What can inactivity (in its various forms) reveal about affective states in non-human animals? A review

Captive/domestic animals are often described as inactive, with the implicit or explicit implication that this high level of inactivity is a welfare problem. Conversely, not being inactive enough may also indicate or cause poor welfare. In humans, too much inactivity can certainly be associated with either negative or positive affective states. In non-human animals, however, the affective states associated with elevated or suppressed levels of inactivity are still not well understood. Part of the complexity is due to the fact that there are many different forms of inactivity, each likely associated with very different affective states. This paper has two aims. One is to identify specific forms of inactivity that can be used as indicators of specific affective states in animals. The other is to identify issues that need to be resolved before we could validly use the remaining, not yet validated forms of inactivity as indicators of affective state. We briefly discuss how inactivity is defined and assessed in the literature, and then how inactivity in its various forms relates to affective (either negative or positive) states in animals, basing our reasoning on linguistic reports of affective states collected from humans displaying inactivity phenotypically similar to that displayed by animals in similar situations, and, when possible, on pharmacological validation. Specific forms of inactivity expressed in response to perceived threats (freezing, tonic immobility, and hiding) appear to be, to date, the best-validated indicators of specific affective states in animals. We also identify a number of specific forms of inactivity likely to reflect either negative (associated with ill-heath, boredom-like, and depression-like conditions), or positive states (e.g. ‘sun-basking’, post-consummatory inactivity), although further research is warranted before we could use those forms as indicators of the affective states. We further discuss the relationship between increased inactivity and affective states by presenting misleading situations likely to yield wrong conclusions. We conclude that more attention should be paid to inactivity in animal welfare studies: specific forms of inactivity identified in this paper are, or have the potential to be, useful indicators of affective (welfare) states in animals

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The social life of monitoring and evaluation: An ethnography of the monitoring and evaluation of an HIV/AIDS prevention program in Ghana

Globally, HIV/AIDS programs face pressure to document accountability and achievement via “evidence-based” criteria or “monitoring and evaluation” (“M&E”). Donors have increasingly made M&E a funding stipulation funding. They want numeric data that speak to universal indicators of efficacy, a newly hegemonic means of assessment in the field of governance based in business management. Advanced by major global institutions like the United States President’s Emergency Plan for AID Relief (PEPFAR), M&E systems—structures of metrics, procedures, people, and technology—are variously set up around the globe. M&E plays an increasingly deeper role through a program’s entire lifespan and in the daily activities of program workers. Yet surprisingly, little is known about how M&E occurs on the ground and the social and political effects: What kinds of actions and social relations does M&E instigate? How does its practice maintain or challenge the status quo? Furthermore, “developing” countries, incredibly dependent on foreign program funding, encounter M&E through uneven postcolonial relations. How does M&E reflect and possibly influence postcolonial relationships, and country sovereignty? My dissertation explores these questions through an ethnographic study of the M&E of an HIV/AIDS prevention program in Ghana called BRIDGES, funded by the United States Agency for International Development (USAID). For 20 months I followed the M&E of BRIDGES through a focus on one non-governmental organization (NGO). I argue that M&E is a key site through which HIV/AIDS intervention is trans/formed. It not only reflects but also produces (unexpected) social relations and habits, which shape how HIV/AIDS intervention operates. In Ghana, M&E unintentionally deepened unequal relations between donor-recipient, organizations, and personnel. I demonstrate that this effect occurred on and through the practices and agency of those governed by M&E. M&E is not an agent in its own right, but is deployed in particular ways by actors in fields of power

Orphans, HIVE and HAND: Who are the watch-keepers?

Untreated children with HIV infection are at risk of central nervous system (CNS) sequelae, with prevalence rates of 20 - 60%. HIV-1 invades the developing CNS earlier and with greater severity than in adults, resulting in the condition known as HIV encephalopathy (HIVE). In addition, patients on highly active antiretroviral therapy may remain vulnerable to the effects of HIV on the brain, because the CNS may be a reservoir for persistent viral replication. The concept of a ‘milder’ form of neurocognitive disturbance in HIV-infected children, akin to the adult condition of HAND (HIV-associated neurocognitive disorder), is recognised but has yet to be defined. In SA, children with severe learning difficulties may remain in mainstream schooling with minimal remedial support. Two short case scenarios and a letter from an educator highlight the limitations of this system in the context of children living with HIV

ELK4 neutralization sensitizes glioblastoma to apoptosis through downregulation of the anti-apoptotic protein Mcl-1

Glioma is the most common adult primary brain tumor. Its most malignant form, glioblastoma multiforme (GBM), is almost invariably fatal, due in part to the intrinsic resistance of GBM to radiation- and chemotherapy-induced apoptosis. We analyzed B-cell leukemia–2 (Bcl-2) anti-apoptotic proteins in GBM and found myeloid cell leukemia–1 (Mcl-1) to be the highest expressed in the majority of malignant gliomas. Mcl-1 was functionally important, as neutralization of Mcl-1 induced apoptosis and increased chemotherapy-induced apoptosis. To determine how Mcl-1 was regulated in glioma, we analyzed the promoter and identified a novel functional single nucleotide polymorphism in an uncharacterized E26 transformation-specific (ETS) binding site. We identified the ETS transcription factor ELK4 as a critical regulator of Mcl-1 in glioma, since ELK4 downregulation was shown to reduce Mcl-1 and increase sensitivity to apoptosis. Importantly the presence of the single nucleotide polymorphism, which ablated ELK4 binding in gliomas, was associated with lower Mcl-1 levels and a greater dependence on Bcl-xL. Furthermore, in vivo, ELK4 downregulation reduced tumor formation in glioblastoma xenograft models. The critical role of ELK4 in Mcl-1 expression and protection from apoptosis in glioma defines ELK4 as a novel potential therapeutic target for GBM

Glioma surgical aspirate: a viable source of tumor tissue for experimental research

Brain cancer research has been hampered by a paucity of viable clinical tissue of sufficient quality and quantity for experimental research. This has driven researchers to rely heavily on long term cultured cells which no longer represent the cancers from which they were derived. Resection of brain tumors, particularly at the interface between normal and tumorigenic tissue, can be carried out using an ultrasonic surgical aspirator (CUSA) that deposits liquid (blood and irrigation fluid) and resected tissue into a sterile bottle for disposal. To determine the utility of CUSA-derived glioma tissue for experimental research, we collected 48 CUSA specimen bottles from glioma patients and analyzed both the solid tissue fragments and dissociated tumor cells suspended in the liquid waste fraction. We investigated if these fractions would be useful for analyzing tumor heterogeneity, using IHC and multi-parameter flow cytometry; we also assessed culture generation and orthotopic xenograft potential. Both cell sources proved to be an abundant, highly viable source of live tumor cells for cytometric analysis, animal studies and in-vitro studies. Our findings demonstrate that CUSA tissue represents an abundant viable source to conduct experimental research and to carry out diagnostic analyses by flow cytometry or other molecular diagnostic procedures