Intracontinental deformation in southern Africa during the late Cretaceous

Intracontinental deformation accommodated along major lithospheric scale shear zone systems and within associated extensional basins has been well documented within West, Central and East Africa during the Late Cretaceous. The nature of this deformation has been established by studies of the tectonic architecture of sedimentary basins preserved in this part of Africa. In southern Africa, where the post break-up history has been dominated by major erosion, little evidence for post-break-up tectonics has been preserved in the onshore geology. Here we present the results of 38 new apatite fission track analyses from the Damara region of northern Namibia and integrate these new data with our previous results that were focused on specific regions or sections only to comprehensively document the thermo-tectonic history of this region since continental break-up in the Early Cretaceous. The apatite fission track ages range from 449 ± 20 Ma to 59 ± 3 Ma, with mean confined track lengths between 14.61 ± 0.1 μm (SD 0.95 μm) to 10.83 ± 0.33 μm (SD 2.84 μm). The youngest ages (c. 80-60 Ma) yield the shortest mean track lengths, and combined with their spatial distribution, indicate major cooling during the latest Cretaceous. A simple numerical thermal model is used to demonstrate that this cooling is consistent with the combined effects of heating caused by magmatic underplating, related to the Etendeka continental flood volcanism associated with rifting and the opening of the South Atlantic, and enhanced erosion caused by major reactivation of major lithospheric structures within southern Africa during a key period of plate kinematic change that occurred in the South Atlantic and SW Indian ocean basins between 87-56 Ma. This phase of intraplate tectonism in northern Namibia, focused in discrete structurally defined zones, is coeval with similar phases elsewhere in Africa and suggests some form of trans-continental linkage between these lithospheric zones

The chronology and tectonic style of landscape evolution along the elevated Atlantic continental margin of South Africa resolved by joint apatite fission track and (U-Th-Sm)/He thermochronology

Atlantic-type continental margins have long been considered “passive” tectonic settings throughout the entire postrift phase. Recent studies question the long-term stability of these margins and have shown that postrift uplift and reactivation of preexisting structures may be a common feature of a continental margin's evolution. The Namaqualand sector of the western continental margin of South Africa is characterized by a ubiquitously faulted basement but lacks preservation of younger geological strata to constrain postrift tectonic fault activity. Here we present the first systematic study using joint apatite fission track and apatite (U-Th-Sm)/He thermochronology to achieve a better understanding on the chronology and tectonic style of landscape evolution across this region. Apatite fission track ages range from 58.3 ± 2.6 to 132.2 ± 3.6 Ma, with mean track lengths between 10.9 ± 0.19 and 14.35 ± 0.22 µm, and mean (U-Th-Sm)/He sample ages range from 55.8 ± 31.3 to 120.6 ± 31.4 Ma. Joint inverse modeling of these data reveals two distinct episodes of cooling at approximately 150–130 Ma and 110–90 Ma with limited cooling during the Cenozoic. Estimates of denudation based on these thermal histories predict approximately 1–3 km of denudation coinciding with two major tectonic events. The first event, during the Early Cretaceous, was driven by continental rifting and the development and removal of synrift topography. The second event, during the Late Cretaceous, includes localized reactivation of basement structures as well as regional mantle-driven uplift. Relative tectonic stability prevailed during the Cenozoic, and regional denudation over this time is constrained to be less than 1 km

Structure and antiparasitic activity relationship of alkylphosphocholine analogues against Leishmania donovani

Miltefosine (Milt) is the only oral treatment for visceral leishmaniasis (VL) but its use is associated with adverse effects e.g. teratogenicity, vomiting, diarrhoea. Understanding how its chemical structure induces cytotoxicity, whilst not compromising its anti-parasitic efficacy, could identify more effective compounds. Therefore we systemically modified the compound’s head, tail and linker tested the in vitro activity of three alkylphosphocholines (APC) series against Leishmania donovani strains with different sensitivities to antimony. The analogue, APC12, with an alkyl carbon chain of 12 atoms, was also tested for anti-leishmanial in vivo activity in a murine VL model. All APCs produced had anti-leishmanial activity in the micromolar range (IC50 and IC90, 0.46 µM - >82.21 µM and 4.14 µM - 739.89 µM; 0.01 - >8.02 µM and 0.09 µM - 72.18 µM respectively against promastigotes and intracellular amastigotes). The analogue, APC12 was the most active, was 4-10 fold more effective than the parent Milt molecule (APC16), irrespective of the strain’s sensitivity to antimony. Intravenous administration of 40 mg/kg APC12 to L. donovani infected BALB/c mice reduced liver and spleen parasite burdens by 60 ± 11% and 60 ± 19% respectively while oral administration reduced parasite load in the bone marrow by 54 ± 34%. These studies confirm that it is possible to alter the Milt structure and produce more active anti-leishmanial compounds

Repurposing dichloroacetate for the treatment of women with endometriosis

Endometriosis is a chronic pain condition affecting ∼176 million women worldwide. It is defined by the presence of endometrium-like tissue (lesions) outside the uterus, most commonly on the pelvic peritoneum. There is no cure for endometriosis. All endometriosis drug approvals to date have been contraceptive, limiting their use in women of child-bearing age. We have shown that human peritoneal mesothelial cells (HPMCs) recovered from the pelvic peritoneum of women with endometriosis exhibit significantly higher glycolysis, lower mitochondrial respiration, decreased enzymatic activity of pyruvate dehydrogenase (PDH), and increased production of lactate compared to HPMCs from women without disease. Transforming growth factor-β1 (TGF-β1) is elevated in the peritoneal fluid from women with endometriosis, and exposure of HPMCs to TGF-β1 exacerbates this abnormal phenotype. Treatment of endometriosis HPMCs with the pyruvate dehydrogenase kinase (PDK) inhibitor/PDH activator dichloroacetate (DCA) normalizes HPMC metabolism, reduces lactate secretion, and abrogates endometrial stromal cell proliferation in a coculture model. Oral DCA reduced peritoneal fluid lactate concentrations and endometriosis lesion size in a mouse model. These findings provide the rationale for targeting metabolic processes as a noncontraceptive treatment for women with endometriosis either as a primary nonhormonal treatment or to prevent recurrence after surgery

Inkjet printed LED based pH chemical sensor for gas sensing

Predictable behaviour is a critical factor when developing a sensor for potential deployment within a wireless sensor network (WSN). The work presented here details the fabrication and performance of an optical chemical sensor for gaseous acetic acid analysis, which was constructed using inkjet printed deposition of a colorimetric chemical sensor. The chemical sensor comprised a pH indicator dye (bromophenol blue), phase transfer salt tetrahexylammonium bromide and polymer ethyl cellulose dissolved in 1-butanol. A paired emitter-detector diode (PEDD) optical detector was employed to monitor responses of the colorimetric chemical sensor as it exhibits good sensitivity, low power consumption, is low cost, accurate and has excellent signal to noise ratios. The chemical sensor formulation was printed directly onto the surface the emitter LED, and the resulting chemical sensors characterised with respect to their layer thickness, response time and recovery time. The fabrication reproducibility of inkjet printed chemical sensors in comparison to drop casted chemical sensors was investigated. Colorimetric chemical sensors produced by inkjet printing, exhibited an improved reproducibility for the detection of gaseous acetic acid with a relative standard deviation of 5.5 % in comparison to 68.0 % calculated for drop casted sensors (n = 10). The stability of the chemical sensor was also investigated through both intra and inter-day studies

Strain-specificity in the hydrogen sulphide signalling network following dietary restriction in recombinant inbred mice

Modulation of the ageing process by dietary restriction (DR) across multiple taxa is well established. While the exact mechanism through which DR acts remains elusive, the gasotransmitter hydrogen sulphide (H2S) may play an important role. We employed a comparative-type approach using females from three ILSXISS recombinant inbred mouse strains previously reported to show differential lifespan responses following 40% DR. Following long-term (10 months) 40% DR, strain TejJ89—reported to show lifespan extension under DR—exhibited elevated hepatic H2S production relative to its strain-specific ad libitum (AL) control. Strain TejJ48 (no reported lifespan effect following 40% DR) exhibited significantly reduced hepatic H2S production, while H2S production was unaffected by DR in strain TejJ114 (shortened lifespan reported following 40% DR). These differences in H2S production were reflected in highly divergent gene and protein expression profiles of the major H2S production and disposal enzymes across strains. Increased hepatic H2S production in TejJ89 mice was associated with elevation of the mitochondrial H2S-producing enzyme 3-mercaptopyruvate sulfurtransferase (MPST). Our findings further support the potential role of H2S in DR-induced longevity and indicate the presence of genotypic-specificity in the production and disposal of hepatic H2S in response to 40% DR in mice

Genomic loci mispositioning in Tmem120a knockout mice yields latent lipodystrophy

Little is known about how the observed fat-specific pattern of 3D-spatial genome organisation is established. Here we report that adipocyte-specific knockout of the gene encoding nuclear envelope transmembrane protein Tmem120a disrupts fat genome organisation, thus causing a lipodystrophy syndrome. Tmem120a deficiency broadly suppresses lipid metabolism pathway gene expression and induces myogenic gene expression by repositioning genes, enhancers and miRNA-encoding loci between the nuclear periphery and interior. Tmem120a(−/−) mice, particularly females, exhibit a lipodystrophy syndrome similar to human familial partial lipodystrophy FPLD2, with profound insulin resistance and metabolic defects that manifest upon exposure to an obesogenic diet. Interestingly, similar genome organisation defects occurred in cells from FPLD2 patients that harbour nuclear envelope protein encoding LMNA mutations. Our data indicate TMEM120A genome organisation functions affect many adipose functions and its loss may yield adiposity spectrum disorders, including a miRNA-based mechanism that could explain muscle hypertrophy in human lipodystrophy

Prenatal Programming of Metabolic Syndrome in the Common Marmoset Is Associated With Increased Expression of 11β-Hydroxysteroid Dehydrogenase Type 1

OBJECTIVE: Recent studies in humans and animal models of obesity have shown increased adipose tissue activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which amplifies local tissue glucocorticoid concentrations. The reasons for this 11beta-HSD1 dysregulation are unknown. Here, we tested whether 11beta-HSD1 expression, like the metabolic syndrome, is "programmed" by prenatal environmental events in a nonhuman primate model, the common marmoset monkey. RESEARCH DESIGN AND METHODS: We used a "fetal programming" paradigm where brief antenatal exposure to glucocorticoids leads to the metabolic syndrome in the offspring. Pregnant marmosets were given the synthetic glucocorticoid dexamethasone orally for 1 week in either early or late gestation, or they were given vehicle. Tissue 11beta-HSD1 and glucocorticoid receptor mRNA expression were examined in the offspring at 4 and 24 months of age. RESULTS: Prenatal dexamethasone administration, selectively during late gestation, resulted in early and persistent elevations in 11beta-HSD1 mRNA expression and activity in the liver, pancreas, and subcutaneous-but not visceral-fat. The increase in 11beta-HSD1 occurred before animals developed obesity or overt features of the metabolic syndrome. In contrast to rodents, in utero dexamethasone exposure did not alter glucocorticoid receptor expression in metabolic tissues in marmosets. CONCLUSIONS: These data suggest that long-term upregulation of 11beta-HSD1 in metabolically active tissues may follow prenatal "stress" hormone exposure and indicates a novel mechanism for fetal origins of adult obesity and the metabolic syndrome

Hepatic hydrogen sulfide levels are reduced in mouse model of Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare human disease characterised by accelerated biological ageing. Current treatments are limited, and most patients die before 15 years of age. Hydrogen sulfide (H2S) is an important gaseous signalling molecule that it central to multiple cellular homeostasis mechanisms. Dysregulation of tissue H2S levels is thought to contribute to an ageing phenotype in many tissues across animal models. Whether H2S is altered in HGPS is unknown. We investigated hepatic H2S production capacity and transcript, protein and enzymatic activity of proteins that regulate hepatic H2S production and disposal in a mouse model of HGPS (G609G mice, mutated Lmna gene equivalent to a causative mutation in HGPS patients). G609G mice were maintained on either regular chow (RC) or high fat diet (HFD), as HFD has been previously shown to significantly extend lifespan of G609G mice, and compared to wild type (WT) mice maintained on RC. RC fed G609G mice had significantly reduced hepatic H2S production capacity relative to WT mice, with a compensatory elevation in mRNA transcripts associated with several H2S production enzymes, including cystathionine-γ-lyase (CSE). H2S levels and CSE protein were partially rescued in HFD fed G609G mice. As current treatments for patients with HGPS have failed to confer significant improvements to symptoms or longevity, the need for novel therapeutic targets is acute and the regulation of H2S through dietary or pharmacological means may be a promising new avenue for research

Mitochondrial dysfunction and mitophagy blockade contribute to renal osteodystrophy in chronic kidney disease-mineral bone disorder

Chronic kidney disease–mineral and bone disorder (CKD-MBD) presents with extra-skeletal calcification and renal osteodystrophy (ROD). The origins of ROD likely lie with elevated uremic toxins and/or an altered hormonal profile but the cellular events responsible remain unclear. Here, we report that stalled mitophagy contributes to mitochondrial dysfunction in bones of a CKD-MBD mouse model, and also human CKD-MBD patients. RNA-seq analysis exposed an altered expression of genes associated with mitophagy and mitochondrial function in tibia of CKD-MBD mice. The accumulation of damaged osteocyte mitochondria and the expression of mitophagy regulators, p62/SQSTM1, ATG7 and LC3 was inconsistent with functional mitophagy, and in mito-QC reporter mice with CKD-MBD, there was a 2.3-fold increase in osteocyte mitolysosomes. Altered expression of mitophagy regulators in human CKD-MBD bones was also observed. To determine if uremic toxins were possibly responsible for these observations, indoxyl sulfate treatment of osteoblasts revealed mitochondria with distorted morphology and whose membrane potential and oxidative phosphorylation were decreased, and oxygen-free radical production increased. The altered p62/SQSTM1 and LC3-II expression was consistent with impaired mitophagy machinery and the effects of indoxyl sulfate were reversible by rapamycin. In conclusion, mitolysosome accumulation from impaired clearance of damaged mitochondria may contribute to the skeletal complications, characteristic of ROD. Targeting mitochondria and the mitophagy process may therefore offer novel routes for intervention to preserve bone health in patients with ROD. Such approaches would be timely as our current armamentarium of anti-fracture medications has not been developed for, or adequately studied in, patients with severe CKD-MBD