Faculty Bibliography
Searched for:
Department/Unit:Cell Biology
Total Results:
14237
Structural and Functional Studies of Phospholamban-Sarcolipin Chimeras [Meeting Abstract]
ISI:000316074303092
ISSN: 0006-3495
CID: 2444852
Mouse prion protein polymorphism Phe-108/Val-189 affects the kinetics of fibril formation and the response to seeding: evidence for a two-step nucleation polymerization mechanism
Prion diseases are fatal neurodegenerative disorders associated with the polymerization of the cellular form of prion protein (PrP(C)) into an amyloidogenic beta-sheet infectious form (PrP(Sc)). The sequence of host PrP is the major determinant of host prion disease susceptibility. In mice, the presence of allele a (Prnp(a), encoding the polymorphism Leu-108/Thr-189) or b (Prnp(b), Phe-108/Val-189) is associated with short or long incubation times, respectively, following infection with PrP(Sc). The molecular bases linking PrP sequence, infection susceptibility, and convertibility of PrP(C) into PrP(Sc) remain unclear. Here we show that recombinant PrP(a) and PrP(b) aggregate and respond to seeding differently in vitro. Our kinetic studies reveal differences during the nucleation phase of the aggregation process, where PrP(b) exhibits a longer lag phase that cannot be completely eliminated by seeding the reaction with preformed fibrils. Additionally, PrP(b) is more prone to propagate features of the seeds, as demonstrated by conformational stability and electron microscopy studies of the formed fibrils. We propose a model of polymerization to explain how the polymorphisms at positions 108 and 189 produce the phenotypes seen in vivo. This model also provides insight into phenomena such as species barrier and prion strain generation, two phenomena also influenced by the primary structure of PrP.
PMCID:3576082
PMID: 23283973
ISSN: 1083-351x
CID: 2444522
Scale-up of a comprehensive harm reduction programme for people injecting opioids: lessons from north-eastern India
PROBLEM: Harm reduction packages for people who inject illicit drugs, including those infected with human immunodeficiency virus (HIV), are cost-effective but have not been scaled up globally. In the north-eastern Indian states of Manipur and Nagaland, the epidemic of HIV infection is driven by the injection of illicit drugs, especially opioids. These states needed to scale up harm reduction programmes but faced difficulty doing so. APPROACH: In 2004, the Bill & Melinda Gates Foundation funded Project ORCHID to scale up a harm reduction programme in Manipur and Nagaland. LOCAL SETTING: In 2003, an estimated 10 000 and 16 000 people were injecting drugs in Manipur and Nagaland, respectively. The prevalence of HIV infection among people injecting drugs was 24.5% in Manipur and 8.4% in Nagaland. RELEVANT CHANGES: By 2012, the harm reduction programme had been scaled up to an average of 9011 monthly contacts outside clinics (80% of target); an average of 1709 monthly clinic visits (15% of target, well above the 5% monthly goal) and an average monthly distribution of needles and syringes of 16 each per programme participant. Opioid agonist maintenance treatment coverage was 13.7% and retention 6 months after enrolment was 63%. Antiretroviral treatment coverage for HIV-positive participants was 81%. LESSONS LEARNT: A harm reduction model consisting of community-owned, locally relevant innovations and business approaches can result in good harm reduction programme scale-up and influence harm reduction policy. Project ORCHID has influenced national harm reduction policy in India and contributed to the development of harm reduction guidelines.
PMCID:3629449
PMID: 23599555
ISSN: 1564-0604
CID: 2439952
How the Avahan HIV prevention program transitioned from the Gates Foundation to the government of India
Developing countries face diminishing development aid and time-limited donor commitments that challenge the long-term sustainability of donor-funded programs to improve the health of local populations. Increasing country ownership of the programs is one solution. Transitioning managerial and financial responsibility for donor-funded programs to governments and local stakeholders represents a highly advanced form of country ownership, but there are few successful examples among large-scale programs. We present a transition framework and describe how it was used to transfer the Bill & Melinda Gates Foundation's HIV/AIDS prevention program, the Avahan program, to the Government of India. Essential features recommended for the transition of donor-funded programs to governments include early planning with the government, aligning donor program components with government structures and funding models prior to transition, building government capacity through active technical and management support, budgeting for adequate support during and after the transition, and dividing the transition into phases to allow time for adjustments and corrections. The transition of programs to governments is an important sustainability strategy for efforts to scale up HIV prevention programs to reach the populations most at risk.
PMID: 23836743
ISSN: 1544-5208
CID: 2439942
Transgenically targeted rabies virus demonstrates a major monosynaptic projection from hippocampal area CA2 to medial entorhinal layer II neurons
The enormous potential of modern molecular neuroanatomical tools lies in their ability to determine the precise connectivity of the neuronal cell types comprising the innate circuitry of the brain. We used transgenically targeted viral tracing to identify the monosynaptic inputs to the projection neurons of layer II of medial entorhinal cortex (MEC-LII) in mice. These neurons are not only major inputs to the hippocampus, the structure most clearly implicated in learning and memory, they also are "grid cells." Here we address the question of what kinds of inputs are specifically targeting these MEC-LII cells. Cell-specific infection of MEC-LII with recombinant rabies virus results in unambiguous labeling of monosynaptic inputs. Furthermore, ratios of labeled neurons in different regions are largely consistent between animals, suggesting that label reflects density of innervation. While the results mostly confirm prior anatomical work, they also reveal a novel major direct input to MEC-LII from hippocampal pyramidal neurons. Interestingly, the vast majority of these direct hippocampal inputs arise not from the major hippocampal subfields of CA1 and CA3, but from area CA2, a region that has historically been thought to merely be a transitional zone between CA3 and CA1. We confirmed this unexpected result using conventional tracing techniques in both rats and mice.
PMCID:3771023
PMID: 24027288
ISSN: 1529-2401
CID: 2436752
Role of malnutrition and parasite infections in the spatial variation in children's anaemia risk in northern Angola
Anaemia is known to have an impact on child development and mortality and is a severe public health problem in most countries in sub-Saharan Africa. We investigated the consistency between ecological and individual-level approaches to anaemia mapping by building spatial anaemia models for children aged 86%) were identified. Using an individual-level approach to anaemia mapping at a small spatial scale, we found that anaemia in children aged
PMID: 23733295
ISSN: 1970-7096
CID: 2412022
Extending helminth control beyond STH and schistosomiasis: the case of human hymenolepiasis
PMCID:3812097
PMID: 24205412
ISSN: 1935-2735
CID: 2412012
New approaches to vaccination
CHICHESTER : JOHN WILEY & SONS LTD, 2013
pp. 327-336
ISBN:
CID: 2394182
Colocalization of different influenza viral RNA segments in the cytoplasm before viral budding as shown by single-molecule sensitivity FISH analysis
The Influenza A virus genome consists of eight negative sense, single-stranded RNA segments. Although it has been established that most virus particles contain a single copy of each of the eight viral RNAs, the packaging selection mechanism remains poorly understood. Influenza viral RNAs are synthesized in the nucleus, exported into the cytoplasm and travel to the plasma membrane where viral budding and genome packaging occurs. Due to the difficulties in analyzing associated vRNPs while preserving information about their positions within the cell, it has remained unclear how and where during cellular trafficking the viral RNAs of different segments encounter each other. Using a multicolor single-molecule sensitivity fluorescence in situ hybridization (smFISH) approach, we have quantitatively monitored the colocalization of pairs of influenza viral RNAs in infected cells. We found that upon infection, the viral RNAs from the incoming particles travel together until they reach the nucleus. The viral RNAs were then detected in distinct locations in the nucleus; they are then exported individually and initially remain separated in the cytoplasm. At later time points, the different viral RNA segments gather together in the cytoplasm in a microtubule independent manner. Viral RNAs of different identities colocalize at a high frequency when they are associated with Rab11 positive vesicles, suggesting that Rab11 positive organelles may facilitate the association of different viral RNAs. Using engineered influenza viruses lacking the expression of HA or M2 protein, we showed that these viral proteins are not essential for the colocalization of two different viral RNAs in the cytoplasm. In sum, our smFISH results reveal that the viral RNAs travel together in the cytoplasm before their arrival at the plasma membrane budding sites. This newly characterized step of the genome packaging process demonstrates the precise spatiotemporal regulation of the infection cycle.
PMCID:3649991
PMID: 23671419
ISSN: 1553-7374
CID: 2385242
Imaging the transcriptome
PMCID:4039379
PMID: 24281056
ISSN: 1744-4292
CID: 2385232
