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1.
Cell ; 184(2): 323-333.e9, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33306959

RESUMO

The December 2019 outbreak of a novel respiratory virus, SARS-CoV-2, has become an ongoing global pandemic due in part to the challenge of identifying symptomatic, asymptomatic, and pre-symptomatic carriers of the virus. CRISPR diagnostics can augment gold-standard PCR-based testing if they can be made rapid, portable, and accurate. Here, we report the development of an amplification-free CRISPR-Cas13a assay for direct detection of SARS-CoV-2 from nasal swab RNA that can be read with a mobile phone microscope. The assay achieved ∼100 copies/µL sensitivity in under 30 min of measurement time and accurately detected pre-extracted RNA from a set of positive clinical samples in under 5 min. We combined crRNAs targeting SARS-CoV-2 RNA to improve sensitivity and specificity and directly quantified viral load using enzyme kinetics. Integrated with a reader device based on a mobile phone, this assay has the potential to enable rapid, low-cost, point-of-care screening for SARS-CoV-2.


Assuntos
Teste de Ácido Nucleico para COVID-19/métodos , Telefone Celular/instrumentação , Imagem Óptica/métodos , RNA Viral/análise , Carga Viral/métodos , Animais , Teste de Ácido Nucleico para COVID-19/economia , Teste de Ácido Nucleico para COVID-19/instrumentação , Sistemas CRISPR-Cas , Linhagem Celular , Proteínas do Nucleocapsídeo de Coronavírus/genética , Humanos , Nasofaringe/virologia , Imagem Óptica/instrumentação , Fosfoproteínas/genética , Testes Imediatos , Interferência de RNA , RNA Viral/genética , Sensibilidade e Especificidade , Carga Viral/economia , Carga Viral/instrumentação
2.
Cell ; 176(1-2): 281-294.e19, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30503209

RESUMO

Influenza viruses inhabit a wide range of host environments using a limited repertoire of protein components. Unlike viruses with stereotyped shapes, influenza produces virions with significant morphological variability even within clonal populations. Whether this tendency to form pleiomorphic virions is coupled to compositional heterogeneity and whether it affects replicative fitness remains unclear. Here, we address these questions by developing a strain of influenza A virus amenable to rapid compositional characterization through quantitative, site-specific labeling of viral proteins. Using this strain, we find that influenza A produces virions with broad variations in size and composition from even single infected cells. This phenotypic variability contributes to virus survival during environmental challenges, including exposure to antivirals. Complementing genetic adaptations that act over larger populations and longer times, this "low-fidelity" assembly of influenza A virus allows small populations to survive environments that fluctuate over individual replication cycles.


Assuntos
Vírus da Influenza A/metabolismo , Montagem de Vírus/fisiologia , Linhagem Celular , Células Cultivadas , Humanos , Vírus da Influenza A/fisiologia , Influenza Humana/virologia , Proteínas Virais , Vírion , Replicação Viral/fisiologia
3.
Cell ; 174(1): 131-142.e13, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29958103

RESUMO

Macrophages protect the body from damage and disease by targeting antibody-opsonized cells for phagocytosis. Though antibodies can be raised against antigens with diverse structures, shapes, and sizes, it is unclear why some are more effective at triggering immune responses than others. Here, we define an antigen height threshold that regulates phagocytosis of both engineered and cancer-specific antigens by macrophages. Using a reconstituted model of antibody-opsonized target cells, we find that phagocytosis is dramatically impaired for antigens that position antibodies >10 nm from the target surface. Decreasing antigen height drives segregation of antibody-bound Fc receptors from the inhibitory phosphatase CD45 in an integrin-independent manner, triggering Fc receptor phosphorylation and promoting phagocytosis. Our work shows that close contact between macrophage and target is a requirement for efficient phagocytosis, suggesting that therapeutic antibodies should target short antigens in order to trigger Fc receptor activation through size-dependent physical segregation.


Assuntos
Anticorpos Monoclonais/imunologia , Antígenos/química , Macrófagos/imunologia , Proteínas Opsonizantes/metabolismo , Fagocitose , Animais , Anticorpos Monoclonais/química , Antígenos/genética , Antígenos/imunologia , Antígeno Carcinoembrionário/química , Antígeno Carcinoembrionário/genética , Antígeno Carcinoembrionário/imunologia , Edição de Genes , Integrinas/metabolismo , Antígenos Comuns de Leucócito/química , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/imunologia , Macrófagos/citologia , Camundongos , Proteínas Opsonizantes/química , Fosforilação , Células RAW 264.7 , Receptores Fc/imunologia , Receptores Fc/metabolismo , Lipossomas Unilamelares/química
4.
Nat Rev Mol Cell Biol ; 21(12): 750-764, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33093672

RESUMO

Cell-cell interfaces are found throughout multicellular organisms, from transient interactions between motile immune cells to long-lived cell-cell contacts in epithelia. Studies of immune cell interactions, epithelial cell barriers, neuronal contacts and sites of cell-cell fusion have identified a core set of features shared by cell-cell interfaces that critically control their function. Data from diverse cell types also show that cells actively and passively regulate the localization, strength, duration and cytoskeletal coupling of receptor interactions governing cell-cell signalling and physical connections between cells, indicating that cell-cell interfaces have a unique membrane organization that emerges from local molecular and cellular mechanics. In this Review, we discuss recent findings that support the emerging view of cell-cell interfaces as specialized compartments that biophysically constrain the arrangement and activity of their protein, lipid and glycan components. We also review how these biophysical features of cell-cell interfaces allow cells to respond with high selectivity and sensitivity to multiple inputs, serving as the basis for wide-ranging cellular functions. Finally, we consider how the unique properties of cell-cell interfaces present opportunities for therapeutic intervention.


Assuntos
Comunicação Celular/fisiologia , Compartimento Celular/fisiologia , Fenômenos Fisiológicos Celulares/fisiologia , Animais , Fusão Celular , Células Epiteliais/citologia , Células Epiteliais/fisiologia , Humanos , Mecanotransdução Celular/fisiologia , Neurônios/citologia , Neurônios/fisiologia
5.
Cell ; 164(1-2): 115-127, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26771487

RESUMO

Branched actin networks--created by the Arp2/3 complex, capping protein, and a nucleation promoting factor--generate and transmit forces required for many cellular processes, but their response to force is poorly understood. To address this, we assembled branched actin networks in vitro from purified components and used simultaneous fluorescence and atomic force microscopy to quantify their molecular composition and material properties under various forces. Remarkably, mechanical loading of these self-assembling materials increases their density, power, and efficiency. Microscopically, increased density reflects increased filament number and altered geometry but no change in average length. Macroscopically, increased density enhances network stiffness and resistance to mechanical failure beyond those of isotropic actin networks. These effects endow branched actin networks with memory of their mechanical history that shapes their material properties and motor activity. This work reveals intrinsic force feedback mechanisms by which mechanical resistance makes self-assembling actin networks stiffer, stronger, and more powerful.


Assuntos
Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Actinas/química , Actinas/metabolismo , Fenômenos Biomecânicos , Humanos , Microscopia de Força Atômica , Microscopia de Fluorescência , Termodinâmica , Família de Proteínas da Síndrome de Wiskott-Aldrich/química , Família de Proteínas da Síndrome de Wiskott-Aldrich/metabolismo
6.
Cell ; 180(1): 205, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31923395
7.
Cell ; 176(3): 678, 2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30682375
8.
Nature ; 614(7946): 144-152, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36509107

RESUMO

Cell adhesion molecules are ubiquitous in multicellular organisms, specifying precise cell-cell interactions in processes as diverse as tissue development, immune cell trafficking and the wiring of the nervous system1-4. Here we show that a wide array of synthetic cell adhesion molecules can be generated by combining orthogonal extracellular interactions with intracellular domains from native adhesion molecules, such as cadherins and integrins. The resulting molecules yield customized cell-cell interactions with adhesion properties that are similar to native interactions. The identity of the intracellular domain of the synthetic cell adhesion molecules specifies interface morphology and mechanics, whereas diverse homotypic or heterotypic extracellular interaction domains independently specify the connectivity between cells. This toolkit of orthogonal adhesion molecules enables the rationally programmed assembly of multicellular architectures, as well as systematic remodelling of native tissues. The modularity of synthetic cell adhesion molecules provides fundamental insights into how distinct classes of cell-cell interfaces may have evolved. Overall, these tools offer powerful abilities for cell and tissue engineering and for systematically studying multicellular organization.


Assuntos
Moléculas de Adesão Celular , Comunicação Celular , Biologia Sintética , Caderinas/química , Adesão Celular , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/metabolismo , Integrinas/química , Biologia Sintética/métodos , Domínios Proteicos , Sítios de Ligação , Engenharia Celular
9.
Physiol Rev ; 100(2): 695-724, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31751165

RESUMO

Physical stimuli are essential for the function of eukaryotic cells, and changes in physical signals are important elements in normal tissue development as well as in disease initiation and progression. The complexity of physical stimuli and the cellular signals they initiate are as complex as those triggered by chemical signals. One of the most important, and the focus of this review, is the effect of substrate mechanical properties on cell structure and function. The past decade has produced a nearly exponentially increasing number of mechanobiological studies to define how substrate stiffness alters cell biology using both purified systems and intact tissues. Here we attempt to identify common features of mechanosensing in different systems while also highlighting the numerous informative exceptions to what in early studies appeared to be simple rules by which cells respond to mechanical stresses.


Assuntos
Microambiente Celular , Mecanotransdução Celular , Animais , Diferenciação Celular , Movimento Celular , Proliferação de Células , Forma Celular , Elasticidade , Humanos , Viscosidade
10.
Proc Natl Acad Sci U S A ; 120(21): e2219778120, 2023 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-37186825

RESUMO

Cells mediate interactions with the extracellular environment through a crowded assembly of transmembrane proteins, glycoproteins and glycolipids on their plasma membrane. The extent to which surface crowding modulates the biophysical interactions of ligands, receptors, and other macromolecules is poorly understood due to the lack of methods to quantify surface crowding on native cell membranes. In this work, we demonstrate that physical crowding on reconstituted membranes and live cell surfaces attenuates the effective binding affinity of macromolecules such as IgG antibodies in a surface crowding-dependent manner. We combine experiment and simulation to design a crowding sensor based on this principle that provides a quantitative readout of cell surface crowding. Our measurements reveal that surface crowding decreases IgG antibody binding by 2 to 20 fold in live cells compared to a bare membrane surface. Our sensors show that sialic acid, a negatively charged monosaccharide, contributes disproportionately to red blood cell surface crowding via electrostatic repulsion, despite occupying only ~1% of the total cell membrane by mass. We also observe significant differences in surface crowding for different cell types and find that expression of single oncogenes can both increase and decrease crowding, suggesting that surface crowding may be an indicator of both cell type and state. Our high-throughput, single-cell measurement of cell surface crowding may be combined with functional assays to enable further biophysical dissection of the cell surfaceome.


Assuntos
Eritrócitos , Proteínas de Membrana , Membrana Celular/metabolismo , Proteínas de Membrana/metabolismo , Substâncias Macromoleculares/metabolismo , Eritrócitos/metabolismo
12.
Annu Rev Phys Chem ; 74: 1-27, 2023 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-36719975

RESUMO

Phillip L. Geissler made important contributions to the statistical mechanics of biological polymers, heterogeneous materials, and chemical dynamics in aqueous environments. He devised analytical and computational methods that revealed the underlying organization of complex systems at the frontiers of biology, chemistry, and materials science. In this retrospective we celebrate his work at these frontiers.


Assuntos
Física , Masculino , Humanos , Estudos Retrospectivos , Físico-Química
13.
Proc Natl Acad Sci U S A ; 118(1)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33443166

RESUMO

Fusion-associated small transmembrane (FAST) proteins are a diverse family of nonstructural viral proteins. Once expressed on the plasma membrane of infected cells, they drive fusion with neighboring cells, increasing viral spread and pathogenicity. Unlike viral fusogens with tall ectodomains that pull two membranes together through conformational changes, FAST proteins have short fusogenic ectodomains that cannot bridge the intermembrane gap between neighboring cells. One orthoreovirus FAST protein, p14, has been shown to hijack the actin cytoskeleton to drive cell-cell fusion, but the actin adaptor-binding motif identified in p14 is not found in any other FAST protein. Here, we report that an evolutionarily divergent FAST protein, p22 from aquareovirus, also hijacks the actin cytoskeleton but does so through different adaptor proteins, Intersectin-1 and Cdc42, that trigger N-WASP-mediated branched actin assembly. We show that despite using different pathways, the cytoplasmic tail of p22 can replace that of p14 to create a potent chimeric fusogen, suggesting they are modular and play similar functional roles. When we directly couple p22 with the parallel filament nucleator formin instead of the branched actin nucleation promoting factor N-WASP, its ability to drive fusion is maintained, suggesting that localized mechanical pressure on the plasma membrane coupled to a membrane-disruptive ectodomain is sufficient to drive cell-cell fusion. This work points to a common biophysical strategy used by FAST proteins to push rather than pull membranes together to drive fusion, one that may be harnessed by other short fusogens responsible for physiological cell-cell fusion.


Assuntos
Actinas/metabolismo , Proteínas de Fusão de Membrana/metabolismo , Fusão de Membrana/fisiologia , Citoesqueleto de Actina/metabolismo , Sequência de Aminoácidos/genética , Animais , Evolução Biológica , Fusão Celular/métodos , Linhagem Celular , Membrana Celular/metabolismo , Citoesqueleto/metabolismo , Evolução Molecular , Humanos , Orthoreovirus/genética , Ligação Proteica/genética , Reoviridae/genética , Proteínas Virais de Fusão/química , Proteínas Virais de Fusão/metabolismo , Proteínas não Estruturais Virais/metabolismo , Internalização do Vírus
14.
Nat Chem Biol ; 17(9): 982-988, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34354262

RESUMO

Direct, amplification-free detection of RNA has the potential to transform molecular diagnostics by enabling simple on-site analysis of human or environmental samples. CRISPR-Cas nucleases offer programmable RNA-guided RNA recognition that triggers cleavage and release of a fluorescent reporter molecule, but long reaction times hamper their detection sensitivity and speed. Here, we show that unrelated CRISPR nucleases can be deployed in tandem to provide both direct RNA sensing and rapid signal generation, thus enabling robust detection of ~30 molecules per µl of RNA in 20 min. Combining RNA-guided Cas13 and Csm6 with a chemically stabilized activator creates a one-step assay that can detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA extracted from respiratory swab samples with quantitative reverse transcriptase PCR (qRT-PCR)-derived cycle threshold (Ct) values up to 33, using a compact detector. This Fast Integrated Nuclease Detection In Tandem (FIND-IT) approach enables sensitive, direct RNA detection in a format that is amenable to point-of-care infection diagnosis as well as to a wide range of other diagnostic or research applications.


Assuntos
COVID-19/genética , Sistemas CRISPR-Cas/genética , RNA Viral/genética , SARS-CoV-2/genética , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
15.
Proc Natl Acad Sci U S A ; 117(25): 14209-14219, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513731

RESUMO

The physical dimensions of proteins and glycans on cell surfaces can critically affect cell function, for example, by preventing close contact between cells and limiting receptor accessibility. However, high-resolution measurements of molecular heights on native cell membranes have been difficult to obtain. Here we present a simple and rapid method that achieves nanometer height resolution by localizing fluorophores at the tip and base of cell surface molecules and determining their separation by radially averaging across many molecules. We use this method, which we call cell surface optical profilometry (CSOP), to quantify the height of key multidomain proteins on a model cell, as well as to capture average protein and glycan heights on native cell membranes. We show that average height of a protein is significantly smaller than its contour length, due to thermally driven bending and rotation on the membrane, and that height strongly depends on local surface and solution conditions. We find that average height increases with cell surface molecular crowding but decreases with solution crowding by solutes, both of which we confirm with molecular dynamics simulations. We also use experiments and simulations to determine the height of an epitope, based on the location of an antibody, which allows CSOP to profile various proteins and glycans on a native cell surface using antibodies and lectins. This versatile method for profiling cell surfaces has the potential to advance understanding of the molecular landscape of cells and the role of the molecular landscape in cell function.


Assuntos
Membrana Celular/química , Proteínas de Membrana/química , Polissacarídeos/química , Anticorpos , Linhagem Celular , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Epitopos , Imunofluorescência , Células HEK293 , Humanos , Lectinas , Bicamadas Lipídicas , Proteínas de Membrana/ultraestrutura , Modelos Moleculares , Polissacarídeos/metabolismo , Domínios Proteicos
16.
Proc Natl Acad Sci U S A ; 117(13): 7208-7215, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32188784

RESUMO

The plasticity of naturally occurring protein structures, which can change shape considerably in response to changes in environmental conditions, is critical to biological function. While computational methods have been used for de novo design of proteins that fold to a single state with a deep free-energy minimum [P.-S. Huang, S. E. Boyken, D. Baker, Nature 537, 320-327 (2016)], and to reengineer natural proteins to alter their dynamics [J. A. Davey, A. M. Damry, N. K. Goto, R. A. Chica, Nat. Chem. Biol. 13, 1280-1285 (2017)] or fold [P. A. Alexander, Y. He, Y. Chen, J. Orban, P. N. Bryan, Proc. Natl. Acad. Sci. U.S.A. 106, 21149-21154 (2009)], the de novo design of closely related sequences which adopt well-defined but structurally divergent structures remains an outstanding challenge. We designed closely related sequences (over 94% identity) that can adopt two very different homotrimeric helical bundle conformations-one short (∼66 Šheight) and the other long (∼100 Šheight)-reminiscent of the conformational transition of viral fusion proteins. Crystallographic and NMR spectroscopic characterization shows that both the short- and long-state sequences fold as designed. We sought to design bistable sequences for which both states are accessible, and obtained a single designed protein sequence that populates either the short state or the long state depending on the measurement conditions. The design of sequences which are poised to adopt two very different conformations sets the stage for creating large-scale conformational switches between structurally divergent forms.


Assuntos
Biologia Computacional/métodos , Proteínas/química , Sequência de Aminoácidos/genética , Aminoácidos/química , Conformação Molecular , Conformação Proteica , Engenharia de Proteínas/métodos , Dobramento de Proteína
17.
Proc Natl Acad Sci U S A ; 117(22): 12452-12463, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32404426

RESUMO

Plastid isoprenoid-derived carotenoids serve essential roles in chloroplast development and photosynthesis. Although nearly all enzymes that participate in the biosynthesis of carotenoids in plants have been identified, the complement of auxiliary proteins that regulate synthesis, transport, sequestration, and degradation of these molecules and their isoprenoid precursors have not been fully described. To identify such proteins that are necessary for the optimal functioning of oxygenic photosynthesis, we screened a large collection of nonphotosynthetic (acetate-requiring) DNA insertional mutants of Chlamydomonas reinhardtii and isolated cpsfl1 The cpsfl1 mutant is extremely light-sensitive and susceptible to photoinhibition and photobleaching. The CPSFL1 gene encodes a CRAL-TRIO hydrophobic ligand-binding (Sec14) domain protein. Proteins containing this domain are limited to eukaryotes, but some may have been retargeted to function in organelles of endosymbiotic origin. The cpsfl1 mutant showed decreased accumulation of plastidial isoprenoid-derived pigments, especially carotenoids, and whole-cell focused ion-beam scanning-electron microscopy revealed a deficiency of carotenoid-rich chloroplast structures (e.g., eyespot and plastoglobules). The low carotenoid content resulted from impaired biosynthesis at a step prior to phytoene, the committed precursor to carotenoids. The CPSFL1 protein bound phytoene and ß-carotene when expressed in Escherichia coli and phosphatidic acid in vitro. We suggest that CPSFL1 is involved in the regulation of phytoene synthesis and carotenoid transport and thereby modulates carotenoid accumulation in the chloroplast.


Assuntos
Carotenoides/metabolismo , Chlamydomonas reinhardtii/crescimento & desenvolvimento , Cloroplastos/metabolismo , Proteínas de Plantas/metabolismo , Chlamydomonas reinhardtii/classificação , Chlamydomonas reinhardtii/genética , Chlamydomonas reinhardtii/metabolismo , Cloroplastos/química , Cloroplastos/genética , Fotossíntese , Filogenia , Proteínas de Plantas/química , Proteínas de Plantas/genética , Domínios Proteicos
18.
EMBO J ; 37(1): 102-121, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29141912

RESUMO

WASP-family proteins are known to promote assembly of branched actin networks by stimulating the filament-nucleating activity of the Arp2/3 complex. Here, we show that WASP-family proteins also function as polymerases that accelerate elongation of uncapped actin filaments. When clustered on a surface, WASP-family proteins can drive branched actin networks to grow much faster than they could by direct incorporation of soluble monomers. This polymerase activity arises from the coordinated action of two regulatory sequences: (i) a WASP homology 2 (WH2) domain that binds actin, and (ii) a proline-rich sequence that binds profilin-actin complexes. In the absence of profilin, WH2 domains are sufficient to accelerate filament elongation, but in the presence of profilin, proline-rich sequences are required to support polymerase activity by (i) bringing polymerization-competent actin monomers in proximity to growing filament ends, and (ii) promoting shuttling of actin monomers from profilin-actin complexes onto nearby WH2 domains. Unoccupied WH2 domains transiently associate with free filament ends, preventing their growth and dynamically tethering the branched actin network to the WASP-family proteins that create it. Collaboration between WH2 and proline-rich sequences thus strikes a balance between filament growth and tethering. Our work expands the number of critical roles that WASP-family proteins play in the assembly of branched actin networks to at least three: (i) promoting dendritic nucleation; (ii) linking actin networks to membranes; and (iii) accelerating filament elongation.


Assuntos
Citoesqueleto de Actina/fisiologia , Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Domínios Proteicos Ricos em Prolina , Família de Proteínas da Síndrome de Wiskott-Aldrich/metabolismo , Humanos , Ligação Proteica
19.
Clin Infect Dis ; 72(12): e1047-e1055, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33289025

RESUMO

BACKGROUND: Mass drug administration (MDA) with ivermectin is the main strategy for onchocerciasis elimination. Ivermectin is generally safe, but is associated with serious adverse events in individuals with high Loa loa microfilarial densities (MFD). Therefore, ivermectin MDA is not recommended in areas where onchocerciasis is hypo-endemic and L loa is co-endemic. To eliminate onchocerciasis in those areas, a test-and-not-treat (TaNT) strategy has been proposed. We investigated whether onchocerciasis elimination can be achieved using TaNT and the required duration. METHODS: We used the individual-based model ONCHOSIM to predict the impact of TaNT on onchocerciasis microfilarial (mf) prevalence. We simulated precontrol mf prevalence levels from 2% to 40%. The impact of TaNT was simulated under varying levels of participation, systematic nonparticipation, and exclusion from ivermectin resulting from high L loa MFD. For each scenario, we assessed the time to elimination, defined as bringing onchocerciasis mf prevalence below 1.4%. RESULTS: In areas with 30% to 40% precontrol mf prevalence, the model predicted that it would take between 14 and 16 years to bring the mf prevalence below 1.4% using conventional MDA, assuming 65% participation. TaNT would increase the time to elimination by up to 1.5 years, depending on the level of systematic nonparticipation and the exclusion rate. At lower exclusion rates (≤2.5%), the delay would be less than 6 months. CONCLUSIONS: Our model predicts that onchocerciasis can be eliminated using TaNT in L loa co-endemic areas. The required treatment duration using TaNT would be only slightly longer than in areas with conventional MDA, provided that participation is good.


Assuntos
Loíase , Oncocercose , Animais , Estudos de Viabilidade , Humanos , Ivermectina/uso terapêutico , Loa , Loíase/diagnóstico , Loíase/tratamento farmacológico , Loíase/epidemiologia , Oncocercose/tratamento farmacológico , Oncocercose/epidemiologia , Oncocercose/prevenção & controle , Prevalência
20.
Nat Rev Mol Cell Biol ; 10(9): 644-50, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19672276

RESUMO

We are much better at taking cells apart than putting them together. Reconstitution of biological processes from component molecules has been a powerful but difficult approach to studying functional organization in biology. Recently, the convergence of biochemical and cell biological advances with new experimental and computational tools is providing the opportunity to reconstitute increasingly complex processes. We predict that this bottom-up strategy will uncover basic processes that guide cellular assembly, advancing both basic and applied sciences.


Assuntos
Fenômenos Fisiológicos Celulares/fisiologia , Modelos Biológicos , Biologia de Sistemas , Animais , Simulação por Computador , Humanos
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