Insights Into Peptide Inhibition of Alpha-Synuclein Aggregation

α-Synuclein (aSyn) aggregation is an attractive target for therapeutic development fora range of neurodegenerative conditions, collectively termed synucleinopathies. Here,we probe the mechanism of action of a peptide 4554W, (KDGIVNGVKA), previously identified through intracellular library screening, to prevent aSyn aggregation and associated toxicity. We utilize NMR to probe association and identify that 4554Wassociates with a “partially aggregated” form of aSyn, with enhanced association occurring over time. We also report the ability of 4554W to undergo modification through deamidation of the central asparagine residue, occurring on the same timescale asaSyn aggregation in vitro,with peptide modification enhancing its association with aSyn.Additionally, we report that 4554W can act to reduce fibril formation of five Parkinson’s disease associated aSyn mutants. Inhibitory peptide binding to partially aggregated forms of aSyn, as identified here, is particularly attractive from a therapeutic perspective,as it would eliminate the need to administer the therapy at pre-aggregation stages,which are difficult to diagnose. Taken together the data suggest that 4554W could bea suitable candidate for future therapeutic development against wild-type, and most mutant aSyn aggregatio

Erodium guicciardii Heldr. und dessen Polymorphismus im Bereiche von Makedonien

Erodium guicciardii Heldr. ist in der Flora von Makedonien eine seltene Art, die nur von einigen Fundorten bekannt ist (Micevski 1973). Die Durchsicht der eingesammelten Herbarbelege aus verschiedenen Gebieten zeigte, dass Exemplare einiger Populationen von den von Boissier (1859:40, 1867:888), Halacsy (1901:307), Hayek (1925: 581) sowie Webb & Chater (1968:201) angeführten Beschreibungen abweichen und mehr derjenigen von Knuth (1912:262) entsprechen. Knuth stellte nämlich als erster fest, dass sich an den Blütenstielen neben den einfachen, anliegenden Haaren auch kurze Drüsenhaare befinden. Aus der Beschreibung von Boissier, die nach Exemplaren von Heldreich verfasst wurde, geht nämlich hervor, dass die Blütenstiele und Kelchblätter ohne Drüsenhaare sind. Doch haben wir am Holotypus, der von Heldreich eingesammelt wurde und sich in der Botanischen Abteilung des Naturhistorischen Museums in Wien befindet, bemerkt, dass auch hier an den Kelchblättern Drüsenhaare anwesend sind. Fast alle Exemplare unserer Art aus dem Bereiche von Makedonien haben die Blütenstiele gewöhnlich drüsig. Der auffallendste Unterschied besteht jedoch im Indument der Kelchblätter. Bei der einen Gruppe der Pflanzen sind die Kelchblätter dicht mit anliegenden, einfachen Haaren bedeckt (Abb. 1, A), doch können in einigen Fällen auch vereinzelte Drüsenhaare vorhanden sein. Die zweite Gruppe der Pflanzen hat dagegen eine durchwegs drüsige Behaarung der Kelchblätter (Abb. 1, B), obwohl hie und da auch hier vereinzelte anliegende Haare eingemischt sein können. Auf Grund der Unterschiede in der Behaarung der Kelchblätter, der Blüten- und Blütenstandstiele können bei Erodiuvn guicciardii Heldr. die nachstehenden Sippen, die im Text beschrieben sind, unterschieden werden: EROD1UM GUICCIARDII Heldr. var. GUICCIARDII Verbreitung: 1,2 — Kicevo; 3 — Demir Hisar; 4 — Klisura Crna Reka; 5,6 — Galicica. var. GLANDULIFERUM Micevski var. nov. Verbreitung: 7,9 — Kicevo; 8 — Klisura Crna Reka; 10 — Galiöica. f. glanduliferum f. viscidum Micevski Verbreitung: Kicevo. Die var. glanduliferum Micevski unterscheidet sich vom Typus dadurch, dass die Blüten- und Blütenstandstiele sowie die Kelchblätter mit langen Drüsenhaaren bedeckt sind, während die einfachen, anliegenden Haare fehlen oder fast fehlen. Die f. viscidum Micevski ist, im Gegenteil zu den anderen Sippen, durch eine drüsige Behaarung der Laubblätter ausgezeichnet

Modelling the impact and cost-effectiveness of combination prevention amongst HIV serodiscordant couples in Nigeria.

OBJECTIVE: To estimate the impact and cost-effectiveness of treatment as prevention (TasP), pre-exposure prophylaxis (PrEP) and condom promotion for serodiscordant couples in Nigeria. DESIGN: Mathematical and cost modelling. METHODS: A deterministic model of HIV-1 transmission within a cohort of serodiscordant couples and to/from external partners was parameterized using data from Nigeria and other African settings. The impact and cost-effectiveness were estimated for condom promotion, PrEP and/or TasP, compared with a baseline where antiretroviral therapy (ART) was offered according to 2010 national guidelines (CD4 <350 cells/μl) to all HIV-positive partners. The impact was additionally compared with a baseline of current ART coverage (35% of those with CD4 <350 cells/μl). Full costs (in US $2012) of programme introduction and implementation were estimated from a provider perspective. RESULTS: Substantial benefits came from scaling up ART to all HIV-positive partners according to 2010 national guidelines, with additional smaller benefits of providing TasP, PrEP or condom promotion. Compared with a baseline of offering ART to all HIV-positive partners at the 2010 national guidelines, condom promotion was the most cost-effective strategy [US$1206/disability-adjusted-life-year (DALY)], the next most cost-effective intervention was to additionally give TasP to HIV-positive partners (incremental cost-effectiveness ratio US $1607/DALY), followed by additionally giving PrEP to HIV-negative partners until their HIV-positive partners initiate ART (US$7870/DALY). When impact was measured in terms of infections averted, PrEP with condom promotion prevented double the number of infections as condom promotion alone. CONCLUSIONS: The first priority intervention for serodiscordant couples in Nigeria should be scaled up ART access for HIV-positive partners. Subsequent incremental benefits are greatest with condom promotion and TasP, followed by PrEP

Certifications of citizenship: the history, politics and materiality of identity documents in South Asian states and diasporas

Experiences in the post-partition Indian subcontinent refute the conventional expectation that the 'possession of citizenship enables the acquisition of documents certifying it' (Jayal, 2013, 71). Instead, identity papers of various types play a vital part in certifying and authenticating claims to citizenship. This is particularly important in a context where the history of state formation, continuous migration flows and the rise of right-wing majoritarian politics has created an uncertain situation for individuals deemed to be on the ‘margins’ of the state. The papers that constitute this special issue bring together a range of disciplinary perspectives in order to investigate the history, politics and materiality of identity documents, and to dismantle citizenship as an absolute and fixed notion, seeking instead to theorise the very mutable ‘hierarchies’ and ‘degrees’ of citizenship. Collectively they offer a valuable lens onto how migrants, refugees and socio-economically marginal individuals negotiate their relationship with the state, both within South Asia and in South Asian diaspora communities. This introduction examines the wider context of the complex intersections between state-issued identity documents and the nature of citizenship and draws out cross-cutting themes across the papers in this collection

Adherence Support Workers: A Way to Address Human Resource Constraints in Antiretroviral Treatment Programs in the Public Health Setting in Zambia

BACKGROUND: In order to address staff shortages and improve adherence counseling for people on antiretroviral therapy (ART), the Zambia Prevention, Care and Treatment Partnership (ZPCT) developed an innovative strategy of training community volunteers to provide adherence support at the health facility and community levels. The objective of this study was to assess the effectiveness of these 'adherence support workers' (ASWs) in adherence counseling, treatment retention and addressing inadequate human resources at health facilities.METHODOLOGY/PRINCIPAL FINDINGS: The study used quantitative and qualitative research techniques at five selected ART sites in four provinces in Zambia. Five hundred patients on ART were interviewed using a structured questionnaire to compare the quality of adherence counseling before and after the ASW scheme was introduced at the selected sites and between ASWs and HCWs after the introduction of ASWs. In addition, 3,903 and 4,972 electronic records of all new patients accessing antiretroviral therapy for the time period of 12 months before and 12 months after the introduction of ASWs respectively, were analyzed to assess loss to follow-up rates. Two focus group discussions with ASWs and health care workers (HCWs) were conducted in each clinic. Key informant interviews in the ART clinics were also conducted. There was a marked shift of workload from HCWs to ASWs without any compromise in the quality of counseling. Quality of adherence counseling by ASWs was comparable to HCWs after their introduction. The findings suggest that the deployment of ASWs helped reduce waiting times for adherence counseling. Loss to follow-up rates of new clients declined from 15% to 0% after the deployment of ASWs.CONCLUSION: Adherence counseling tasks can be shifted to lay cadres like ASWs without compromising the quality of counseling. Follow-up of clients by ASWs within the community is necessary to improve retention of clients on ART

A taxonomy for community-based care programs focused on HIV/AIDS prevention, treatment, and care in resource-poor settings

Community-based care (CBC) can increase access to key services for people affected by HIV/AIDS through the mobilization of community interests and resources and their integration with formal health structures. Yet, the lack of a systematic framework for analysis of CBC focused on HIV/AIDS impedes our ability to understand and study CBC programs. We sought to develop taxonomy of CBC programs focused on HIV/AIDS in resource-limited settings in an effort to understand their key characteristics, uncover any gaps in programming, and highlight the potential roles they play. Our review aimed to systematically identify key CBC programs focused on HIV/AIDS in resource-limited settings. We used both bibliographic database searches (Medline, CINAHL, and EMBASE) for peer-reviewed literature and internet-based searches for gray literature. Our search terms were &#x2018;HIV&#x2019; or &#x2018;AIDS&#x2019; and &#x2018;community-based care&#x2019; or &#x2018;CBC&#x2019;. Two co-authors developed a descriptive taxonomy through an iterative, inductive process using the retrieved program information. We identified 21 CBC programs useful for developing taxonomy. Extensive variation was observed within each of the nine categories identified: region, vision, characteristics of target populations, program scope, program operations, funding models, human resources, sustainability, and monitoring and evaluation strategies. While additional research may still be needed to identify the conditions that lead to overall program success, our findings can help to inform our understanding of the various aspects of CBC programs and inform potential logic models for CBC programming in the context of HIV/AIDS in resource-limited settings. Importantly, the findings of the present study can be used to develop sustainable HIV/AIDS-service delivery programs in regions with health resource shortages

The Anatomy of Memory Politics: A Formalist Analysis of Tate Britain’s ‘Artist and Empire’ and the Struggle over Britain’s Imperial Past

In this paper, I propose a new approach for understanding the meaning of memory politics, which draws upon the archetypal literary criticism of Northrop Frye. I suggest that the four archetypes elaborated by Frye—comedy, romance, tragedy, and satire—can be used as a heuristic device for interpreting the contested historical narratives that are associated with the politics of memory. I illustrate this approach through a case-study of Artists and Empire: Facing Britain’s Imperial Past, an exhibition held at Tate Britain in 2016, amidst increasing contestation over the meaning of the British Empire. In sum, I find that the exhibit narrated Britain’s imperial past as a comedy, in which a key theme was the progressive cultural mixing of the British and the people they colonized. To conclude, I discuss the implications of such a narrative for constructing an inclusive, postcolonial British identity. As an alternative, I draw on Aristotle to suggest that a tragic narrative would have been more propitious

Treatment for Chronic Depression Using Schema Therapy

Schema therapy (ST) is an integrative treatment approach to chronic lifelong problems with an established effectiveness for treating personality disorders. This article describes the adaptation of ST to chronic depression by reviewing the literature on the underlying risk factors to chronic depression. A model of chronic depression is presented, describing the interplay between empirically supported risk factors to chronic depression (early adversity, cognitive factors, personality pathology, interpersonal factors). We provide a treatment protocol of ST for chronic depression describing techniques that can be used in ST to target these underlying risk factors. Based on the current body of empirical evidence for the underlying risk factors to chronic depression, ST appears to be a promising new treatment approach to chronic depression, as it directly targets these underlying risk factors. © 2013 American Psychological Association