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Bentley, L.

Publications and source records attributed to Bentley, L..

9 recordsLinked to original sources

Integrating migratory marine connectivity into shark conservation

Understanding migratory connectivity is important for the conservation of highly mobile marine species that face escalating threats across the globe. Establishing baseline information on migratory connectivity is therefore needed to identify regions of conservation focus. Despite efforts to track migratory sharks and rays, information on transboundary movements is limited and often inaccessible to managers and policymakers. Here, we synthesised multimethod movement data for migratory Australian shark and ray species, investigating which species require international engagement to support their population recovery. Based on data from a systematic literature review, we built connectivity networks from telemetry and mark-recapture studies that provide a first baseline for transboundary migratory connectivity for Australian sharks and rays. Of the 31 shark and ray species reviewed, we identified 6 species that link the Australian Exclusive Economic Zone to other national jurisdictions via multispecies migratory connections through the Tasman Sea to New Zealand, through the Tasman and Coral Sea to New Caledonia, and north across the Timor Sea and Torres Strait to Indonesia and Papua New Guinea. White sharks (Carcharhinus carcharias) and whale sharks (Rhincodon typus) were the most data rich, whereas 14 shark and ray species had no movement information. There is a grave deficiency in available information for endangered or critically endangered migratory shark and ray populations, with 76% having only one or no published studies. This work supports future conservation strategies for migratory sharks that require robust international collaboration and the adoption of integrated and dynamic management approaches.

ecology↗

TBX15 regulates a network of immune response genes in adipose tissue and alters fat mass and depot weight in heterozygous knockout mice

Adipose tissue distribution in the body is an indicator of metabolic disease risk, independent of body mass index (BMI), and is indirectly measured by waist-hip-ratio (WHR). T-Box transcription factor-15 (TBX15) has been implicated in regulation of adipose distribution in multiple human and mouse studies, and the TBX15-WARS2 genome-wide association study locus has been associated with BMI-adjusted-WHR signals in multiple investigations. As a potential mediator of this signal, we investigated the role of Tbx15 using heterozygous and homozygous mouse knockout models to determine if loss of this gene alters adipose physiology, and to identify the transcriptional network regulated by Tbx15 in adipose tissue and preadipocyte cells. In a metabolic phenotyping experiment we provided either low fat diet (LFD) or high fat diet (HFD) to male and female heterozygous Tbx15+/- and wildtype Tbx15+/+mice from weaning and maintained for 24 weeks. Only Tbx15+/-mice maintained on LFD weighed less than wildtype LFD controls, and female LFD Tbx15+/- mice had lower fat mass overall. We found that in LFD Tbx15+/- mice, multiple visceral fat depots weighed less than wildtype controls, and this was maintained when corrected for body mass for both gonadal and mesenteric visceral adipose depots. When comparing adipocyte size in multiple adipose depots, some reduction in number of larger adipocytes was detected in the perirenal adipose tissue of female HFD Tbx15+/- vs Tbx15+/+ mice, mesenteric adipose tissue from female LFD Tbx15+/- vs Tbx15+/+ mice and male HFD Tbx15+/- vs Tbx15+/+mice. RNA-sequencing of subcutaneous (inguinal) adipose tissues from 12-week old male and female knockout Tbx15-/-, Tbx15+/- and Tbx15+/+ mice raised on a standard chow diet identified 897 upregulated genes and 2328 downregulated genes in female Tbx15-/- mice compared to Tbx15+/+mice. We then combined this dataset with TBX15 ChIP-sequencing data from mouse preadipocyte 3T3-L1 cells overexpressing TBX15 to identify a credible set of genes directly regulated by TBX15. These 52 genes were enriched for B- and T-cell receptor signalling, JAK-STAT signalling and haematopoietic cell lineage pathways; suggesting a direct regulatory role for TBX15 in these pathways in adipose tissue. Together, these data highlight a role for TBX15 in regulation of differential adipose tissue expansion, particularly under low caloric conditions. Further, we identify a potentially important role for TBX15 in the well described adipocyte-immune cell crosstalk associated with obesity and type 2 diabetes mellitus.

physiology↗

Loss of RREB1 reduces adipogenesis and improves insulin sensitivity in mouse and human adipocytes

There are multiple independent genetic signals at the Ras-responsive element binding protein 1 (RREB1) locus associated with type 2 diabetes risk, fasting glucose, ectopic fat, height, and bone mineral density. We have previously shown that loss of RREB1 in pancreatic beta cells reduces insulin content and impairs islet cell development and function. However, RREB1 is a widely expressed transcription factor and the metabolic impact of RREB1 loss in vivo remains unknown. Here, we show that male and female global heterozygous knockout (Rreb1+/-) mice have reduced body length, weight, and fat mass on high-fat diet. Rreb1+/- mice have sex- and diet-specific decreases in adipose tissue and adipocyte size; male mice on high-fat diet had larger gonadal adipocytes, while males on standard chow and females on high-fat diet had smaller, more insulin sensitive subcutaneous adipocytes. Mouse and human precursor cells lacking RREB1 have decreased adipogenic gene expression and activated transcription of genes associated with osteoblast differentiation, which was associated with Rreb1+/- mice having increased bone mineral density in vivo. Finally, human carriers of RREB1 T2D protective alleles have smaller adipocytes, consistent with RREB1 loss-of-function reducing diabetes risk.

physiology↗

A missense mutation in zinc finger homeobox-3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice.

A protein altering variant in the gene encoding zinc finger homeobox-3 (ZFHX3) has recently been associated with lower BMI in a human genome-wide association study. We investigated metabolic parameters in mice harbouring a missense mutation in Zfhx3 (Zfhx3Sci/+) and looked for altered in situ expression of transcripts that are associated with energy balance in the hypothalamus to understand how ZFHX3 may influence growth and metabolic effects. One year old male and female Zfhx3Sci/+ mice weighed less, had shorter body length, reduced fat mass, smaller mesenteric fat depots, and lower circulating insulin, leptin, and insulin-like growth factor-1 (IGF1) concentrations than Zfhx3+/+ littermates. In a second cohort of 9 - 20-week-old males and females, Zfhx3Sci/+ mice ate less than wildtype controls, in proportion to body weight. In a third cohort of female-only Zfhx3Sci/+ and Zfhx3+/+ mice that underwent metabolic phenotyping from 6 - 14 weeks old, Zfhx3Sci/+ mice weighed less and had lower lean mass and energy expenditure, but fat mass didnt differ. We detected increased expression of somatostatin, and decreased expression of growth hormone-releasing hormone and growth hormone-receptor mRNAs in the arcuate nucleus (ARC). Similarly, ARC expression of orexigenic neuropeptide Y was decreased and ventricular ependymal expression of orphan G protein-coupled receptor Gpr50 was decreased. We demonstrate for the first time an energy balance effect of the Zfhx3Sci mutation, likely by altering expression of key ARC neuropeptides to alter growth, food intake and energy expenditure.

physiology↗

A Wars2 mutant mouse shows a sex and diet specific change in fat distribution, reduced food intake and depot-specific upregulation of WAT browning

1.BackgroundIncreased waist-to-hip ratio (WHR) is associated with increased mortality and risk of type 2 diabetes and cardiovascular disease. The TBX15-WARS2 locus has consistently been associated with increased WHR. Previous study of the hypomorphic Wars2V117L/V117L mouse model found phenotypes including severely reduced fat mass, and white adipose tissue (WAT) browning, suggesting Wars2 could be a potential modulator of fat distribution and WAT browning. MethodsTo test for differences in browning induction across different adipose depots of Wars2V117L/V117L mice, we measured multiple browning markers of a 4-month old chow-fed cohort in subcutaneous and visceral WAT and brown adipose tissue (BAT). To explain previously observed fat mass loss, we also tested for the upregulation of plasma mitokines FGF21 and GDF15 and for differences in food intake in the same cohort. Finally, to test for diet-associated differences in fat distribution, we placed Wars2V117L/V117L mice on low-fat or high-fat diet (LFD, HFD) and assessed their body composition by Echo-MRI and compared terminal adipose depot weights at 6 months of age. ResultsThe chow-fed Wars2V117L/V117L mice showed more changes in WAT browning marker gene expression in the subcutaneous inguinal WAT depot (iWAT) than in the visceral gonadal WAT depot (gWAT). These mice also demonstrated reduced food intake and elevated plasma FGF21 and GDF15, and mRNA from heart and BAT. When exposed to HFD, the Wars2V117L/V117L mice showed resistance to diet-induced obesity and a male and HFD-specific reduction of gWAT : iWAT ratio. ConclusionSevere reduction of Wars2 gene function causes a systemic phenotype which leads to upregulation of FGF21 and GDF15, resulting in reduced food intake and depot-specific changes in browning and fat mass.

physiology↗

SARS-COV-2 Delta variant displays moderate resistance to neutralizing antibodies and spike protein properties of higher soluble ACE2 sensitivity, enhanced cleavage and fusogenic activity

The SARS-CoV-2 B.1.617 lineage variants, Kappa (B.1.617.1) and Delta (B.1.617.2, AY) emerged during the second wave of infections in India, but the Delta variants have become dominant worldwide and continue to evolve. The spike proteins of B.1.617.1, B.1.617.2, and AY.1 variants have several substitutions in the receptor binding domain (RBD), including L452R+E484Q, L452R+T478K, and K417N+L452R+T478K, respectively, that could potentially reduce effectiveness of therapeutic antibodies and current vaccines. Here we compared B.1.617 variants, and their single and double RBD substitutions for resistance to neutralization by convalescent sera, mRNA vaccine-elicited sera, and therapeutic neutralizing antibodies using a pseudovirus neutralization assay. Pseudoviruses with the B.1.617.1, B.1.617.2, and AY.1 spike showed a modest 1.5 to 4.4-fold reduction in neutralization titer by convalescent sera and vaccine-elicited sera. In comparison, similar modest reductions were also observed for pseudoviruses with C.37, P.1, R.1, and B.1.526 spikes, but seven- and sixteen-fold reduction for vaccine-elicited and convalescent sera, respectively, was seen for pseudoviruses with the B.1.351 spike. Four of twenty-three therapeutic neutralizing antibodies showed either complete or partial loss of neutralization against B.1.617.2 pseudoviruses due to the L452R substitution, whereas six of twenty-three therapeutic neutralizing antibodies showed either complete or partial loss of neutralization against B.1.617.1 pseudoviruses due to either the E484Q or L452R substitution. Against AY.1 pseudoviruses, the L452R and K417N substitutions accounted for the loss of neutralization by four antibodies and one antibody, respectively, whereas one antibody lost potency that could not be fully accounted for by a single RBD substitution. The modest resistance of B.1.617 variants to vaccine-elicited sera suggest that current mRNA-based vaccines will likely remain effective in protecting against B.1.617 variants, but the therapeutic antibodies need to be carefully selected based on their resistance profiles. Finally, the spike proteins of B.1.617 variants are more efficiently cleaved due to the P681R substitution, and the spike of Delta variants exhibited greater sensitivity to soluble ACE2 neutralization, as well as fusogenic activity, which may contribute to enhanced spread of Delta variants.

microbiology↗

Key substitutions in the spike protein of SARS-CoV-2 variants can predict resistance to monoclonal antibodies, but other substitutions can modify the effects

Mutations in the spike protein of SARS-CoV-2 variants can compromise the effectiveness of therapeutic antibodies. Most clinical-stage therapeutic antibodies target the spike receptor binding domain (RBD), but variants often have multiple mutations in several spike regions. To help predict antibody potency against emerging variants, we evaluated 25 clinical-stage therapeutic antibodies for neutralization activity against 60 pseudoviruses bearing spikes with single or multiple substitutions in several spike domains, including the full set of substitutions in B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.429 (Epsilon), B.1.526 (Iota), A.23.1 and R.1 variants. We found that 14 of 15 single antibodies were vulnerable to at least one RBD substitution, but most combination and polyclonal therapeutic antibodies remained potent. Key substitutions in variants with multiple spike substitutions predicted resistance, but the degree of resistance could be modified in unpredictable ways by other spike substitutions that may reside outside of the RBD. These findings highlight the importance of assessing antibody potency in the context of all substitutions in a variant and show that epistatic interactions in spike can modify virus susceptibility to therapeutic antibodies. ImportanceTherapeutic antibodies are effective in preventing severe disease from SARS-CoV-2 infection (COVID-19), but their effectiveness may be reduced by virus variants with mutations affecting the spike protein. To help predict resistance to therapeutic antibodies in emerging variants, we profiled resistance patterns of 25 antibody products in late stages of clinical development against a large panel of variants that include single and multiple substitutions found in the spike protein. We found that the presence of a key substitution in variants with multiple spike substitutions can predict resistance against a variant, but that other substitutions can affect the degree of resistance in unpredictable ways. These finding highlight complex interactions among substitutions in the spike protein affecting virus neutralization and potentially virus entry into cells.

microbiology↗

Akr1d1-/- mice have a sexually dimorphic metabolic phenotype with reduced fat mass, increased insulin sensitivity and hypertriglyceridemia in males

BackgroundSteroid 5{beta}-reductase (AKR1D1) plays important roles in hepatic glucocorticoid clearance and bile acid synthesis. Glucocorticoids and bile acids are potent metabolic regulators, but whether AKR1D1 controls metabolic phenotype in vivo is unknown. MethodsAkr1d1-/-mice were generated on a C57BL/6 background. Liquid chromatography / mass spectrometry, metabolomic and transcriptomic approaches were used to determine effects on glucocorticoid and bile acid homeostasis. Metabolic phenotypes including body weight and composition, lipid homeostasis, glucose tolerance and insulin sensitivity were evaluated. Molecular changes were assessed by RNASeq and western blotting. Male Akr1d1-/-mice were challenged with a 60% high fat diet. ResultsAkr1d1-/-mice had a sex specific metabolic phenotype. At 30-weeks of age male, but not female, Akr1d1-/-mice were more insulin sensitive and had reduced lipid accumulation in the liver and adipose tissue, concomitant with hypertriglyceridemia and increased intramuscular triacylglycerol. This phenotype was underpinned by sexually dimorphic changes in bile acid metabolism and composition, but without overt effects on glucocorticoid action. Male Akr1d1-/-mice were not protected against diet induced obesity and insulin resistance. ConclusionThis study shows that AKR1D1 controls bile acid homeostasis in vivo and that altering its activity can affect insulin sensitivity and lipid homeostasis in a sex dependent manner.

physiology↗

Loss of Bardet-Biedl syndrome proteins causes synaptic aberrations in principal neurons

Bardet-Biedl syndrome (BBS), a ciliopathy, is a rare genetic condition characterised by retina degeneration, obesity, kidney failure and cognitive impairment. In spite of a progress made in general understanding of BBS aetiology, the molecular mechanism of cognitive impairment remains elusive. Here we report that loss of Bardet-Biedl syndrome proteins causes synaptic dysfunction in principal neurons providing possible explanation for cognitive impairment phenotype in BBS patients. Using synaptosomal proteomics and immunocytochemistry we demonstrate the presence of Bbs in postsynaptic density of hippocampal neurons. Loss of Bbs results in the significant reduction of dendritic spines in principal neurons of Bbs mice models. Furthermore, we demonstrate that spine deficiency correlates with events that destabilize spine architecture, such as, impaired spine membrane receptors signalling known to be involved in the maintenance of dendritic spines. Finally, we show that voluntary exercise rescues spine deficiency in the neurons. Based on our data, we propose a model in which Bbs proteins, similar to their function in primary cilia, regulate trafficking of signalling receptors into and out of the membrane of dendritic spines, thus providing the basis for synaptic plasticity.

cell biology↗