Crosstalk of lysosomes, autophagy and apoptosis in dioxin-induced chloracne in vitro

PhD ThesisChloracne is a hyperkeratotic acneform skin disease caused by exposure to 2,3,7,8-tetrachlorodibenzo–p-dioxin (TCDD), a potent agonist of the aryl-hydrocarbon receptor (AhR). Despite the known role of TCDD exposure in the pathogenesis of chloracne, the molecular mechanisms mediating the disease remain poorly defined. Using a previously optimised in vitro primary human keratinocyte epidermal equivalent model, we demonstrated the temporal regulation and development of a significantly reduced viable cell layer and compacted stratum corneum over 7 days with 10nM TCDD. These morphological changes were paralleled by cumulative AhR protein degradation and increased mRNA levels of CYP1A1. One of the key findings was a significant increase in the expression of the apoptotic marker, caspase-3 whilst there was no significant effect on Ki67 staining. Furthermore, TCDD treatment caused de-regulated epidermal differentiation as evidenced by increased mRNA expression but decreased protein expression of late differentiation markers. Treatment with TCDD also resulted in an induction of LC3 lipidation and endogenous LC3 protein expression as well as decreased P62 protein expression, well-established markers of autophagy induction. Interestingly, co-treatment of epidermal equivalents with TCDD and the lysosomal inhibitor, bafilomycin or cathepsin D inhibition (by pepstatin A or shRNA knockdown) resulted in restoration of the viable cell layer and reduction in TCDD-induced caspase-3 expression. Similar results were also seen after blockade of the autophagy pathway by ATG7 knockdown. Results also demonstrated lysosomal function and autophagy are required for TCDD-induced AhR degradation, indicating a potential role for chaperone-mediated autophagy. Collectively these data suggest exposure to TCDD results in deregulated epidermal differentiation, induction of autophagy, reduction of a viable cell layer and caspase-3 dependent cell death, likely mediated via lysosomal processing. Results provide an insight into the pathophysiology of chloracne, and demonstrate novel findings including TCDD-induced autophagy and potential role of lysosomal function in TCDD-induced death and AhR degradation.Biotechnology and Biological Sciences Research Council (BBSRC) and AstraZeneca

A late-Holocene multiproxy fire record from a tropical savanna, eastern Arnhem Land, Northern Territory, Australia

Fire has a long history in Australia and is a key driver of vegetation dynamics in the tropical savanna ecosystems that cover one quarter of the country. Fire reconstructions are required to understand ecosystem dynamics over the long term but these data are lacking for the extensive savannas of northern Australia. This paper presents a multiproxy palaeofire record for Marura sinkhole in eastern Arnhem Land, Northern Territory, Australia. The record is constructed by combining optical methods (counts and morphology of macroscopic and microscopic charcoal particles) and chemical methods (quantification of abundance and stable isotope composition of pyrogenic carbon by hydrogen pyrolysis). This novel combination of measurements enables the generation of a record of relative fire intensity to investigate the interplay between natural and anthropogenic influences. The Marura palaeofire record comprises three main phases: 4600–2800 cal BP, 2800–900 cal BP and 900 cal BP to present. Highest fire incidence occurs at ~4600–4000 cal BP, coinciding with regional records of high effective precipitation, and all fire proxies decline from that time to the present. 2800–900 cal BP is characterised by variable fire intensities and aligns with archaeological evidence of occupation at nearby Blue Mud Bay. All fire proxies decline significantly after 900 cal BP. The combination of charcoal and pyrogenic carbon measures is a promising proxy for relative fire intensity in sedimentary records and a useful tool for investigating potential anthropogenic fire regimes

Fanconi Anaemia, Childhood Cancer and the BRCA Genes

From MDPI via Jisc Publications RouterHistory: accepted 2021-09-25, pub-electronic 2021-09-27Publication status: PublishedFunder: Fanconi Hope, UK; Grant(s): 01-2020Fanconi anaemia (FA) is an inherited chromosomal instability disorder characterised by congenital and developmental abnormalities and a strong cancer predisposition. In less than 5% of cases FA can be caused by bi-allelic pathogenic variants (PGVs) in BRCA2/FANCD1 and in very rare cases by bi-allelic PGVs in BRCA1/FANCS. The rarity of FA-like presentation due to PGVs in BRCA2 and even more due to PGVs in BRCA1 supports a fundamental role of the encoded proteins for normal development and prevention of malignant transformation. While FA caused by BRCA1/2 PGVs is strongly associated with distinct spectra of embryonal childhood cancers and AML with BRCA2-PGVs, and also early epithelial cancers with BRCA1 PGVs, germline variants in the BRCA1/2 genes have also been identified in non-FA childhood malignancies, and thereby implying the possibility of a role of BRCA PGVs also for non-syndromic cancer predisposition in children. We provide a concise review of aspects of the clinical and genetic features of BRCA1/2-associated FA with a focus on associated malignancies, and review novel aspects of the role of germline BRCA2 and BRCA1 PGVs occurring in non-FA childhood cancer and discuss aspects of clinical and biological implications

Parity and breast cancer risk among BRCA1 and BRCA2 mutation carriers.

INTRODUCTION: Increasing parity and age at first full-term pregnancy are established risk factors for breast cancer in the general population. However, their effects among BRCA1 and BRCA2 mutation carriers is still under debate. We used retrospective data on BRCA1 and BRCA2 mutation carriers from the UK to assess the effects of parity-related variables on breast cancer risk. METHODS: The data set included 457 mutation carriers who developed breast cancer (cases) and 332 healthy mutation carriers (controls), ascertained through families seen in genetic clinics. Hazard ratios were estimated by using a weighted cohort approach. RESULTS: Parous BRCA1 and BRCA2 mutation carriers were at a significantly lower risk of developing breast cancer (hazard ratio 0.54, 95% confidence interval 0.37 to 0.81; p = 0.002). The protective effect was observed only among carriers who were older than 40 years. Increasing age at first live birth was associated with an increased breast cancer risk among BRCA2 mutation carriers (p trend = 0.002) but not BRCA1 carriers. However, the analysis by age at first live birth was based on small numbers. CONCLUSION: The results suggest that the relative risks of breast cancer associated with parity among BRCA1 and BRCA2 mutation carriers may be similar to those in the general population and that reproductive history may be used to improve risk prediction in carriers.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Wellbeing and Protracted Urban Displacement: Refugees and Hosts in Jordan and Lebanon

The war in Syria, now in its eighth year, has led to the mass exodus of the Syrian people. Lebanon and Jordan have achieved a remarkable feat by hosting millions of refugees, with many having located to urban areas, where the great majority of local populations are already situated. The war has slowed down the Lebanese and Jordanian economies. Simultaneously, the refugee influx has put tremendous pressure on urban systems providing housing and basic services (health, education, water, sanitation, electricity and waste collection) that were already strained prior to the crisis. The mass arrival has seen accelerated house rent inflation, severely diminished water supplies, daily power outages, higher unemployment rates, rising poverty, and the inability of health-care and education providers to cope with demand. Charged regional politics are severely challenging delicate societal and inter-communal harmony. There are large discrepancies in perceptions of inequality and threats between Syrian refugees and host groups. Many refugees complain about their discriminatory treatment by local business and state institutions, whereas hosts consider Syrian refugees as disproportionately benefiting from international aid and an economic threat. This research project, conducted between April 2017 and February 2018, aimed to answer the following research questions: (1) what modalities of reception drive what kind of gendered wellbeing outcomes for refugee and host communities in cities across Jordan and Lebanon? What explains for these outcomes? (2) in what ways can policymakers, practitioners and donors support modalities of reception that promote gender equitable, improved wellbeing outcomes for urban refugees and host communities?Netherlands Organisation for Scientific Research-Foundation for the Advancement of Tropical ResearchSave the Childre

Curing vector for IncI1 plasmids and its use to provide evidence for a metabolic burden of IncI1 CTX-M-1 plasmid pIFM3791 on Klebsiella pneumoniae

Using a sequence based approach we previously identified an IncI1 CTX-M-1 plasmid,pIFM3791, on a single pig farm in the UK that was harboured by K. pneumoniae,Escherichia coli and Salmonella enterica serotype 4,5,12,i:-. To test the hypothesis that the plasmid had spread rapidly into these differing host bacteria we wished to assess whether the plasmid conferred a fitness advantage. To do this an IncI1 curing vector was constructed and used to displace the IncI1 CTX-M-1 plasmids from K. pneumoniae strain B3791 and several other unrelated IncI1 harbouring strains indicating the potential wider application of the curing plasmid. The IncI1 CTX-M-1 plasmid was re-introduced by conjugation into the cured K. pneumoniae strain and also a naturally IncI1 plasmid free S. enterica serotype 4,5,12,i:-, S348/1. Original, cured and complemented strains were tested for metabolic competence using BiologTM technology and in competitive growth, association to mammalian cells and biofilm formation experiments. The plasmid-cured K. pneumoniae strain grew more rapidly than either the original plasmid-carrying strain or plasmid-complemented strains in competition experiments. Additionally, the plasmid-cured strain was significantly better at respiring with L-sorbose as a carbon source and putrescine, γ-amino-n-butyric acid,L-alanine, L-proline as a nitrogen sources. By contrast, no differences in phenotype were found when comparing plasmid harbouring and plasmid free S. enterica S348/11. In conclusion, the IncI1 curing vector successfully displaced multiple IncI plasmids. The IncI1 CTX-M1 plasmid conferred a growth disadvantage upon K. pneumoniae, possibly by imposing a metabolic burden the mechanism of which remains to be determined

Multiproxy Holocene fire records from the tropical savannas of northern Cape York Peninsula, Queensland, Australia

Palaeoecology has demonstrated potential to inform current and future land management by providing long-term baselines for fire regimes, over thousands of years covering past periods of lower/higher rainfall and temperatures. To extend this potential, more work is required for methodological innovation able to generate nuanced, relevant and clearly interpretable results. This paper presents records from Cape York Peninsula, Queensland, Australia, as a case study where fire management is an important but socially complex modern management issue, and where palaeofire records are limited. Two new multiproxy palaeofire records are presented from Sanamere Lagoon (8150-6600 cal BP) and Big Willum Swamp (3900 cal BP to present). These records combine existing methods to investigate fire occurrence, vegetation types, and relative fire intensity. Results presented here demonstrate a diversity of fire histories at different sites across Cape York Peninsula, highlighting the need for finer scale palaeofire research. Future fire management planning on Cape York Peninsula must take into account the thousands of years of active Indigenous management and this understanding can be further informed by palaeoecological research

In search of a marker of altered cerebrovascular function in hypertension: Analysis of the fractional amplitude of low-frequency fluctuations in UK Biobank resting state fMRI data

The selfish brain mechanism proposes that in some patients with impaired cerebral blood flow (CBF) or cerebrovascular function, hypertension may develop as a compensatory mechanism that aims to maintain CBF by increasing systemic blood pressure through an increase in cardiovascular sympathetic tone. The amplitude of low frequency fluctuations (ALFF) in the resting state blood oxygenation level dependent (BOLD) functional MRI signal has been previously posited as an index of cerebrovascular reactivity. We investigated whether regional fractional ALFF (fALFF) differs between 2054 hypertensives and 1724 normotensives using data from the UK Biobank dataset. Our primary hypothesis was that cerebrovascular function in the medulla and other regions involved in sympathetic regulation differs between hypertensives and normotensives, and that this is reflected by regional variations in fALFF. There is a significant regional variation in fALFF (F(14) =1126.17, p < 2 × 10−16, partial η2 = 0.22), but this regional variation does not differ between hypertensives and normotensives (F(14) = 0.23, p = 0.99, partial η2 = 8 × 10−5). Prospective longitudinal studies of cerebral haemodynamics in hypertensives and normotensives are required to further investigate the selfish brain mechanism