Amphibian disease risks and the anthropogenic dispersal of invasive Litoria species : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Ecology at Massey University, Albany, New Zealand

The scope of this research is to provide a broad outline of the interaction between anthropogenic disease spread, risk of an invasive amphibian species establishing into the New Zealand environs, and prevalence of amphibian chytrid in wild introduced amphibian populations. The objective of this overview is to identify risk pathways that could threaten New Zealand’s four endemic Leiopelma species of frogs. Worldwide amphibian populations are in decline with an estimated 32.5% of amphibians globally threatened (IUCN 2008). New Zealand’s four endemic amphibians Leiopelma spp. are high on the ICUN list of critically endangered animals, further, two of the three introduced tree frogs (Litoria spp..) are listed endangered and vulnerable in their native home. Disease has been one factor implicated in the worldwide amphibian decline in particular the two diseases Chytridiomycosis and Ranavirus. Although Chytridiomycosis has had the most profound effect on the decline of amphibian species. The spread of such diseases is, at least in part, human-mediated through media such as the bait trade, food industry, and possibly the pet trade. To date, there have been no reports of Ranavirus in New Zealand amphibians. Conversely, amphibians chytrid fungus is widespread and has been implicated in the decline of the endemic Leiopelma archeyi. This makes amphibian chytrid an ideal disease to model disease transmission with particular reference to the anthropogenic movement of amphibians. The two main goals of this Ph.D. were to investigate specific anthropogenic mediated risks of spreading disease using the pathogen Batrachochytrium dendrobatidis (Bd), which is responsible for amphibian chytrid fungus, as a modality to model this. Included in this will be the enquiry into how Bd entered New Zealand and how it spread so quickly via the movement of Litoria spp.. Furthermore, to look at invasive amphibian species incursion risks by evaluating previous border seizures. Currently, it is unknown how the amphibian chytrid entered New Zealand and whether New Zealand’s borders are a high-risk entry pathway for amphibian disease. Examining the anthropogenic dispersal of Litoria in New Zealand and developing systems that reduce the risk of introducing disease into naive populations is an important role in ensuring the long-term survival of New Zealand’s endangered Leiopelma spp. frogs. The presence of Bd in New Zealand has been recorded but the prevalence of the pathogen in populations is unknown. Identifying the prevalence of infection within populations will provide insight into how populations of Litoria spp. are surviving Bd infection. Furthermore, this Ph.D. project will assess the risk of invasive exotic amphibians entering New Zealand and becoming naturalised. Education is one of the important areas that will greatly help the plight of New Zealand’s frogs. For education to be successful it needs to be targeted, therefore assessing risk areas of amphibian disease is imperative. Furthermore, understanding the public’s knowledge of frogs in New Zealand will further help in the development of resource material and targeting the main groups where education is needed. Key findings of this research are that the three species of Litoria frogs are moved around New Zealand in large numbers via the pet trade. The spread of amphibian chytrid has most likely been so rapid due to the frequency and volume of tadpoles and frogs being bought and sold. The pet trade thereby effectively and inadvertently is a major means of the unregulated translocation of Litoria amphibians throughout New Zealand. Results of this research also show there is a gap in the knowledge about amphibians in areas of husbandry, disease, species identification, and legal responsibilities in the ownership and containment of amphibians in New Zealand. Additionally, the introduction of a new disease is more likely to occur than the risk of an invasive species becoming established. Finally, the wild populations of Litoria frogs were surviving with a high prevalence of amphibian chytrid fungus in two of the three study sites in this research, the third site which had the presence of a reservoir species had low numbers of frogs present

A manual to support clerical interventions for African American women with despression [sic]

vi, 99 leaves ; 29 cmMany cultural factors influence how African American women experience and manifest depression, as well as how they seek treatment for it. Many rely on their clergy for support. Through review of current research and best practices literature, strategies African American clergy can use to provide culturally appropriate treatment to African American women with depression were identified and compiled into an outline to develop a counselling manual. The proposed manual was developed with a focus on the unique cultural concerns of African American women, and Africentric worldview. The outline describes empirically supported interventions in language that is easily understood by clergy, counsellors, and laypeople. The development of such a manual should increase the culturally appropriate resources available to African American women battling depression, and pave the way for future collaboration between counsellors and clergy in developing culturally appropriate interventions. For this proposed manual, African American and Black women are defined as female descendants of Africans brought to the United States in slavery, and that align themselves with this cultural group

Extending the remit of evidence-based policing

Evidence-based policing (EBP) is an important strand of the UK’s College of Policing’s Police Education Qualifications Framework (PEQF), itself a component of a professionalisation agenda. This article argues that the two dominant approaches to EBP, experimental criminology and crime science, offer limited scope for the development of a comprehensive knowledge base for policing. Although both approaches share a common commitment to the values of science, each recognizes their limited coverage of policing topics. The fundamental difference between them is what each considers ‘best’ evidence. This article critically examines the generation of evidence by these two approaches and proposes an extension to the range of issues EBP should cover by utilizing a greater plurality of methods to exploit relevant research. Widening the scope of EBP would provide a broader foundational framework for inclusion in the PEQF and offers the potential for identifying gaps in the research, constructing blocks for knowledge building, and syllabus development in higher level police education

Nomenclature for kidney function and disease: report of a Kidney Disease:Improving Global Outcomes (KDIGO) Consensus Conference

The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use "kidney" rather than "renal" or "nephro-" when referring to kidney disease and kidney function; (ii) to use "kidney failure" with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than "end-stage kidney disease"; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than "abnormal" or "reduced" kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements