-H) enzyme family is part of the human innate immune system that restricts pathogens by scrambling pathogenic single-stranded (ss) DNA by deamination of cytosines to produce uracil residues. However, APOBEC3-mediated mutagenesis of viral and cancer DNA promotes its evolution, thus enabling disease progression and the development of drug resistance. Therefore, APOBEC3 inhibition offers a new strategy to complement existing antiviral and anticancer therapies by making such therapies effective for longer periods of time, thereby preventing the emergence of drug resistance. Here, we have synthesised 2'-deoxynucleoside forms of several known inhibitors of cytidine deaminase (CDA), incorporated them into oligodeoxynucleotides (oligos) in place of 2'-deoxycytidine in the preferred substrates of APOBEC3A, APOBEC3B, and APOBEC3G, and evaluated their inhibitory potential against these enzymes. An oligo containing a 5-fluoro-2'-deoxyzebularine (5FdZ) motif exhibited an inhibition constant against APOBEC3B 3.5 times better than that of the comparable 2'-deoxyzebularine-containing (dZ-containing) oligo. A similar inhibition trend was observed for wild-type APOBEC3A. In contrast, use of the 5FdZ motif in an oligo designed for APOBEC3G inhibition resulted in an inhibitor that was less potent than the dZ-containing oligo both in the case of APOBEC3GCTD and in that of full-length wild-type APOBEC3G.


Subject(s)
APOBEC-3G Deaminase/metabolism , Cytidine/analogs & derivatives , DNA, Single-Stranded/chemistry , Fluorine/chemistry , APOBEC-3G Deaminase/antagonists & inhibitors , APOBEC-3G Deaminase/genetics , Base Sequence , Cytidine/chemistry , DNA, Single-Stranded/metabolism , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/genetics , Isoenzymes/metabolism , Kinetics , Mutagenesis , Nuclear Magnetic Resonance, Biomolecular , Oligodeoxyribonucleotides/chemistry , Oligodeoxyribonucleotides/metabolism , Organophosphorus Compounds/chemistry
15.
Org Biomol Chem ; 17(43): 9435-9441, 2019 11 06.
Article in English | MEDLINE | ID: mdl-31603457

ABSTRACT

To restrict pathogens, in a normal human cell, APOBEC3 enzymes mutate cytosine to uracil in foreign single-stranded DNAs. However, in cancer cells, APOBEC3B (one of seven APOBEC3 enzymes) has been identified as the primary source of genetic mutations. As such, APOBEC3B promotes evolution and progression of cancers and leads to development of drug resistance in multiple cancers. As APOBEC3B is a non-essential protein, its inhibition can be used to suppress emergence of drug resistance in existing anti-cancer therapies. Because of the vital role of APOBEC3 enzymes in innate immunity, selective inhibitors targeting only APOBEC3B are required. Here, we use the discriminative properties of wild-type APOBEC3A, APOBEC3B and APOBEC3G to deaminate different cytosines in the CCC-recognition motif in order to best place the cytidine analogue 2'-deoxyzebularine (dZ) in the CCC-motif. Using several APOBEC3 variants that mimic deamination patterns of wild-type enzymes, we demonstrate that selective inhibition of APOBEC3B in preference to other APOBEC3 constructs is feasible for the dZCC motif. This work is an important step towards development of in vivo tools to inhibit APOBEC3 enzymes in living cells by using short, chemically modified oligonucleotides.


Subject(s)
Cytidine Deaminase/antagonists & inhibitors , Cytidine/analogs & derivatives , DNA, Single-Stranded/pharmacology , Enzyme Inhibitors/pharmacology , Proteins/antagonists & inhibitors , Cell Line , Cytidine/chemistry , Cytidine/pharmacology , Cytidine Deaminase/metabolism , DNA, Single-Stranded/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Proteins/metabolism
16.
J Electrocardiol ; 55: 65-71, 2019.
Article in English | MEDLINE | ID: mdl-31082614

ABSTRACT

BACKGROUND: Risk stratification in Brugada syndrome remains a controversial and unresolved clinical problem, especially in asymptomatic patients with a type 1 ECG pattern. The purpose of this study is to derive and validate a prediction model based on clinical and ECG parameters to effectively identify patients with a type 1 ECG pattern who are at high risk of major arrhythmic events (MAE) during follow-up. METHODS: This study analysed data from 103 consecutive patients with Brugada Type 1 ECG pattern and no history of previous cardiac arrest. The prediction model was derived using logistic regression with MAE as the primary outcome, and patient demographic and electrocardiographic parameters as potential predictor variables. The model was externally validated in an independent cohort of 42 patients. RESULTS: The final model (Brugada Risk Stratification [BRS] score) consisted of 4 independent predictors (1 point each) of MAE during follow-up (median 85.3 months): spontaneous type 1 pattern, QRS fragments in inferior leads≥3,S wave upslope duration ratio ≥ 0.8, and T peak - T end ≥ 100 ms. The BRS score (AUC = 0.95,95% CI 0.0.92-0.98) stratifies patients with a type 1 ECG pattern into low (BRS score ≤ 2) and high (BRS score ≥ 3) risk classes, with a class specific risk of MAE of 0-1.1% and 92.3-100% across the derivation and validation cohorts, respectively. CONCLUSIONS: The BRS score is a simple bed-side tool with high predictive accuracy, for risk stratification of patients with a Brugada Type 1 ECG pattern. Prospective validation of the prediction model is necessary before this score can be implemented in clinical practice.


Subject(s)
Brugada Syndrome , Brugada Syndrome/diagnosis , Death, Sudden, Cardiac , Electrocardiography , Humans , Prospective Studies , Risk Assessment , Ventricular Fibrillation
17.
Environ Health Insights ; 12: 1178630218806892, 2018.
Article in English | MEDLINE | ID: mdl-30369786

ABSTRACT

OBJECTIVE: To assess the sanitary condition and water quality of household wells and to depict it spatially using Geographic Information System (GIS) in an urban area of Trivandrum, Kerala state, India. STUDY DESIGN: A community-based cross-sectional census-type study. METHODS: Study was conducted in an urban area of Trivandrum. All households (n = 449) residing in a 1.05 km2 area were enrolled in the study. Structured questionnaire and Differential Global Positioning System (DGPS) device were used for data collection. Water samples taken were analyzed in an accredited laboratory. RESULTS: Most of the wells were in an intermediate-high contamination risk state, with more than 77% of wells having a septic tank within 7.5 m radius. Coliform contamination was prevalent in 73% of wells, and the groundwater was predominantly acidic with a mean of 5.4, rendering it unfit for drinking. The well chlorination and cleaning practices were inadequate, which were significantly associated with coliform contamination apart from a closely located septic tank. However, water purification practices like boiling were practiced widely in the area. CONCLUSION: Despite the presence of wells with high risk of contamination and inadequate chlorination practices, the apparent rarity of Water-borne diseases in the area may be attributed to the widespread boiling and water purification practices at the consumption level by the households. GIS technology proves useful in picking environmental determinants like polluting sources near the well and to plan control activities.

18.
Mitochondrial DNA A DNA Mapp Seq Anal ; 29(6): 885-896, 2018 08.
Article in English | MEDLINE | ID: mdl-28988502

ABSTRACT

Pseudodiaptomus binghami Sewell, 1912 was first described from the Rangoon River (now Yangon River) estuary, Myanmar. Pseudodiaptomus malayalus Wellershaus, 1969 previously known as P. binghami malayalus, is a typical brackish-water calanoid copepod from Cochin Estuary, Kerala. Morphological examination of P. malayalus and P. binghami collected from Cochin Estuary and the Nambur canal in Andhra Pradesh revealed crucial differences between the two congeners. Female specimens of P. malayalus exhibited marked differences from those described by Wellershaus. They are (1) the number of terminal spines on P5, (2) ornamentation of GS, (3) ornamentation of Ur1-4, (4) length ratio of the Ur and CR segments and (5) length:width ratio of the CR setae. Furthermore, significant and discrete morphological differences were observed between the two Indian species in their P5 and urosome. But the male specimens of P. malayalus did not show any major differences from the original description. In addition, distance matrix data revealed 22% interspecific divergence values which in turn confirmed the status of P. malayalus and P. binghami as two distinct species.


Subject(s)
Copepoda/classification , Electron Transport Complex IV/genetics , Phylogeny , Animals , Copepoda/anatomy & histology , Copepoda/genetics , Female , Male , Myanmar
19.
Indian Pacing Electrophysiol J ; 17(6): 176-179, 2017.
Article in English | MEDLINE | ID: mdl-29231821

ABSTRACT

Multiple reports of familial clustering suggest that genetic factors may contribute in the pathogenesis of atrioventricular nodal re-entrant tachycardia (AVNRT). We report three cases of AVNRT in a father and his two sons along with a review of literature of other similar cases. Electrophysiological studies induced typical AVNRT, which was successfully eliminated by radiofrequency ablation in all of them. Of the 22 reported cases, 96% had typical (slow-fast) variant of AVNRT. The predominant pattern of inheritance appears to be autosomal dominant, though other patterns may exist. Further research is needed to understand the genetic influence of AVNRT and its pathophysiology.

20.
Mitochondrial DNA A DNA Mapp Seq Anal ; 28(6): 872-879, 2017 11.
Article in English | MEDLINE | ID: mdl-27549575

ABSTRACT

Morphological identification of the marine cyclopoid copepod Dioithona rigida in combination with sequencing a 645 bp fragment of mitochondrial cytochrome oxidase c subunit I (mtCOI) gene, collected from offshore waters of Kavarathi Island, Lakshadweep Sea, is presented in this study. Kiefer in 1935 classified Dioithona as a separate genus from Oithona. The main distinguishing characters observed in the collected samples, such as the presence of well-developed P5 with 2 setae, 5 segmented urosome, 12 segmented antennule, compact dagger-like setae on the inner margin of proximal segment of exopod ramus in P1-P4 and engorged portion of P1-bearing a spine, confirmed their morphology to D. rigida. A comparison of setal formulae of the exopod and endopod of D. rigida with those recorded previously by various authors are also presented here. Maximum likelihood Tree analysis exhibited the clustering of D. rigida sequences into a single clade (accession numbers KP972540.1-KR528588.1), which in contrast was 37-42% divergent from other Oithona species. Further intra-specific divergence values of 0-2% also confirmed the genetic identity of D. rigida species. Paracyclopina nana was selected as an out group displayed a diverged array. The present results distinctly differentiated D. rigida from other Oithona species.


Subject(s)
Copepoda/anatomy & histology , Copepoda/genetics , Genes, Mitochondrial , Animals , Copepoda/classification , Copepoda/enzymology , Electron Transport Complex IV/genetics , Female , Genetic Variation , India , Molecular Typing , Phylogeny , Sequence Analysis, DNA
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