Publications by authors named "Helen Irving"

131 Publications

The cytochrome P450 CYP325A is a major driver of pyrethroid resistance in the major malaria vector Anopheles funestus in Central Africa.

Insect Biochem Mol Biol 2021 Sep 13:103647. Epub 2021 Sep 13.

Centre for Research in Infectious Diseases (CRID), P.O. BOX 13591, Yaoundé, Cameroon; Vector Biology Department, Liverpool School of Tropical Medicine (LSTM), Pembroke Place, Liverpool, L3 5QA, UK. Electronic address:

The overexpression and overactivity of key cytochrome P450s (CYP450) genes are major drivers of metabolic resistance to insecticides in African malaria vectors such as Anopheles funestus s.s. Previous RNAseq-based transcription analyses revealed elevated expression of CYP325A specific to Central African populations but its role in conferring resistance has not previously been demonstrated. In this study, RT-qPCR consistently confirmed that CYP325A is highly over-expressed in pyrethroid-resistant An. funestus from Cameroon, compared with a control strain and insecticide-unexposed mosquitoes. A synergist bioassay with PBO significantly recovered susceptibility for permethrin and deltamethrin indicating P450-based metabolic resistance. Analyses of the coding sequence of CYP325A Africa-wide detected high-levels of polymorphism, but with no predominant alleles selected by pyrethroid resistance. Geographical amino acid changes were detected notably in Cameroon. In silico homology modelling and molecular docking simulations predicted that CYP325A binds and metabolises type I and type II pyrethroids. Heterologous expression of recombinant CYP325A and metabolic assays confirmed that the most-common Cameroonian haplotype metabolises both type I and type II pyrethroids with depletion rate twice that the of the DR Congo haplotype. Analysis of the 1 kb putative promoter of CYP325A revealed reduced diversity in resistant mosquitoes compared to susceptible ones, suggesting a potential selective sweep in this region. The establishment of CYP325A as a pyrethroid resistance metabolising gene further explains pyrethroid resistance in Central African populations of An. funestus. Our work will facilitate future efforts to detect the causative resistance markers in the promoter region of CYP325A to design field applicable DNA-based diagnostic tools.
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http://dx.doi.org/10.1016/j.ibmb.2021.103647DOI Listing
September 2021

Genome-Wide Transcriptional Analysis and Functional Validation Linked a Cluster of Epsilon Glutathione S-Transferases with Insecticide Resistance in the Major Malaria Vector across Africa.

Genes (Basel) 2021 04 13;12(4). Epub 2021 Apr 13.

LSTM Research Unit, Centre for Research in Infectious Diseases (CRID), Yaoundé P.O. Box 13591, Cameroon.

Resistance is threatening the effectiveness of insecticide-based interventions in use for malaria control. Pinpointing genes associated with resistance is crucial for evidence-based resistance management targeting the major malaria vectors. Here, a combination of RNA-seq based genome-wide transcriptional analysis and RNA-silencing in vivo functional validation were used to identify key insecticide resistance genes associated with DDT and DDT/permethrin cross-resistance across Africa. A cluster of glutathione-S-transferase from epsilon group were found to be overexpressed in resistant populations of across Africa including [Cameroon (fold change, FC: 2.54), Ghana (4.20), Malawi (2.51)], [Cameroon (4.47), Ghana (7.52), Malawi (2.13)], [Cameroon (2.49), Uganda (2.60)], in Ghana (3.47), [Ghana (2.94), Malawi (2.26)], [Cameroun (3.0), Ghana (3.11), Malawi (3.07), Uganda (3.78)] and (2.39) in Ghana. Validation of genes expression profiles by qPCR confirmed that the genes are differentially expressed across Africa with a greater overexpression in DDT-resistant mosquitoes. RNAi-based knock-down analyses supported that five genes are playing a major role in resistance to pyrethroids (permethrin and deltamethrin) and DDT in , with a significant recovery of susceptibility observed when , , , and were silenced. These findings established that , , and contribute to DDT resistance and should be further characterized to identify their specific genetic variants, to help design DNA-based diagnostic assays, as previously done for the mutation. This study highlights the role of s in the development of resistance to insecticides in malaria vectors and calls for actions to mitigate this resistance.
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http://dx.doi.org/10.3390/genes12040561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069850PMC
April 2021

Intrinsic and extrinsic apoptosis responses in leukaemia cells following daunorubicin treatment.

BMC Cancer 2021 Apr 21;21(1):438. Epub 2021 Apr 21.

Department of Pharmacy and Biomedical Science, La Trobe Institute for Molecular Science (LIMS), La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, Australia.

Background: Daunorubicin is used clinically in the treatment of myeloma, acute lymphatic and myelocytic leukaemia. The toxic lesions caused by daunorubicin induce various modes of cell death, including apoptosis. Apoptosis is highly regulated programmed cell death that can be initiated mainly via two pathways, through death receptors (extrinsic) or involvement of the mitochondria (intrinsic). Induction of apoptosis via these pathways has been alluded following treatment with daunorubicin, but never compared in acute lymphoblastic leukaemia over a time course.

Methods: This study investigated the mechanisms of daunorubicin induced apoptosis in the treatment of CCRF-CEM, MOLT-4 (acute T-lymphoblastic leukaemia) and SUP-B15 (acute B-lymphoblastic leukaemia) cells. Cells were treated with daunorubicin for 4 h, and then placed in recovery medium (without daunorubicin) for 4 h, 12 h and 24 h. Apoptotic response was analysing using annexin-V expression, caspase activity, mitochondrial membrane potential change and an array to detect 43 apoptotic proteins.

Results: Daunorubicin induced apoptosis in all leukemic cell lines, but with different levels and duration of response. Both apoptosis levels and caspase activity increased after four hours recovery then declined in CCRF-CEM and MOLT-4 cells. However, SUP-B15 cells displayed initially comparable levels but remained elevated over the 24 h assessment period. Changes in mitochondrial membrane potential occurred in both MOLT-4 and CCRF-CEM cells but not in SUP-B15 cells. Expression of apoptotic proteins, including Bcl-2, Bax, caspase 3 and FADD, indicated that daunorubicin potentially induced both extrinsic and intrinsic apoptosis in both CCRF-CEM and MOLT-4 cells, but only extrinsic apoptosis in SUP-B15 cells.

Conclusions: This study describes variations in sensitivities and timing of apoptotic responses in different leukaemia cell lines. These differences could be attributed to the lack of functional p53 in coordinating the cells response following cytotoxic treatment with daunorubicin, which appears to delay apoptosis and utilises alternative signalling mechanisms that need to be further explored.
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http://dx.doi.org/10.1186/s12885-021-08167-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059319PMC
April 2021

High pyrethroid/DDT resistance in major malaria vector Anopheles coluzzii from Niger-Delta of Nigeria is probably driven by metabolic resistance mechanisms.

PLoS One 2021 11;16(3):e0247944. Epub 2021 Mar 11.

Vector Biology Department, Liverpool School of Tropical Medicine (LSTM), Liverpool, United Kingdom.

Entomological surveillance of local malaria vector populations is an important component of vector control and resistance management. In this study, the resistance profile and its possible mechanisms was characterised in a field population of the major malaria vector Anopheles coluzzii from Port Harcourt, the capital of Rivers state, in the Niger-Delta Region of Nigeria. Larvae collected in Port-Harcourt, were reared to adulthood and used for WHO bioassays. The population exhibited high resistance to permethrin, deltamethrin and DDT with mortalities of 6.7% ± 2.4, 37.5% ± 3.2 and 6.3% ± 4.1, respectively, but were fully susceptible to bendiocarb and malathion. Synergist bioassays with piperonylbutoxide (PBO) partially recovered susceptibility, with mortalities increasing to 53% ± 4, indicating probable role of CYP450s in permethrin resistance (χ2 = 29.48, P < 0.0001). Transcriptional profiling revealed five major resistance-associated genes overexpressed in the field samples compared to the fully susceptible laboratory colony, Ngoussou. Highest fold change (FC) was observed with GSTe2 (FC = 3.3 in permethrin exposed and 6.2 in unexposed) and CYP6Z3 (FC = 1.4 in exposed and 4.6 in unexposed). TaqMan genotyping of 32 F0 females detected the 1014F and 1575Y knockdown resistance (kdr) mutations with frequencies of 0.84 and 0.1, respectively, while 1014S mutation was not detected. Sequencing of a fragment of the voltage-gated sodium channel, spanning exon 20 from 13 deltamethrin-resistant and 9 susceptible females revealed only 2 distinct haplotypes with a low haplotype diversity of 0.33. The findings of high pyrethroid resistance but with a significant degree of recovery after PBO synergist assay suggests the need to move to PBO-based nets. This could be complemented with carbamate- or organophosphate-based indoor residual spraying in this area.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247944PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951933PMC
March 2021

Effects of Caffeine on Brown Adipose Tissue Thermogenesis and Metabolic Homeostasis: A Review.

Front Neurosci 2021 4;15:621356. Epub 2021 Feb 4.

Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC, Australia.

The impact of brown adipose tissue (BAT) metabolism on understanding energy balance in humans is a relatively new and exciting field of research. The pathogenesis of obesity can be largely explained by an imbalance between caloric intake and energy expenditure, but the underlying mechanisms are far more complex. Traditional non-selective sympathetic activators have been used to artificially elevate energy utilization, or suppress appetite, however undesirable side effects are apparent with the use of these pharmacological interventions. Understanding the role of BAT, in relation to human energy homeostasis has the potential to dramatically offset the energy imbalance associated with obesity. This review discusses paradoxical effects of caffeine on peripheral adenosine receptors and the possible role of adenosine in increasing metabolism is highlighted, with consideration to the potential of central rather than peripheral mechanisms for caffeine mediated BAT thermogenesis and energy expenditure. Research on the complex physiology of adipose tissue, the embryonic lineage and function of the different types of adipocytes is summarized. In addition, the effect of BAT on overall human metabolism and the extent of the associated increase in energy expenditure are discussed. The controversy surrounding the primary β-adrenoceptor involved in human BAT activation is examined, and suggestions as to the lack of translational findings from animal to human physiology and human to models are provided. This review compares and distinguishes human and rodent BAT effects, thus developing an understanding of human BAT thermogenesis to aid lifestyle interventions targeting obesity and metabolic syndrome. The focus of this review is on the effect of BAT thermogenesis on overall metabolism, and the potential therapeutic effects of caffeine in increasing metabolism via its effects on BAT.
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http://dx.doi.org/10.3389/fnins.2021.621356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889509PMC
February 2021

Moonlighting Proteins Shine New Light on Molecular Signaling Niches.

Int J Mol Sci 2021 Jan 29;22(3). Epub 2021 Jan 29.

Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC 3550, Australia.

Plants as sessile organisms face daily environmental challenges and have developed highly nuanced signaling systems to enable suitable growth, development, defense, or stalling responses. Moonlighting proteins have multiple tasks and contribute to cellular signaling cascades where they produce additional variables adding to the complexity or fuzziness of biological systems. Here we examine roles of moonlighting kinases that also generate 3',5'-cyclic guanosine monophosphate (cGMP) in plants. These proteins include receptor like kinases and lipid kinases. Their guanylate cyclase activity potentiates the development of localized cGMP-enriched nanodomains or niches surrounding the kinase and its interactome. These nanodomains contribute to allosteric regulation of kinase and other molecules in the immediate complex directly or indirectly modulating signal cascades. Effects include downregulation of kinase activity, modulation of other members of the protein complexes such as cyclic nucleotide gated channels and potential triggering of cGMP-dependent degradation cascades terminating signaling. The additional layers of information provided by the moonlighting kinases are discussed in terms of how they may be used to provide a layer of fuzziness to effectively modulate cellular signaling cascades.
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http://dx.doi.org/10.3390/ijms22031367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866414PMC
January 2021

Ethical climate in contemporary paediatric intensive care.

J Med Ethics 2021 Jan 11. Epub 2021 Jan 11.

School of Medicine, University of Queensland, Brisbane, Queensland, Australia.

Ethical climate (EC) has been broadly described as how well institutions respond to ethical issues. Developing a tool to study and evaluate EC that aims to achieve sustained improvements requires a contemporary framework with identified relevant drivers. An extensive literature review was performed, reviewing existing EC definitions, tools and areas where EC has been studied; ethical challenges and relevance of EC in contemporary paediatric intensive care (PIC); and relevant ethical theories. We surmised that existing EC definitions and tools designed to measure it fail to capture nuances of the PIC environment, and sought to address existing gaps by developing an EC framework for PIC founded on ethical theory. In this article, we propose a Paediatric Intensive Care Ethical Climate (PICEC) conceptual framework and four measurable domains to be captured by an assessment tool. We define PICEC as the collective felt experience of interdisciplinary team members arising from those factors that enable or constrain their ability to navigate ethical aspects of their work. PICEC both results from and is influenced by how well ethical issues are understood, identified, explored, reflected on, responded to and addressed in the workplace. PICEC encompasses four, core inter-related domains representing drivers of EC including: (1) organisational culture and leadership; (2) interdisciplinary team relationships and dynamics; (3) integrated child and family-centred care; and (4) ethics literacy. Future directions involve developing a PICEC measurement tool, with implications for benchmarking as well as guidance for, and evaluation of, targeted interventions to foster a healthy EC.
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http://dx.doi.org/10.1136/medethics-2020-106818DOI Listing
January 2021

Arabidopsis Plant Natriuretic Peptide Is a Novel Interactor of Rubisco Activase.

Life (Basel) 2020 Dec 31;11(1). Epub 2020 Dec 31.

Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC 3552, Australia.

Plant natriuretic peptides (PNPs) are a group of systemically acting peptidic hormones affecting solute and solvent homeostasis and responses to biotrophic pathogens. Although an increasing body of evidence suggests PNPs modulate plant responses to biotic and abiotic stress, which could lead to their potential biotechnological application by conferring increased stress tolerance to plants, the exact mode of PNPs action is still elusive. In order to gain insight into PNP-dependent signalling, we set out to identify interactors of PNP present in the model plant , termed AtPNP-A. Here, we report identification of rubisco activase (RCA), a central regulator of photosynthesis converting Rubisco catalytic sites from a closed to an open conformation, as an interactor of AtPNP-A through affinity isolation followed by mass spectrometric identification. Surface plasmon resonance (SPR) analyses reveals that the full-length recombinant AtPNP-A and the biologically active fragment of AtPNP-A bind specifically to RCA, whereas a biologically inactive scrambled peptide fails to bind. These results are considered in the light of known functions of PNPs, PNP-like proteins, and RCA in biotic and abiotic stress responses.
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http://dx.doi.org/10.3390/life11010021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823470PMC
December 2020

Analysis of interleukin-1 receptor associated kinase-3 (IRAK3) function in modulating expression of inflammatory markers in cell culture models: A systematic review and meta-analysis.

PLoS One 2020 31;15(12):e0244570. Epub 2020 Dec 31.

Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia.

Background: IRAK3 is a critical modulator of inflammation in innate immunity. IRAK3 is associated with many inflammatory diseases, including sepsis, and is required in endotoxin tolerance to maintain homeostasis of inflammation. The impact of IRAK3 on inflammatory markers such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cell culture models remains controversial.

Objective: To analyse temporal effects of IRAK3 on inflammatory markers after one- or two-challenge interventions in cell culture models.

Methods: A systematic search was performed to identify in vitro cell studies reporting outcome measures of expression of IRAK3 and inflammatory markers. Meta-analyses were performed where sufficient data were available. Comparisons of outcome measures were performed between different cell lines and human and mouse primary cells.

Results: The literature search identified 7766 studies for screening. After screening titles, abstracts and full-texts, a total of 89 studies were included in the systematic review.

Conclusions: The review identifies significant effects of IRAK3 on decreasing NF-κB DNA binding activity in cell lines, TNF-α protein level at intermediate time intervals (4h-15h) in cell lines or at long term intervals (16h-48h) in mouse primary cells following one-challenge. The patterns of TNF-α protein expression in human cell lines and human primary cells in response to one-challenge are more similar than in mouse primary cells. Meta-analyses confirm a negative correlation between IRAK3 and inflammatory cytokine (IL-6 and TNF-α) expression after two-challenges.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244570PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774834PMC
March 2021

Investigation of DDT resistance mechanisms in Anopheles funestus populations from northern and southern Benin reveals a key role of the GSTe2 gene.

Malar J 2020 Dec 17;19(1):456. Epub 2020 Dec 17.

International Institute of Tropical Agriculture, Cotonou, 08 BP 0932, Benin.

Background: Understanding the molecular basis of insecticide resistance in mosquito, such as Anopheles funestus, is an important step in developing strategies to mitigate the resistance problem. This study aims to assess the role of the GSTe2 gene in DDT resistance and determine the genetic diversity of this gene in An. funestus.

Methods: Gene expression analysis was performed using microarrays and PCR while the potential mutation associated with resistance was determined using sequencing.

Results: Low expression level of GSTe2 gene was recorded in Burkina-Faso samples with a fold change of 3.3 while high expression (FC 35.6) was recorded in southern Benin in Pahou (FC 35.6) and Kpome (FC 13.3). The sequencing of GSTe2 gene in six localities showed that L119F-GSTe2 mutation is almost getting fixed in highly DDT-resistant Benin (Pahou, Kpome, Doukonta) and Nigeria (Akaka Remo) mosquitoes with a low mutation rate observed in Tanongou (Benin) and Burkina-Faso mosquitoes.

Conclusion: This study shows the key role of the GSTe2 gene in DDT resistant An. funestus in Benin. Polymorphism analysis of this gene across Benin revealed possible barriers to gene flow, which could impact the design and implementation of resistance management strategies in the country.
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http://dx.doi.org/10.1186/s12936-020-03503-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745352PMC
December 2020

Multiple insecticide resistance and infection in the principal malaria vectors and in a forested locality close to the Yaoundé airport, Cameroon.

Wellcome Open Res 2020 5;5:146. Epub 2020 Nov 5.

Department of Parasitology and Medical Entomology, Centre for Research in Infectious Diseases (CRID), Yaounde, Centre Region, 237, Cameroon.

Reducing the burden of malaria requires better understanding of vector populations, particularly in forested regions where the incidence remains elevated. Here, we characterized malaria vectors in a locality near the Yaoundé international airport, Cameroon, including species composition, abundance, infection rate, insecticide resistance profiles and underlying resistance mechanisms. Blood-fed adult mosquitoes resting indoors were aspirated from houses in April 2019 at Elende, a locality situated 2 km from the Yaoundé-Nsimalen airport. Female mosquitoes were forced to lay eggs to generate F adults. Bioassays were performed to assess resistance profile to the four insecticides classes. The threshold of insecticide susceptibility was defined above 98% mortality rate and mortality rates below 90% were indicative of confirmed insecticide resistance. Furthermore, the molecular basis of resistance and infection rates were investigated. s.s. was the most abundant species in Elende (85%) followed by s.s. (15%) with both having similar sporozoite rate. Both species exhibited high levels of resistance to the pyrethroids, permethrin and deltamethrin (<40% mortality). s.s. was resistant to DDT (9.9% mortality) and bendiocarb (54% mortality) while susceptible to organophosphate. s.s. was resistant to dieldrin (1% mortality), DDT (86% mortality) but susceptible to carbamates and organophosphates. The L119F-GSTe2 resistance allele (8%) and G119S -1 resistance allele (15%) were detected in s.s. and s.s., respectively Furthermore, the high pyrethroid/DDT resistances in corresponded with an increase frequency of 1014F allele (95%). Transcriptional profiling of candidate cytochrome P450 genes reveals the over-expression of , and The resistance to multiple insecticide classes observed in these vector populations alongside the significant sporozoite rate highlights the challenges that vector control programs encounter in sustaining the regular benefits of contemporary insecticide-based control interventions in forested areas.
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http://dx.doi.org/10.12688/wellcomeopenres.15818.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667521PMC
November 2020

Clinical trials with cannabis medicines-guidance for ethics committees, governance officers and researchers to streamline ethics applications and ensuring patient safety: considerations from the Australian experience.

Trials 2020 Nov 17;21(1):932. Epub 2020 Nov 17.

Chris O'Brien Lifehouse Comprehensive Cancer Hospital, Camperdown, New South Wales, Australia.

With cannabis medicines now obtaining legal status in many international jurisdictions (generally on the authorisation of a medical professional), a rapid increase in consumer demand for access to cannabis as a therapeutic option in the treatment and management of a range of indications is being noted. Despite this accessibility, knowledge on optimal use is lacking. Further drug development and clinical trials at regulatory standards are necessary both if a better understanding of the efficacy of cannabis medicines, optimal product formulation and indication-specific dosing is needed and to ensure the broader quality and safety of cannabis medicines in the clinical setting.To enable this, clinical, academic and public calls for the undertaking of rigorous clinical trials to establish an evidence base for the therapeutic use of cannabis medicines have been made internationally. While this commitment to undertake human studies with cannabis medicines is welcomed, it has highlighted unique challenges, notably in the review stages of ethics and governance. This often results in lengthy delays to approval by Human Research Ethics Committees (herein 'HREC', Australia's nomenclature for Institutional Review Boards) and trial commencement. A principal concern in these cases is that in contrast to clinical trials using other more conventional pharmaceutical products, trials of cannabis medicines in humans often involve the use of an investigational product prior to some (or any) of the preclinical and pharmaceutical safety issues being established. This paucity of data around product safety, potential drug interactions, continuity of supply, shelf life and product storage results in apprehension by HRECs and governance bodies to endorse trials using cannabis medicines.This manuscript draws from the experiences of Australian researchers and staff involved in clinical trials of cannabis medicines to describe some of the common difficulties that may be faced in the HREC approval process. It also presents practical advice aimed to assist researchers, HRECs and governance officers navigate this complex terrain. While the authors' experiences are situated within the Australian setting, many of the barriers described are applicable within the international context and thus, the solutions that have been proposed are typically adaptive for use within other jurisdictions.
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http://dx.doi.org/10.1186/s13063-020-04862-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673085PMC
November 2020

A natriuretic peptide from Arabidopsis thaliana (AtPNP-A) can modulate catalase 2 activity.

Sci Rep 2020 11 12;10(1):19632. Epub 2020 Nov 12.

Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC, 3552, Australia.

Analogues of vertebrate natriuretic peptides (NPs) present in plants, termed plant natriuretic peptides (PNPs), comprise a novel class of hormones that systemically affect salt and water balance and responses to plant pathogens. Several lines of evidence indicate that Arabidopsis thaliana PNP (AtPNP-A) affects cellular redox homeostasis, which is also typical for the signaling of its vertebrate analogues, but the molecular mechanism(s) of this effect remains elusive. Here we report identification of catalase 2 (CAT2), an antioxidant enzyme, as an interactor of AtPNP-A. The full-length AtPNP-A recombinant protein and the biologically active fragment of AtPNP-A bind specifically to CAT2 in surface plasmon resonance (SPR) analyses, while a biologically inactive scrambled peptide does not. In vivo bimolecular fluorescence complementation (BiFC) showed that CAT2 interacts with AtPNP-A in chloroplasts. Furthermore, CAT2 activity is lower in homozygous atpnp-a knockdown compared with wild type plants, and atpnp-a knockdown plants phenocopy CAT2-deficient plants in their sensitivity to elevated HO, which is consistent with a direct modulatory effect of the PNP on the activity of CAT2 and hence HO homeostasis. Our work underlines the critical role of AtPNP-A in modulating the activity of CAT2 and highlights a mechanism of fine-tuning plant responses to adverse conditions by PNPs.
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http://dx.doi.org/10.1038/s41598-020-76676-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665192PMC
November 2020

CYP6P9-Driven Signatures of Selective Sweep of Metabolic Resistance to Pyrethroids in the Malaria Vector Reveal Contemporary Barriers to Gene Flow.

Genes (Basel) 2020 11 5;11(11). Epub 2020 Nov 5.

LSTM Research Unit, Centre for Research in Infectious Diseases (CRID), P.O. Box 13591 Yaoundé, Cameroon.

Pyrethroid resistance in major malaria vectors such as threatens malaria control efforts in Africa. Cytochrome P450-mediated metabolic resistance is best understood for genes in southern Africa in . However, we do not know if this resistance mechanism is spreading across Africa and how it relates to broader patterns of gene flow across the continent. Nucleotide diversity of the gene and the diversity pattern of five gene fragments spanning a region of 120 kb around the gene were surveyed in mosquitoes from southern, eastern and central Africa. These analyses revealed that a resistance-associated allele has swept through southern and eastern Africa and is now fixed in these regions. A similar diversity profile was observed when analysing genomic regions located 34 kb upstream to 86 kb downstream of the locus, concordant with a selective sweep throughout the rp1 locus. We identify reduced gene flow between southern/eastern Africa and central Africa, which we hypothesise is due to the Great Rift Valley. These potential barriers to gene flow are likely to prevent or slow the spread of -based resistance mechanism to other parts of Africa and would to be considered in future vector control interventions such as gene drive.
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http://dx.doi.org/10.3390/genes11111314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694540PMC
November 2020

Visualising functional 5-HT receptors containing A and C subunits at or near the cell surface.

Biomed Pharmacother 2020 Dec 12;132:110860. Epub 2020 Oct 12.

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC, 3052, Australia; La Trobe Institute for Molecular Science, La Trobe University, PO Box 199, Bendigo, VIC, 3552, Australia. Electronic address:

Five different subunits of the human serotonin 3 (5-hydroxytrptamine 3; 5-HT) receptor exist and these are present in both central and peripheral systems. Different subunits alter the efficacy of 5-HT receptor antagonists used to treat diarrhoea predominant-irritable bowel syndrome, chemotherapy induced nausea and vomiting and depression. Cell surface arrangement of 5-HT receptor complexes and the contribution of C, D and E subunits to receptor function is poorly understood. Here, we examine interactions of A and C subunits using 5-HT receptor subunits containing fluorescent protein inserts between the 3rd and 4th transmembrane spanning region. HEK293T cells that do not normally express 5-HT receptor subunits, were transiently transfected with A or C or both subunits. Patch clamp experiments show that cells transfected with either fluorescent protein tagged A or A and C subunits generate whole cell currents in response to 5-HT. These findings correlate with the apparent distribution of fluorescent protein tagged A and C subunits at or near cell surfaces detected using TIRF microscopy. In co-transfected cells, the A and C subunits are associated forming AC heteromer complexes at or near the cell surface and a proportion can also form A or C homomers. In conclusion, it is likely that both A homomers and AC heteromers contribute to whole cell currents in response to 5-HT with minimal contribution from C homomers.
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http://dx.doi.org/10.1016/j.biopha.2020.110860DOI Listing
December 2020

A 6.5-kb intergenic structural variation enhances P450-mediated resistance to pyrethroids in malaria vectors lowering bed net efficacy.

Mol Ecol 2020 11 11;29(22):4395-4411. Epub 2020 Oct 11.

Vector Biology Department, Liverpool School of Tropical Medicine, Liverpool, UK.

Elucidating the complex evolutionary armory that mosquitoes deploy against insecticides is crucial to maintain the effectiveness of insecticide-based interventions. Here, we deciphered the role of a 6.5-kb structural variation (SV) in driving cytochrome P450-mediated pyrethroid resistance in the malaria vector, Anopheles funestus. Whole-genome pooled sequencing detected an intergenic 6.5-kb SV between duplicated CYP6P9a/b P450s in pyrethroid-resistant mosquitoes through a translocation event. Promoter analysis revealed a 17.5-fold higher activity (p < .0001) for the SV- carrying fragment than the SV- free one. Quantitative real-time PCR expression profiling of CYP6P9a/b for each SV genotype supported its role as an enhancer because SV+/SV+ homozygote mosquitoes had a significantly greater expression for both genes than heterozygotes SV+/SV- (1.7- to 2-fold) and homozygotes SV-/SV- (4-to 5-fold). Designing a PCR assay revealed a strong association between this SV and pyrethroid resistance (SV+/SV+ vs. SV-/SV-; odds ratio [OR] = 2,079.4, p < .001). The 6.5-kb SV is present at high frequency in southern Africa (80%-100%) but absent in East/Central/West Africa. Experimental hut trials revealed that homozygote SV mosquitoes had a significantly greater chance to survive exposure to pyrethroid-treated nets (OR 27.7; p < .0001) and to blood feed than susceptible mosquitoes. Furthermore, mosquitoes homozygote-resistant at the three loci (SV+/CYP6P9a_R/CYP6P9b_R) exhibited a higher resistance level, leading to a far superior ability to survive exposure to nets than those homozygotes susceptible at the three loci, revealing a strong additive effect. This study highlights the important role of structural variations in the development of insecticide resistance in malaria vectors and their detrimental impact on the effectiveness of pyrethroid-based nets.
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http://dx.doi.org/10.1111/mec.15645DOI Listing
November 2020

Development of Donor Family-Oriented Resources to Facilitate Authorization for Reconstructive Transplantation.

Prog Transplant 2020 12 10;30(4):398-399. Epub 2020 Sep 10.

Hansjörg Wyss Department of Plastic Surgery, 12297NYU Langone Health, NY, USA.

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http://dx.doi.org/10.1177/1526924820958122DOI Listing
December 2020

Investigating the molecular basis of multiple insecticide resistance in a major malaria vector Anopheles funestus (sensu stricto) from Akaka-Remo, Ogun State, Nigeria.

Parasit Vectors 2020 Aug 18;13(1):423. Epub 2020 Aug 18.

International Institute of Tropical Agriculture, 08 BP 0932, Cotonou, Benin.

Background: Understanding the mechanisms used by Anopheles mosquitoes to survive insecticide exposure is key to manage existing insecticide resistance and develop more suitable insecticide-based malaria vector control interventions as well as other alternative integrated tools. To this regard, the molecular basis of permethrin, DDT and dieldrin resistance in Anopheles funestus (sensu stricto) at Akaka-Remo was investigated.

Methods: Bioassays were conducted on 3-5-day-old adult An. funestus (s.s.) mosquitoes for permethrin, DDT and dieldrin susceptibility test. The molecular mechanisms of mosquito resistance to these insecticides were investigated using microarray and reverse transcriptase PCR techniques. The voltage-gated sodium channel region of mosquitoes was also screened for the presence of knockdown resistance mutations (kdr west and east) by sequencing method.

Results: Anopheles funestus (s.s.) population was resistant to permethrin (mortality rate of 68%), DDT (mortality rate of 10%) and dieldrin (mortality rate of 8%) insecticides. Microarray and RT-PCR analyses revealed the overexpression of glutathione S-transferase genes, cytochrome P450s, esterase, trypsin and cuticle proteins in resistant mosquitoes compared to control. The GSTe2 was the most upregulated detoxification gene in permethrin-resistant (FC = 44.89), DDT-resistant (FC = 57.39) and dieldrin-resistant (FC = 41.10) mosquitoes compared to control population (FC = 22.34). The cytochrome P450 gene, CYP6P9b was also upregulated in both permethrin- and DDT-resistant mosquitoes. The digestive enzyme, trypsin (hydrolytic processes) and the cuticle proteins (inducing cuticle thickening leading to reduced insecticides penetration) also showed high involvement in insecticide resistance, through their overexpression in resistant mosquitoes compared to control. The kdr east and west were absent in all mosquitoes analysed, suggesting their non-involvement in the observed mosquito resistance.

Conclusions: The upregulation of metabolic genes, especially the GSTe2 and trypsin, as well as the cuticle proteins is driving insecticide resistance of An. funestus (s.s.) population. However, additional molecular analyses, including functional metabolic assays of these genes as well as screening for a possible higher cuticular hydrocarbon and lipid contents, and increased procuticle thickness in resistant mosquitoes are needed to further describe their distinct roles in mosquito resistance.
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http://dx.doi.org/10.1186/s13071-020-04296-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436991PMC
August 2020

A Rare and Unusual Cause of Unilateral Ureteric Obstruction in a Child.

Clin Chem 2020 08;66(8):1006-1009

Department of Endocrinology and Diabetes, Queensland Children's Hospital, South Brisbane, QLD, Australia.

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http://dx.doi.org/10.1093/clinchem/hvaa059DOI Listing
August 2020

Innervation of supraclavicular adipose tissue: A human cadaveric study.

PLoS One 2020 23;15(7):e0236286. Epub 2020 Jul 23.

Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia.

Functional brown adipose tissue (BAT) was identified in adult humans only in 2007 with the use of fluorodeoxyglucose positron emission tomography imaging. Previous studies have demonstrated a negative correlation between obesity and BAT presence in humans. It is proposed that BAT possesses the capacity to increase metabolism and aid weight loss. In rodents it is well established that BAT is stimulated by the sympathetic nervous system with the interscapular BAT being innervated via branches of intercostal nerves. Whilst there is evidence to suggest that BAT possesses beta-3 adrenoceptors, no studies have identified the specific nerve branch that carries sympathetic innervation to BAT in humans. The aim of this study was to identify and trace the peripheral nerve or nerves that innervate human BAT in the supraclavicular region. The posterior triangle region of the neck of cadaveric specimens were dissected in order to identify any peripheral nerve branches piercing and/or terminating in supraclavicular BAT. A previously undescribed branch of the cervical plexus terminating in a supraclavicular adipose depot was identified in all specimens. This was typically an independent branch of the plexus, from the third cervical spinal nerve, but in one specimen was a branch of the supraclavicular nerve. Histological analysis revealed the supraclavicular adipose depot contained tyrosine hydroxylase immunoreactive structures, which likely represent sympathetic axons. This is the first study that identifies a nerve branch to supraclavicular BAT-like tissue. This finding opens new avenues for the investigation of neural regulation of fat metabolism in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236286PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377457PMC
September 2020

New York Transplant Teams Versus COVID-19.

Prog Transplant 2020 09 30;30(3):194-198. Epub 2020 Jun 30.

New York University Langone Health, NY, USA.

New York State, and especially New York City, were hit hard by the coronavirus disease 2019 (COVID-19) virus. While we followed its course in other parts of the world, and began preparations, there was no way we could have been prepared for the volume and severity of illness that began to overflow in our emergency departments and hospital units. We expanded intensive care units into our medical surgical units while turning conference rooms into medical surgical patient care areas. Clinicians at the bedside described war-like situations with numerous patients arresting and requiring ventilator support. Our New York consortia and organ procurement organizations met online 3 times a week and shared creative strategies to address clinical care and work processes. We would like to share strategies from what we hope was a once in a lifetime experience.
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http://dx.doi.org/10.1177/1526924820938346DOI Listing
September 2020

There are no best practices in a pandemic: Organ donation within the COVID-19 epicenter.

Am J Transplant 2020 11 15;20(11):3089-3093. Epub 2020 Jul 15.

LiveOnNY, New York, NY.

LiveOnNY, the organ procurement organization (OPO) for the greater New York metropolitan area, suspended several best practices to manage the rising referrals of deaths from hospitals during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. On April 2, 2020 hospitals in the donor service area were notified that coronavirus disease 2019 (COVID-19) referrals should be deferred. Still, only 2% of referred patients to the OPO in April 2020 were on ventilators and considered possible organ donors, versus a baseline of 11% in 2019. Few of these deaths were unrelated to COVID-19. Accordingly, organ donors declined to 10 in April (from 26 in March). Despite the exclusion of marginal donors and organs, the implementation of COVID-19 donor testing, and the availability of local procurement surgeons, only 1 organ (a liver) was accepted by a transplant center outside of New York State and 8 organs (5 livers, 4 kidneys) were transplanted in state; 11 organs (1 liver, 10 kidneys) were discarded. Allocation was unsuccessful for 11 additional organs (1 liver, 4 kidneys, 4 hearts, 2 lungs). Despite the obstacles, organ donation remained an important model of collaboration and satisfaction for the health care community in the pandemic's US epicenter. Declining COVID-19 deaths led to the resumption of the comprehensive referral policy on May 6, 2020, with improvement to 18 donors in May.
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http://dx.doi.org/10.1111/ajt.16157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361464PMC
November 2020

An Africa-wide genomic evolution of insecticide resistance in the malaria vector Anopheles funestus involves selective sweeps, copy number variations, gene conversion and transposons.

PLoS Genet 2020 06 4;16(6):e1008822. Epub 2020 Jun 4.

Vector Biology Department, Liverpool School of Tropical Medicine (LSTM), Pembroke Place, Liverpool, United Kingdom.

Insecticide resistance in malaria vectors threatens to reverse recent gains in malaria control. Deciphering patterns of gene flow and resistance evolution in malaria vectors is crucial to improving control strategies and preventing malaria resurgence. A genome-wide survey of Anopheles funestus genetic diversity Africa-wide revealed evidences of a major division between southern Africa and elsewhere, associated with different population histories. Three genomic regions exhibited strong signatures of selective sweeps, each spanning major resistance loci (CYP6P9a/b, GSTe2 and CYP9K1). However, a sharp regional contrast was observed between populations correlating with gene flow barriers. Signatures of complex molecular evolution of resistance were detected with evidence of copy number variation, transposon insertion and a gene conversion between CYP6P9a/b paralog genes. Temporal analyses of samples before and after bed net scale up suggest that these genomic changes are driven by this control intervention. Multiple independent selective sweeps at the same locus in different parts of Africa suggests that local evolution of resistance in malaria vectors may be a greater threat than trans-regional spread of resistance haplotypes.
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http://dx.doi.org/10.1371/journal.pgen.1008822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297382PMC
June 2020

Dataset on interactors of the Plant Natriuretic Peptide (AtPNP-A) determined by mass spectrometry.

Data Brief 2020 Jun 22;30:105606. Epub 2020 Apr 22.

Biomolecular Laboratory, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.

Interactors of the plant natriuretic peptide present in , termed AtPNP-A, were affinity-based isolated from (Col-0) leaf mesophyll cell protoplasts by incubating the protoplasts with biologically active biotinylated peptide corresponding to amino acid sequence of the active site of AtPNP-A (pAtPNP-A), either in the presence or absence of a cross-linking agent, 3,3'-dithiobis(sulfosuccinimidyl propionate) (DTSSP), or with equimolar amount of biotin with DTSSP (negative control). Upon biotin/streptavidin-based isolation of proteins bound to the pAtPNP-A or biotin, the proteins were separated by sodium dodecyl sulphate - polyacrylamide gel electrophoresis (SDS-PAGE), digested with trypsin and subjected to identification with liquid chromatography tandem mass spectrometry (LC-MS/MS). Label-free quantification of identified proteins allowed identification of binding partners of AtPNP-A, paving the way for pinpointing novel signal transduction pathways AtPNP-A is involved in. The raw and processed LC-MS/MS data reported in this article have been deposited to the ProteomeXchange Consortium with the dataset identifier PXD017925.
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http://dx.doi.org/10.1016/j.dib.2020.105606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210391PMC
June 2020

Global trends in incidence rates of childhood liver cancers: A systematic review and meta-analysis.

Paediatr Perinat Epidemiol 2020 09 26;34(5):609-617. Epub 2020 Apr 26.

Cancer Research Centre, Cancer Council Queensland, Brisbane, QLD, Australia.

Background: Childhood liver cancers are relatively rare, hence inferences on incidence trends over time are limited by lack of precision in most studies.

Objective: To conduct a systematic review and meta-analysis of published contemporary trends on childhood liver cancer incidence rates worldwide.

Data Sources: PubMed, EMBASE, CINAHL, Web of Science.

Study Selection And Data Extraction: English-language peer-reviewed articles published from 1 January 2008 to 1 December 2019 that presented quantitative estimates of incidence trends for childhood liver cancer and diagnostic subgroups. Review was conducted per PRISMA guidelines. Two authors independently extracted data and critically assessed studies.

Synthesis: Random effects meta-analysis models were used to estimate pooled incidence trends by diagnostic subgroups. Heterogeneity was measured using the Q and I statistics and publication bias evaluated using Egger's test.

Results: Eighteen studies were included, all based on population-based cancer registries. Trends were reported on average for 18 years. Overall pooled estimates of the annual percentage change (APC) were 1.4 (95% confidence interval [CI] 0.5, 2.3) for childhood liver cancers, 2.8 (95% CI 1.8, 3.8) for hepatoblastoma and -3.0 (95% CI -11.0, 4.9) for hepatocellular carcinoma. Sub-group analysis by region indicated increasing trends for childhood liver cancers in North America/Europe/Australia (APC 1.7, 95% CI 0.7, 2.8) whereas corresponding trends were stable in Asia (APC 1.4, 95%CI -0.3, 2.7). Publication bias was not detected for any of these analyses. The I statistic indicated that the heterogeneity among included studies was low for combined liver cancers, moderate for hepatoblastoma and high for hepatocellular carcinoma.

Conclusions: Incidence is increasing for childhood liver cancers and the most commonly diagnosed subgroup hepatoblastoma. Lack of knowledge of the etiology of childhood liver cancers limited the ability to understand the reasons for observed incidence trends. This review highlighted the need for ongoing monitoring of incidence trends and etiological studies.
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http://dx.doi.org/10.1111/ppe.12671DOI Listing
September 2020

Exploring the Mechanisms of Multiple Insecticide Resistance in a Highly -Infected Malaria Vector Sensu Stricto from Sahel of Northern Nigeria.

Genes (Basel) 2020 04 22;11(4). Epub 2020 Apr 22.

Vector Biology Department, Liverpool School of Tropical Medicine (LSTM), Liverpool L3 5QA, UK.

The Nigerian Government is scaling up the distribution of insecticide-treated bed nets for malaria control, but the lack of surveillance data, especially in the Sudan/Sahel region of the country, may hinder targeting priority populations. Here, the vectorial role and insecticide resistance profile of a population of a major malaria vector sensu stricto from Sahel of Nigeria was characterised. s.s. was the only vector found, with a high human blood index (100%) and a biting rate of 5.3/person/night. High infection was discovered (sporozoite rate = 54.55%). The population is resistant to permethrin (mortality = 48.30%, LT = 65.76 min), deltamethrin, DDT (dichlorodiphenyltrichloroethane) and bendiocarb, with mortalities of 29.44%, 56.34% and 54.05%, respectively. Cone-bioassays established loss of efficacy of the pyrethroid-only long-lasting insecticidal nets (LLINs); but 100% recovery of susceptibility was obtained for piperonylbutoxide (PBO)-containing PermaNet3.0. Synergist bioassays with PBO and diethyl maleate recovered susceptibility, implicating CYP450s (permethrin mortality = 78.73%, χ = 22.33, < 0.0001) and GSTs (DDT mortality = 81.44%, χ = 19.12, < 0.0001). A high frequency of 119F mutation (0.84) was observed (OR = 16, χ = 3.40, = 0.05), suggesting the preeminent role of metabolic resistance. These findings highlight challenges associated with deployment of LLINs and indoor residual spraying (IRS) in Nigeria.
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http://dx.doi.org/10.3390/genes11040454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230678PMC
April 2020

Exploring the impact of glutathione  -transferase (GST)-based metabolic resistance to insecticide on vector competence of for .

Wellcome Open Res 2019 19;4:52. Epub 2019 Mar 19.

Department of parasitology, Centre for Research in Infectious Disease (CRID), Yaoundé, P.O. Box 13591, Cameroon.

Malaria control heavily relies on insecticide-based interventions against mosquito vectors. However, the increasing spread of insecticide resistance is a major threat. The extent to which such resistance, notably metabolic resistance, interferes with the development of the parasite and its impact on overall malaria transmission remains poorly characterized. Here, we investigated whether glutathione S-transferase-based resistance could influence development in . females were infected with gametocytes and midguts were dissected at day 7 post infection for detection/quantification of oocysts. Infection parameters were compared between individual with different L119F-GSTe2 genotypes, and the polymorphism of the GSTe2 gene was analyzed in infected and uninfected mosquito groups. Overall, 403 mosquitoes were dissected and genotyped. The frequency of the L119F-GSTe2 resistance allele was significantly higher in non-infected (55.88%) compared to infected (40.99%) mosquitoes (Fisher's exact test, P<0.0001). Prevalence of infection was significantly higher in heterozygous and homozygous susceptible genotypes (P<0.001). However, homozygous resistant and heterozygous mosquitoes exhibited significantly higher infection intensity (P<0.01). No association was observed between the GSTe2 polymorphism and the infection status of mosquitoes. Altogether, these results suggest that GSTe2-based metabolic resistance may affect the vectorial competence of resistant mosquitoes to infection, by increasing its permissiveness to infection.
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http://dx.doi.org/10.12688/wellcomeopenres.15061.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957023PMC
March 2019

The capacity for oestrogen to influence obesity through brown adipose tissue thermogenesis in animal models: A systematic review and meta-analysis.

Obes Sci Pract 2019 Dec 11;5(6):592-602. Epub 2019 Nov 11.

La Trobe Institute for Molecular Science, Department of Pharmacy and Biomedical Sciences La Trobe University Bendigo Victoria Australia.

Pharmacological interventions to aid weight loss have historically targeted either appetite suppression or increased metabolic rate. Brown adipose tissue (BAT) possesses the capacity to expend energy in a futile cycle, thus increasing basal metabolic rate. In animal models, oestrogen has been implicated in the regulation of body weight, and it is hypothesized that oestrogen is acting by modulating BAT metabolism. A systematic search was performed, to identify research articles implementing in vivo oestrogen-related interventions and reporting outcome measures that provide direct or indirect measures of BAT metabolism. Meta-analyses were conducted where sufficient data were available. The final library of 67 articles were predominantly in rodent models and provided mostly indirect measures of BAT metabolism. Results of this review found that oestrogen's effects on body weight, in rats and possibly mice, are likely facilitated by both metabolic and appetitive mechanisms but are largely only found in ovariectomized models. There is a need for further studies to clarify the potential effects of oestrogen on BAT metabolism in gonad-intact and castrated male animal models.
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http://dx.doi.org/10.1002/osp4.368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934433PMC
December 2019

Cis-regulatory CYP6P9b P450 variants associated with loss of insecticide-treated bed net efficacy against Anopheles funestus.

Nat Commun 2019 10 11;10(1):4652. Epub 2019 Oct 11.

Vector Biology Department, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.

Elucidating the genetic basis of metabolic resistance to insecticides in malaria vectors is crucial to prolonging the effectiveness of insecticide-based control tools including long lasting insecticidal nets (LLINs). Here, we show that cis-regulatory variants of the cytochrome P450 gene, CYP6P9b, are associated with pyrethroid resistance in the African malaria vector Anopheles funestus. A DNA-based assay is designed to track this resistance that occurs near fixation in southern Africa but not in West/Central Africa. Applying this assay we demonstrate, using semi-field experimental huts, that CYP6P9b-mediated resistance associates with reduced effectiveness of LLINs. Furthermore, we establish that CYP6P9b combines with another P450, CYP6P9a, to additively exacerbate the reduced efficacy of insecticide-treated nets. Double homozygote resistant mosquitoes (RR/RR) significantly survive exposure to insecticide-treated nets and successfully blood feed more than other genotypes. This study provides tools to track and assess the impact of multi-gene driven metabolic resistance to pyrethroids, helping improve resistance management.
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http://dx.doi.org/10.1038/s41467-019-12686-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789023PMC
October 2019
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