Health systems’ responses to the roll-out of antiretroviral therapy (ART) in India: a comparison of two HIV high-prevalence settings

The government of India launched the free anti-retroviral therapy (ART) initiative in 2004 and the programme has since scaled up expansion in a phased manner. Programme authorities acknowledge problems in scale-up, yet discussions have been restricted to operational constraints, with little consideration for how local health system responses to HIV/AIDS influence the delivery of ART. This paper draws on the perspectives of key informants and people living with HIV (PLHIV) to compare delivery of ART in two ART centres in the States of Maharashtra and Andhra Pradesh at two distinct points of time. In 2005, data were collected through key informant interviews (KIIs) using interview guides and a survey of PLHIV using a semi-structured interview schedule. Differences were observed in the functioning and resources of the two centres, indicating different levels of preparedness which in turn influenced PLHIV's pathways in accessing ART. We examine these differences in the light of programme leadership, ownership and the roles of public, private and non-governmental organisation actors in HIV care. KIIs conducted during a follow-up visit in 2009 focused on changes in ART delivery. Many operational problems had been resolved; however, new challenges were emerging as a result of the increased patient load. An understanding of how ART programmes evolve within local health systems has bearing on future developments of the ART programme and must include a consideration of the wider socio-political environment within which HIV programmes are embedded

Mask formulas for cograssmannian Kazhdan-Lusztig polynomials

We give two contructions of sets of masks on cograssmannian permutations that can be used in Deodhar's formula for Kazhdan-Lusztig basis elements of the Iwahori-Hecke algebra. The constructions are respectively based on a formula of Lascoux-Schutzenberger and its geometric interpretation by Zelevinsky. The first construction relies on a basis of the Hecke algebra constructed from principal lower order ideals in Bruhat order and a translation of this basis into sets of masks. The second construction relies on an interpretation of masks as cells of the Bott-Samelson resolution. These constructions give distinct answers to a question of Deodhar.Comment: 43 page

De novo design of proteins housing excitonically coupled chlorophyll special pairs

Natural photosystems couple light harvesting to charge separation using a ‘special pair’ of chlorophyll molecules that accepts excitation energy from the antenna and initiates an electron-transfer cascade. To investigate the photophysics of special pairs independently of the complexities of native photosynthetic proteins, and as a first step toward creating synthetic photosystems for new energy conversion technologies, we designed C2-symmetric proteins that hold two chlorophyll molecules in closely juxtaposed arrangements. X-ray crystallography confirmed that one designed protein binds two chlorophylls in the same orientation as native special pairs, whereas a second designed protein positions them in a previously unseen geometry. Spectroscopy revealed that the chlorophylls are excitonically coupled, and fluorescence lifetime imaging demonstrated energy transfer. The cryo-electron microscopy structure of a designed 24-chlorophyll octahedral nanocage with a special pair on each edge closely matched the design model. The results suggest that the de novo design of artificial photosynthetic systems is within reach of current computational methods

Altered translation of GATA1 in Diamond-Blackfan anemia

Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA), congenital asplenia and T cell leukemia. Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type- and tissue-specific defects remains unknown. Here, we identify mutations in GATA1, encoding the critical hematopoietic transcription factor GATA-binding protein-1, that reduce levels of full-length GATA1 protein and cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can lead to decreased GATA1 mRNA translation, possibly resulting from a higher threshold for initiation of translation of this mRNA in comparison with other mRNAs. In primary hematopoietic cells from patients with mutations in RPS19, encoding ribosomal protein S19, the amplitude of a transcriptional signature of GATA1 target genes was globally and specifically reduced, indicating that the activity, but not the mRNA level, of GATA1 is decreased in patients with DBA associated with mutations affecting ribosomal proteins. Moreover, the defective hematopoiesis observed in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations affecting ubiquitous ribosomal proteins can result in human disease

Longitudinal single-cell dynamics of chromatin accessibility and mitochondrial mutations in chronic lymphocytic leukemia mirror disease history

While cancers evolve during disease progression and in response to therapy, temporal dynamics remain difficult to study in humans due to the lack of consistent barcodes marking individual clones in vivo. We employ mitochondrial single-cell assay for transposase-accessible chromatin with sequencing to profile 163,279 cells from 9 patients with chronic lymphocytic leukemia (CLL) collected across disease course and utilize mitochondrial DNA (mtDNA) mutations as natural genetic markers of cancer clones. We observe stable propagation of mtDNA mutations over years in the absence of strong selective pressure indicating clonal persistence, but dramatic changes following tight bottlenecks including disease transformation and relapse post-therapy, paralleled by acquisition of copy number variants, changes in chromatin accessibility and gene expression. Furthermore, we link CLL subclones to distinct chromatin states, providing insight into non-genetic sources of relapse. mtDNA mutations thus mirror disease history and provide naturally-occurring genetic barcodes to enable patient-specific study of cancer subclonal dynamics