One Health, veterinarians and the nexus between disease and food security

Achieving ecologically sustainable food systems for people and animals is one of the greatest challenges facing our world today. Four interdisciplinary approaches that promote a holistic, systems approach to disease prevention and food security are introduced. Current domestic and international initiatives that link disease prevention with food and nutrition security are presented, with an emphasis on animal‐source food and examples from Australia, Tanzania and Timor‐Leste. Veterinarians are uniquely placed to use their training in comparative physiology in support of the production of sustainable, nutritious, ethical and safe food delivered with minimal waste to promote human, animal and environmental health

INdigenous Systems and Policies Improved and Reimagined for Ear and hearing care (INSPIRE): A multi-method study protocol

Introduction Otitis media (middle ear disease) severity and chronicity among Aboriginal and Torres Strait Islander people, as well as gaps in socioeconomic outcomes related to hearing loss, indicates a breakdown in the current ear and hearing care system. The ear and hearing care system spans multiple sectors due to long-term impacts of otitis media and hearing loss in health, education and employment, necessitating a multi-disciplinary cross-sectorial approach to ear and hearing care. Public policies shape the current ear and hearing care system and here it is argued that a critical public policy analysis across different sectors is needed, with strong Aboriginal and Torres Strait Islander leadership and guidance. The current study aims to establish consensus-based ear and hearing care policy solutions for Aboriginal and Torres Strait Islander people in Australia. Methods and analysis This multi-method study will be guided by a Brains Trust with strong Aboriginal and Torres Strait Islander leadership. Public policies in hearing health, social services, and education will be scoped to identify policy gaps, using the World Health Organization framework. Qualitative data will be collected through a culturally specific process of yarning circles to identify policy challenges and/or limitations in enabling accessible ear and hearing care programs/services for Aboriginal and Torres Strait Islander people, using dimensions of Morestin's public policy appraisal tool as an interview guide for stakeholders. Themes from the yarning circles will be used to inform an expert Delphi process to establish consensus-based policy solutions for optimising the ear and hearing care system for Aboriginal and Torres Strait Islander people. Ethics and dissemination This study has approval from the Australian Institute of Aboriginal and Torres Strait Islander Studies Ethics Committee. Study findings will be disseminated to community through Brains Trust members and study participants, as well as through publications in peer-reviewed journals and research forum presentations

Hi-C as a tool for precise detection and characterisation of chromosomal rearrangements and copy number variation in human tumours

Chromosomal rearrangements occur constitutionally in the general population and somatically in the majority of cancers. Detection of balanced rearrangements, such as reciprocal translocations and inversions, is troublesome, which is particularly detrimental in oncology where rearrangements play diagnostic and prognostic roles. Here we describe the use of Hi-C as a tool for detection of both balanced and unbalanced chromosomal rearrangements in primary human tumour samples, with the potential to define chromosome breakpoints to bp resolution. In addition, we show copy number profiles can also be obtained from the same data, all at a significantly lower cost than standard sequencing approaches

Brucella suis Seroprevalence and Associated Risk Factors in Dogs in Eastern Australia, 2016 to 2019

Brucella suis is a zoonotic disease of feral pigs that also affects pig hunting dogs, pig hunters, veterinarians and veterinary staff. In recent years the incidence of B. suis in the eastern Australian states of New South Wales (NSW) and Queensland (QLD) has increased. A cross-sectional study was conducted to document the seroprevalence, geographical extent and risk factors for B. suis in dogs at-risk of contracting the disease. Eligible dogs were those that were known to hunt or consume feral pig meat. Dogs were enrolled through private veterinary clinics and/or directly by District Veterinarians in six regions of NSW and QLD. Blood was collected by venepuncture and tested for B. suis antibodies using the Rose Bengal Test (RBT) followed by a Complement Fixation Test (CFT) if they returned a positive RBT. Owners were invited to complete a questionnaire on the dogs' signalment, husbandry including hunting practices and locations, and any clinical signs referable to brucellosis. Of the 317 dogs included in the prevalence survey, 21 were seropositive returning a survey-adjusted true seroprevalence of 9.3 (95% CI 0.45 to 18) B. suis positive dogs per 100 dogs at-risk. True seroprevalence ranged from 0 to 24 B. suis positive dogs per 100 across eastern Australia, with the highest prevalence in central west NSW and southern QLD. Adjusted for other factors, dogs that shared a household with other seropositive dogs and those that traveled away from their home regions to hunt were more likely to be seropositive. Clinical signs at presentation were not predictive of serostatus, with seropositive and seronegative dogs equally likely to present with signs consistent with brucellosis. The results obtained from this study show that B. suis exposure is relatively common in dogs that have contact with feral pigs, with one in 10 testing seropositive. Further studies are needed to understand the progression and risk of transmission from seropositive dogs

Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent Apoptosis, but are insensitive to direct activation with exogenous fas ligand

Introduction Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesis of which remains uncertain. No common genetic defects have been described but it is accepted that chronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members; CD40 and Fas (CD95). Functional deficiency of CD154, the ligand for CD40, leads to a failure of clearance of biliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosis and the development of cholangiocarcinoma. Aims To determine whether malignant cholangiocytes display defects in CD40 mediated apoptosis. By comparing CD40 and Fas-mediated apoptosis and intracellular signalling in primary human cholangiocytes and three cholangiocyte cell lines. Results Primary cholangiocytes and cholangiocyte cell lines were relatively insensitive to direct Fas-mediated killing with exogenous FasL when compared with Jurkat cells, which readily underwent Fas-mediated apoptosis, but were extremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and was STAT-3 and AP-1 dependent in both. Conclusions 1) Both primary and malignant cholangiocytes are relatively resistant to Fas–mediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignant cholangiocytes 2) The relative insensitivity of cholangiocytes to Fas activation demonstrates the importance of CD40 augmentation of Fas dependent death in these cells. Agonistic therapies which target CD40 and associated intracellular signalling pathways may be effective in promoting apoptosis of malignant cholangiocytes

The association of Alu repeats with the generation of potential AU-rich elements (ARE) at 3' untranslated regions.

BACKGROUND: A significant portion (about 8% in the human genome) of mammalian mRNA sequences contains AU (Adenine and Uracil) rich elements or AREs at their 3' untranslated regions (UTR). These mRNA sequences are usually stable. However, an increasing number of observations have been made of unstable species, possibly depending on certain elements such as Alu repeats. ARE motifs are repeats of the tetramer AUUU and a monomer A at the end of the repeats ((AUUU)(n)A). The importance of AREs in biology is that they make certain mRNA unstable. Proto-oncogene, such as c-fos, c-myc, and c-jun in humans, are associated with AREs. Although it has been known that the increased number of ARE motifs caused the decrease of the half-life of mRNA containing ARE repeats, the exact mechanism is as of yet unknown. We analyzed the occurrences of AREs and Alu and propose a possible mechanism for how human mRNA could acquire and keep AREs at its 3' UTR originating from Alu repeats. RESULTS: Interspersed in the human genome, Alu repeats occupy 5% of the 3' UTR of mRNA sequences. Alu has poly-adenine (poly-A) regions at its end, which lead to poly-thymine (poly-T) regions at the end of its complementary Alu. It has been found that AREs are present at the poly-T regions. From the 3' UTR of the NCBI's reference mRNA sequence database, we found nearly 40% (38.5%) of ARE (Class I) were associated with Alu sequences (Table 1) within one mismatch allowance in ARE sequences. Other ARE classes had statistically significant associations as well. This is far from a random occurrence given their limited quantity. At each ARE class, random distribution was simulated 1,000 times, and it was shown that there is a special relationship between ARE patterns and the Alu repeats. CONCLUSION: AREs are mediating sequence elements affecting the stabilization or degradation of mRNA at the 3' untranslated regions. However, AREs' mechanism and origins are unknown. We report that Alu is a source of ARE. We found that half of the longest AREs were derived from the poly-T regions of the complementary Alu

Association of CD99 short and long forms with MHC class I, MHC class II and tetraspanin CD81 and recruitment into immunological synapses

<p>Abstract</p> <p>Background</p> <p>CD99, a leukocyte surface glycoprotein, is broadly expressed in many cell types. On the cell surface, CD99 is expressed as two distinct isoforms, a long form and a short form. CD99 has been demonstrated to play a key role in several biological processes, including the regulation of T cell activation. However, the molecular mechanisms by which CD99 participates in such processes are unclear. As CD99 contains a short cytoplasmic tail, it is unlikely that CD99 itself takes part in its multi-functions. Association of CD99 with other membrane proteins has been suggested to be necessary for exerting its functions.</p> <p>Results</p> <p>In this study, we analyzed the association of CD99 with other cell surface molecules involved in T cell activation. We demonstrate the association of MHC class I, MHC class II and tetraspanin CD81 with CD99 molecules on the cell surface. Association of CD99 with its partners was observed for both isoforms. In addition, we determined that CD99 is a lipid raft-associated membrane protein and is recruited into the immunologic synapse during T cell activation. The implication of CD99 on T cell activation was investigated. Inhibition of anti-CD3 induced T cell proliferation by an anti-CD99 monoclonal antibody was observed.</p> <p>Conclusions</p> <p>We provide evidence that CD99 directly interact and form the complex with the MHC class I and II, and tetraspanin CD81, and is functionally linked to the formation of the immunologic synapse. Upon T cell activation, CD99 engagement can inhibit T cell proliferation. We speculate that the CD99-MHC-CD81 complex is a tetraspanin web that plays an important role in T cell activation.</p

CD40L induces multidrug resistance to apoptosis in breast carcinoma and lymphoma cells through caspase independent and dependent pathways

BACKGROUND: CD40L was found to reduce doxorubicin-induced apoptosis in non Hodgkin's lymphoma cell lines through caspase-3 dependent mechanism. Whether this represents a general mechanism for other tumor types is unknown. METHODS: The resistance induced by CD40L against apoptosis induced by a panel of cytotoxic chemotherapeutic drugs in non Hodgkin's lymphoma and breast carcinoma cell lines was investigated. RESULTS: Doxorubicin, cisplatyl, etoposide, vinblastin and paclitaxel increased apoptosis in a dose-dependent manner in breast carcinoma as well as in non Hodgkin's lymphoma cell lines. Co-culture with irradiated L cells expressing CD40L significantly reduced the percentage of apoptotic cells in breast carcinoma and non Hodgkin's lymphoma cell lines treated with these drugs. In breast carcinoma cell lines, these 5 drugs induced an inconsistent increase of caspase-3/7 activity, while in non Hodgkin's lymphoma cell lines all 5 drugs increased caspase-3/7 activity up to 28-fold above baseline. Co-culture with CD40L L cells reduced (-39% to -89%) the activation of caspase-3/7 induced by these agents in all 5 non Hodgkin's lymphoma cell lines, but in none of the 2 breast carcinoma cell lines. Co culture with CD40L L cells also blocked the apoptosis induced by exogenous ceramides in breast carcinoma and non Hodgkin's lymphoma cell lines through a caspase-3-like, 8-like and 9-like dependent pathways. CONCLUSION: These results indicate that CD40L expressed on adjacent non tumoral cells induces multidrug resistance to cytotoxic agents and ceramides in both breast carcinoma and non Hodgkin's lymphoma cell lines, albeit through a caspase independent and dependent pathway respectively

Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor

Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.We acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre. Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) (U19 CA 148537 for Elucidating Loci Involved in Prostate cancer Susceptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I). Additional analytical support was provided by NIH NCI U01 CA188392. The PRACTICAL consortium was supported by Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692 and C16913/A6135; the European Commission’s Seventh Framework Programme grant agreement 223175 (HEALTH-F2-2009-223175) (D.F.E., R.E. and Z.K.-J.); and the NIH Cancer Post-Cancer GWAS initiative grant 1 U19 CA 148537-01 (the GAME-ON initiative). We thank the following for funding support: the Institute of Cancer Research and the Everyman Campaign, the Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), the Orchid Cancer Appeal, the National Cancer Research Network UK and the National Cancer Research Institute (NCRI) UK. We are grateful for NIHR funding to the Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust. We acknowledge funding from the Swedish Cancer Society (CAN2011/484 and CAN2012/823), the Norwegian Cancer Society (grants 418975-71081-PR-2006-0387 and PK01-2007- 0375) and the Nordic Cancer Union (grant S-12/07). This study was supported by the Movember Foundation and the Institute of Cancer Research. K.L. is supported by a PhD fellowship from Cancer Research UK. R.S.H. and P.B. are supported by Cancer Research UK (C1298/A8362 Bobby Moore Fund for Cancer Research UK)