Neglected Tropical Diseases, Neglected Data Sources, and Neglected Issues

BACKGROUND: Lymphatic filariasis (LF) is a so-called neglected tropical disease, currently overshadowed by higher-profile efforts to address malaria, tuberculosis, and HIV/AIDS. Despite recent successes in arresting transmission, some 40 million people who already have the disease have been largely neglected. This study aims to increase understanding of how this vulnerable, neglected group can be helped. METHODS: We used purposive sampling to select 60 men and women with filarial lymphoedema (45 with filarial elephantiasis and 15 men with filarial hydrocoele) from the south of Sri Lanka in 2004-2005. Participants were selected to give a balance of men and women and poor and nonpoor, and a range of stages of the disease. Participants' experiences and the consequences of their disease for the household were explored with in-depth qualitative, semistructured interviews. FINDINGS: LF was extremely debilitating to participants over long periods of time. The stigma attached to the condition caused social isolation and emotional distress, and delayed diagnosis and treatment, resulting in undue advancement of the disease. Free treatment services at government clinics were avoided because the participants' condition would be identifiable in public. Loss of income due to the condition was reported by all households in the sample, not just the poorest. Households that were already on low incomes were pushed into near destitution, from which it was almost impossible to escape. Affected members of low-income households also had less opportunity to obtain appropriate treatment from distant clinics, and had living and working conditions that made hygiene and compliance difficult. SIGNIFICANCE: This highly vulnerable category of patients has low visibility, thus becoming marginalized and forgotten. With an estimated 300,000 total cases of elephantiasis and/or oedema in Sri Lanka, and around 300,000 men with filarial hydrocoele, the affected households will need help and support for many years to come. These individuals should be specially targeted for identification, outreach, and care. The global strategy for elimination is aimed at the cessation of transmission, but there will remain some 40 million individuals with clinical manifestations whose needs and problems are illustrated in this study

Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of meier-gorlin syndrome

Mutations in ORC1, ORC4, ORC6, CDT1, and CDC6, which encode proteins required for DNA replication origin licensing, cause Meier-Gorlin syndrome (MGS), a disorder conferring microcephaly, primordial dwarfism, underdeveloped ears, and skeletal abnormalities. Mutations in ATR, which also functions during replication, can cause Seckel syndrome, a clinically related disorder. These findings suggest that impaired DNA replication could underlie the developmental defects characteristic of these disorders. Here, we show that although origin licensing capacity is impaired in all patient cells with mutations in origin licensing component proteins, this does not correlate with the rate of progression through S phase. Thus, the replicative capacity in MGS patient cells does not correlate with clinical manifestation. However, ORC1-deficient cells from MGS patients and siRNA-mediated depletion of origin licensing proteins also have impaired centrosome and centriole copy number. As a novel and unexpected finding, we show that they also display a striking defect in the rate of formation of primary cilia. We demonstrate that this impacts sonic hedgehog signalling in ORC1-deficient primary fibroblasts. Additionally, reduced growth factor-dependent signaling via primary cilia affects the kinetics of cell cycle progression following cell cycle exit and re-entry, highlighting an unexpected mechanism whereby origin licensing components can influence cell cycle progression. Finally, using a cell-based model, we show that defects in cilia function impair chondroinduction. Our findings raise the possibility that a reduced efficiency in forming cilia could contribute to the clinical features of MGS, particularly the bone development abnormalities, and could provide a new dimension for considering developmental impacts of licensing deficiency

A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2

During development of the vertebrate CNS, the basic helix-loop-helix (bHLH) transcription factor Olig2 sustains replication competence of progenitor cells that give rise to neurons and oligodendrocytes. A pathological counterpart of this developmental function is seen in human glioma, wherein Olig2 is required for maintenance of stem-like cells that drive tumor growth. The mitogenic/gliomagenic functions of Olig2 are regulated by phosphorylation of a triple serine motif (S10, S13, and S14) in the amino terminus. Here, we identify a set of three serine/threonine protein kinases (glycogen synthase kinase 3α/β [GSK3α/β], casein kinase 2 [CK2], and cyclin-dependent kinases 1/2 [CDK1/2]) that are, collectively, both necessary and sufficient to phosphorylate the triple serine motif. We show that phosphorylation of the motif itself serves as a template to prime phosphorylation of additional serines and creates a highly charged "acid blob" in the amino terminus of Olig2. Finally, we show that small molecule inhibitors of this forward-feeding phosphorylation cascade have potential as glioma therapeutics.We thank the American Brain Tumor Association for postdoctoral fellowship support (to A.-C.T.) and the American Association for Cancer Research (AACR) for a Anna D. Baker Fellowship in Basic Cancer Research (to A.G.). This work was supported by grants from NIH ( NS057727 to C.D.S. and NS040511 to D.H.R.) and by funding from the Dana-Farber Strategic Research Initiative (to J.A.M.), Howard Hughes Medical Institute (to D.H.R.), and A Kids' Brain Tumor Cure Foundation (to C.D.S.)

Constitutive Notch2 signaling in neural stem cells promotes tumorigenic features and astroglial lineage entry

Recent studies identified a highly tumorigenic subpopulation of glioma stem cells (GSCs) within malignant gliomas. GSCs are proposed to originate from transformed neural stem cells (NSCs). Several pathways active in NSCs, including the Notch pathway, were shown to promote proliferation and tumorigenesis in GSCs. Notch2 is highly expressed in glioblastoma multiforme (GBM), a highly malignant astrocytoma. It is therefore conceivable that increased Notch2 signaling in NSCs contributes to the formation of GBM. Here, we demonstrate that mice constitutively expressing the activated intracellular domain of Notch2 in NSCs display a hyperplasia of the neurogenic niche and reduced neuronal lineage entry. Neurospheres derived from these mice show increased proliferation, survival and resistance to apoptosis. Moreover, they preferentially differentiate into astrocytes, which are the characteristic cellular population of astrocytoma. Likewise, we show that Notch2 signaling increases proliferation and resistance to apoptosis in human GBM cell lines. Gene expression profiling of GBM patient tumor samples reveals a positive correlation of Notch2 transcripts with gene transcripts controlling anti-apoptotic processes, stemness and astrocyte fate, and a negative correlation with gene transcripts controlling proapoptotic processes and oligodendrocyte fate. Our data show that Notch2 signaling in NSCs produces features of GSCs and induces astrocytic lineage entry, consistent with a possible role in astrocytoma formation

Molecular diagnosis of bird-mediated pest consumption in tropical farmland

Biodiversity loss will likely have surprising and dramatic consequences for human wellbeing. Identifying species that benefit society represents a critical first step towards predicting the consequences of biodiversity loss. Though natural predators prevent billions of dollars in agricultural pest damage annually, characterizing which predators consume pests has proven challenging. Emerging molecular techniques may illuminate these interactions. In the countryside of Costa Rica, we identified avian predators of coffee’s most damaging insect pest, the coffee berry borer beetle (Coleoptera:Scolytidae Hypothenemus hampeii), by assaying 1430 fecal samples of 108 bird species for borer DNA. While feeding trials confirmed the efficacy of our approach, detection rates were low. Nevertheless, we identified six species that consume the borer. These species had narrow diet breadths, thin bills, and short wings; traits shared with borer predators in other systems. Borer predators were not threatened; therefore, safeguarding pest control necessitates managing species beyond those at risk of regional extinction by maintaining populations in farmland habitats. Generally, our results demonstrate potential for pairing molecular methods with ecological analyses to yield novel insights into species interactions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2193-1801-3-630) contains supplementary material, which is available to authorized users

Short-Term Hurricane Impacts on a Neotropical Community of Marked Birds and Implications for Early-Stage Community Resilience

Populations in fragmented ecosystems risk extirpation through natural disasters, which must be endured rather than avoided. Managing communities for resilience is thus critical, but details are sketchy about the capacity for resilience and its associated properties in vertebrate communities. We studied short-term resilience in a community of individually marked birds, following this community through the catastrophic destruction of its forest habitat by Hurricane Iris in Belize, Central America. We sampled for 58 d immediately before the storm, 28 d beginning 11 d after Hurricane Iris, and for 69 d approximately one year later. Our data showed that the initial capacity for resilience was strong. Many banded individuals remained after the storm, although lower post-hurricane recapture rates revealed increased turnover among individuals. Changes occurred in community dynamics and in abundances among species and guilds. Survivors and immigrants both were critical components of resilience, but in a heterogeneous, species-specific manner. Delayed effects, including higher fat storage and increased species losses, were evident one year later

The Probable Cell of Origin of NF1- and PDGF-Driven Glioblastomas

Primary glioblastomas are subdivided into several molecular subtypes. There is an ongoing debate over the cell of origin for these tumor types where some suggest a progenitor while others argue for a stem cell origin. Even within the same molecular subgroup, and using lineage tracing in mouse models, different groups have reached different conclusions. We addressed this problem from a combined mathematical modeling and experimental standpoint. We designed a novel mathematical framework to identify the most likely cells of origin of two glioma subtypes. Our mathematical model of the unperturbed in vivo system predicts that if a genetic event contributing to tumor initiation imparts symmetric self-renewing cell division (such as PDGF overexpression), then the cell of origin is a transit amplifier. Otherwise, the initiating mutations arise in stem cells. The mathematical framework was validated with the RCAS/tv-a system of somatic gene transfer in mice. We demonstrated that PDGF-induced gliomas can be derived from GFAP-expressing cells of the subventricular zone or the cortex (reactive astrocytes), thus validating the predictions of our mathematical model. This interdisciplinary approach allowed us to determine the likelihood that individual cell types serve as the cells of origin of gliomas in an unperturbed system

Loss of heterozygosity of TRIM3 in malignant gliomas

<p>Abstract</p> <p>Background</p> <p>Malignant gliomas are frequent primary brain tumors associated with poor prognosis and very limited response to conventional chemo- and radio-therapies. Besides sharing common growth features with other types of solid tumors, gliomas are highly invasive into adjacent brain tissue, which renders them particularly aggressive and their surgical resection inefficient. Therefore, insights into glioma formation are of fundamental interest in order to provide novel molecular targets for diagnostic purposes and potential anti-cancer drugs. Human <it>Tripartite motif protein 3 </it>(<it>TRIM3</it>) encodes a structural homolog of <it>Drosophila brain tumor </it>(<it>brat</it>) implicated in progenitor cell proliferation control and cancer stem cell suppression. <it>TRIM3 </it>is located within the loss of allelic heterozygosity (LOH) hotspot of chromosome segment 11p15.5, indicating a potential role in tumor suppression. ...</p> <p>Methods</p> <p>Here we analyze 70 primary human gliomas of all types and grades and report somatic deletion mapping as well as single nucleotide polymorphism analysis together with quantitative real-time PCR of chromosome segment 11p15.5.</p> <p>Results</p> <p>Our analysis identifies LOH in 17 cases (24%) of primary human glioma which defines a common 130 kb-wide interval within the <it>TRIM3 </it>locus as a minimal area of loss. We further detect altered genomic dosage of <it>TRIM3 </it>in two glioma cases with LOH at 11p15.5, indicating homozygous deletions of <it>TRIM3</it>.</p> <p>Conclusion</p> <p>Loss of heterozygosity of chromosome segment 11p15.5 in malignant gliomas suggests <it>TRIM3 </it>as a candidate brain tumor suppressor gene.</p

A Protective Role for ELR+ Chemokines during Acute Viral Encephalomyelitis

The functional role of ELR-positive CXC chemokines in host defense during acute viral-induced encephalomyelitis was determined. Inoculation of the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of mice resulted in the rapid mobilization of PMNs expressing the chemokine receptor CXCR2 into the blood. Migration of PMNs to the CNS coincided with increased expression of transcripts specific for the CXCR2 ELR-positive chemokine ligands CXCL1, CXCL2, and CXCL5 within the brain. Treatment of JHMV-infected mice with anti-CXCR2 blocking antibody reduced PMN trafficking into the CNS by >95%, dampened MMP-9 activity, and abrogated blood-brain-barrier (BBB) breakdown. Correspondingly, CXCR2 neutralization resulted in diminished infiltration of virus-specific T cells, an inability to control viral replication within the brain, and 100% mortality. Blocking CXCR2 signaling did not impair the generation of virus-specific T cells, indicating that CXCR2 is not required to tailor anti-JHMV T cell responses. Evaluation of mice in which CXCR2 is genetically silenced (CXCR2−/− mice) confirmed that PMNs neither expressed CXCR2 nor migrated in response to ligands CXCL1, CXCL2, or CXCL5 in an in vitro chemotaxis assay. Moreover, JHMV infection of CXCR2−/− mice resulted in an approximate 60% reduction of PMN migration into the CNS, yet these mice survived infection and controlled viral replication within the brain. Treatment of JHMV-infected CXCR2−/− mice with anti-CXCR2 antibody did not modulate PMN migration nor alter viral clearance or mortality, indicating the existence of compensatory mechanisms that facilitate sufficient migration of PMNs into the CNS in the absence of CXCR2. Collectively, these findings highlight a previously unappreciated role for ELR-positive chemokines in enhancing host defense during acute viral infections of the CNS

Calmodulin Activation by Calcium Transients in the Postsynaptic Density of Dendritic Spines

The entry of calcium into dendritic spines can trigger a sequence of biochemical reactions that begins with the activation of calmodulin (CaM) and ends with long-term changes to synaptic strengths. The degree of activation of CaM can depend on highly local elevations in the concentration of calcium and the duration of transient increases in calcium concentration. Accurate measurement of these local changes in calcium is difficult because the spaces are so small and the numbers of molecules are so low. We have therefore developed a Monte Carlo model of intracellular calcium dynamics within the spine that included calcium binding proteins, calcium transporters and ion channels activated by voltage and glutamate binding. The model reproduced optical recordings using calcium indicator dyes and showed that without the dye the free intracellular calcium concentration transient was much higher than predicted from the fluorescent signal. Excitatory postsynaptic potentials induced large, long-lasting calcium gradients across the postsynaptic density, which activated CaM. When glutamate was released at the synapse 10 ms before an action potential occurred, simulating activity patterns that strengthen hippocampal synapses, the calcium gradient and activation of CaM in the postsynaptic density were much greater than when the order was reversed, a condition that decreases synaptic strengths, suggesting a possible mechanism underlying the induction of long-term changes in synaptic strength. The spatial and temporal mechanisms for selectivity in CaM activation demonstrated here could be used in other signaling pathways