Spectral flow invariants and twisted cyclic theory from the Haar state on SU_q(2)

In [CPR2], we presented a K-theoretic approach to finding invariants of algebras with no non-trivial traces. This paper presents a new example that is more typical of the generic situation. This is the case of an algebra that admits only non-faithful traces, namely SU_q(2), and also KMS states. Our main results are index theorems (which calculate spectral flow), one using ordinary cyclic cohomology and the other using twisted cyclic cohomology, where the twisting comes from the generator of the modular group of the Haar state. In contrast to the Cuntz algebras studied in [CPR2], the computations are considerably more complex and interesting, because there are nontrivial `eta' contributions to this index.Comment: 25 pages, 1 figur

Secular trends in under-reporting in young people

Original article can be found at: http://journals.cambridge.org/action/displayJournal?jid=BJN Copyright The Authors. DOI: 10.1079/BJN20041307National survey data show that reported energy intake has decreased in recent decades despite a rise in the prevalence of obesity. This disparity may be due to a secular increase in under-reporting or a quantitatively greater decrease in energy expenditure. This study examines the extent of under-reporting of energy intake in the National Diet and Nutrition Survey (NDNS) in young people aged 4–18 years in 1997 using published equations to calculate estimated energy requirements. It explores secular changes by comparison with the Diets of British School Children (DBSC) survey in 10–11- and 14–15-year-olds in 1983. In the NDNS, under-reporting (estimated energy requirements – energy intake) represented 21 % of energy needs in girls and 20 % in boys. The magnitude of under-reporting increased significantly with age (P<0·001) and was higher in overweight than lean individuals over 7 years of age. To compare reported energy intake in DBSC and NDNS, the estimated physical activity level from dietary records (dPAL=reported energy intake/predicted BMR) was calculated. If there were no under-reporting, dPAL would represent the subject's true activity level. However, dPAL from the NDNS was significantly lower than that from the DBSC by 8 % and 9 % in boys and girls for those aged 10–11 years, and by 14 % and 11 % for 14–15-year-olds respectively, reaching physiologically implausible levels in the 14–15-year-old girls (dPAL=1·17). If activity levels have remained constant between the two surveys, under-reporting has increased by 8–14 %. The evidence supports a secular trend towards increased under-reporting between the two surveys, but the precise magnitude cannot be quantified in the absence of historical measures of energy expenditure.Peer reviewe

Resistance of uveal melanoma to the interstrand cross-linking agent mitomycin C is associated with reduced expression of CYP450R

background: Uveal melanoma (UM) is the most common primary intraocular tumour of adults, frequently metastasising to the liver. Hepatic metastases are difficult to treat and are mainly unresponsive to chemotherapy. To investigate why UM are so chemo-resistant we explored the effect of interstrand cross-linking agents mitomycin C (MMC) and cisplatin in comparison with hydroxyurea (HU). methods: Sensitivity to MMC, cisplatin and HU was tested in established UM cell lines using clonogenic assays. The response of UM to MMC was confirmed in MTT assays using short-term cultures of primary UM. The expression of cytochrome P450 reductase (CYP450R) was analysed by western blotting, and DNA cross-linking was assessed using COMET analysis supported by γ-H2AX foci formation. results: Both established cell lines and primary cultures of UM were resistant to the cross-linking agent MMC (in each case P<0.001 in Student's t-test compared with controls). In two established UM cell lines, DNA cross-link damage was not induced by MMC (in both cases P<0.05 in Students's t-test compared with damage induced in controls). In all, 6 out of 6 UMs tested displayed reduced expression of the metabolising enzyme CYP450R and transient expression of CYP450R increased MMC sensitivity of UM. conclusion: We suggest that reduced expression of CYP450R is responsible for MMC resistance of UM, through a lack of bioactivation, which can be reversed by complementing UM cell lines with CYP450R

‘We Need to Deploy Them Very Thoughtfully and Carefully’: Perceptions of Analytical Treatment Interruptions in HIV Cure Research in the United States – A Qualitative Inquiry

Strategies to control HIV in the absence of antiretroviral therapy are needed to cure HIV. However, such strategies will require analytical treatment interruptions (ATIs) to determine their efficacy. We investigated how U.S. stakeholders involved in HIV cure research perceive ATIs. We conducted 36 in-depth interviews with three groups of stakeholders: 12 people living with HIV, 11 clinician-researchers, and 13 policy-makers/bioethicists. Qualitative data revealed several themes. First, there was little consensus on when ATIs would be ethically warranted. Second, the most frequent perceived hypothetical motivators for participating in research on ATIs were advancing science and contributing to society. Third, risks related to viral rebound were the most prevalent concerns related to ATIs. Stakeholders suggested ways to minimize the risks of ATIs in HIV cure research. Increased cooperation between scientists and local communities may be useful for minimizing risk. Further ethics research is necessary

Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site

Repair of DNA damage is critical to genomic integrity and frequently disrupted in cancers. Ubiquitin-specific protease 1 (USP1), a nucleus-localized deubiquitinase, lies at the interface of multiple DNA repair pathways and is a promising drug target for certain cancers. Although multiple inhibitors of this enzyme, including one in phase 1 clinical trials, have been established, their binding mode is unknown. Here, we use cryo–electron microscopy to study an assembled enzyme-substrate-inhibitor complex of USP1 and the well-established inhibitor, ML323. Achieving 2.5-Å resolution, with and without ML323, we find an unusual binding mode in which the inhibitor disrupts part of the hydrophobic core of USP1. The consequent conformational changes in the secondary structure lead to subtle rearrangements in the active site that underlie the mechanism of inhibition. These structures provide a platform for structure-based drug design targeting USP1

Interrupting Antiretroviral Treatment in HIV Cure Research: Scientific and Ethical Considerations

Over the past several years there has been intense activity directed at the possibility of achieving remission or eradication of HIV infection. Current assays for the measurement of latent HIV are insufficient to demonstrate complete clearance of replication-competent HIV. Therefore, the ultimate test for assessing whether investigational interventions have resulted in HIV remission or eradication is to interrupt standard antiretroviral therapy (ART) in a carefully controlled clinical trial setting. These procedures, known as analytic treatment interruptions (ATIs), raise important scientific and ethical questions. The lack of definitive assays for measuring viral reservoirs not only makes research on HIV remission or cure challenging, it also affects the ability to assess risks from ATIs themselves. In spite of these challenges, basic ethical criteria can be met with careful study design and close monitoring. In this brief report we outline ethical standards for HIV cure research involving ATIs. These criteria should be revisited as the science evolves

Perceptions of Equipoise, Risk/Benefit Ratios, and ‘Otherwise Healthy Volunteers’ in the Context of Early-Phase HIV Cure Research in the United States – A Qualitative Inquiry

Early-phase HIV cure research is conducted against a background of highly effective antiretroviral therapy, and involves risky interventions in individuals who enjoy an almost normal life expectancy. To explore perceptions of three ethical topics in the context of HIV cure research—(a) equipoise, (b) risk–benefit ratios, and (c) “otherwise healthy volunteers”—we conducted 36 in-depth interviews (IDIs) with three groups of purposively selected key informants: clinician-researchers (n = 11), policy-makers and bioethicists (n = 13), and people living with HIV (PLWHIV; n = 12). Our analysis revealed variability in perceptions of equipoise. Second, most key informants believed there was no clear measure of risk–benefit ratios in HIV cure research, due in part to the complexity of weighing (sometimes unknown) risks to participants and (sometimes speculative) benefits to science and society. Third, most clinician-researchers and policy-makers/bioethicists viewed potential HIV cure study participants as “otherwise healthy volunteers,” but this perception was not shared among PLWHIV in our study

Willingness to Participate in HIV Cure Research: Survey Results from 400 People Living with HIV in the United States

Introduction Participation in early-phase HIV cure studies includes clinical risks with little to no likelihood of clinical benefit. Examining the willingness of people living with HIV to participate is important to guide study design and informed consent. Our study examined the overall willingness of people living with HIV to participate in HIV cure research in the US, focusing on perceived risks and benefits of participation. Methods We undertook an online survey of adults living with HIV in the US. Survey questions were developed based on previous research and a scoping review of the literature. We quantitatively assessed individuals’ perceived risks and benefits of HIV cure-related research and respondents’ willingness to participate in different modalities of HIV cure studies. Results We recruited 409 study participants of whom 400 were eligible for the study and were included in the analysis (nine were not eligible due to self-declared HIV-negative status). We found >50% willingness to participate in 14 different types of HIV cure studies. Perceived clinical benefits and social benefits were important motivators, while personal clinical risks appeared to deter potential participation. Roughly two-thirds of survey respondents (68%) indicated that they were somewhat willing to stop treatment as part of HIV cure research. In the bivariate models, females, African Americans/blacks, Hispanics, individuals in the lowest income bracket, people living with HIV for longer periods of their lives, and people who were self-perceived ‘very healthy’ were less willing to participate in certain types of HIV cure studies than others. Multivariate results showed the perceived benefits (adjusted odds ratios >1) and perceived risks (adjusted odds ratios <1) acted as potential motivators and deterrents to participation, respectively. Conclusion Our study is the first attempt to quantify potential motivators and deterrents of participation in HIV cure research in the US using perceived risks and benefits. The results offer guidance to HIV cure researchers and developers of interventions about the beneficial and detrimental characteristics of HIV cure strategies that are most meaningful to people living with HIV. The study also highlights new potential lines of inquiry for further social science and ethics research

Characterisation of cardiac health in the reduced uterine perfusion pressure model and a 3D cardiac spheroid model, of preeclampsia

BACKGROUND: Preeclampsia is a dangerous cardiovascular disorder of pregnancy that leads to an increased risk of future cardiovascular and metabolic disorders. Much of the pathogenesis and mechanisms involved in cardiac health in preeclampsia are unknown. A novel anti-angiogenic protein, FKBPL, is emerging as having a potential role in both preeclampsia and cardiovascular disease (CVD). Therefore, in this study we aimed to characterise cardiac health and FKBPL regulation in the rat reduced uterine perfusion pressure (RUPP) and a 3D cardiac spheroid model of preeclampsia. METHODS: The RUPP model was induced in pregnant rats and histological analysis performed on the heart, kidney, liver and placenta (n ≥ 6). Picrosirius red staining was performed to quantify collagen I and III deposition in rat hearts, placentae and livers as an indicator of fibrosis. RT-qPCR was used to determine changes in Fkbpl, Icam1, Vcam1, Flt1 and Vegfa mRNA in hearts and/or placentae and ELISA to evaluate cardiac brain natriuretic peptide (BNP45) and FKBPL secretion. Immunofluorescent staining was also conducted to analyse the expression of cardiac FKBPL. Cardiac spheroids were generated using human cardiac fibroblasts and human coronary artery endothelial cells and treated with patient plasma from normotensive controls, early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE); n = 3. FKBPL and CD31 expression was quantified by immunofluorescent labelling. RESULTS: The RUPP procedure induced significant increases in blood pressure (p < 0.001), collagen deposition (p < 0.001) and cardiac BNP45 (p < 0.05). It also induced a significant increase in cardiac FKBPL mRNA (p < 0.05) and protein  expression  (p < 0.01). RUPP placentae also exhibited increased collagen deposition and decreased Flt1 mRNA expression (p < 0.05). RUPP kidneys revealed an increase in average glomerular size (p < 0.05). Cardiac spheroids showed a significant increase in FKBPL expression when treated with LOPE plasma (p < 0.05) and a trend towards increased FKBPL expression following treatment with EOPE plasma (p = 0.06). CONCLUSIONS: The rat RUPP model induced cardiac, renal and placental features reflective of preeclampsia. FKBPL was increased in the hearts of RUPP rats and cardiac spheroids treated with plasma from women with preeclampsia, perhaps reflective of restricted angiogenesis and inflammation in this disorder. Elucidation of these novel FKBPL mechanisms in cardiac health in preeclampsia could be key in preventing future CVD