A remote secondary binding pocket promotes heteromultivalent targeting of DC-SIGN

Dendritic cells (DC) are antigen-presenting cells coordinating the interplay of the innate and the adaptive immune response. The endocytic C-type lectin receptors DC-SIGN and Langerin display expression profiles restricted to distinct DC subtypes and have emerged as prime targets for next-generation immunotherapies and anti-infectives. Using heteromultivalent liposomes copresenting mannosides bearing aromatic aglycones with natural glycan ligands, we serendipitously discovered striking cooperativity effects for DC-SIGN+ but not for Langerin+ cell lines. Mechanistic investigations combining NMR spectroscopy with molecular docking and molecular dynamics simulations led to the identification of a secondary binding pocket for the glycomimetics. This pocket, located remotely of DC-SIGN’s carbohydrate bindings site, can be leveraged by heteromultivalent avidity enhancement. We further present preliminary evidence that the aglycone allosterically activates glycan recognition and thereby contributes to DC-SIGN-specific cell targeting. Our findings have important implications for both translational and basic glycoscience, showcasing heteromultivalent targeting of DCs to improve specificity and supporting potential allosteric regulation of DC-SIGN and CLRs in general

Geração de índices de vegetação diários em uma pastagem.

Os índices de vegetação são importantes ferramentas para a agricultura de precisão (AP), que fornecem informações para a tomada de decisão de manejo das culturas. Os espectros de luz refletidos pelo dossel de cada cultura podem fornecer informações sobre produção de biomassa, qualidade e da ocorrência de estresses bióticos e abióticos

Soluble NgR Fusion Protein Modulates the Proliferation of Neural Progenitor Cells via the Notch Pathway

NogoA, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein are CNS myelin molecules that bind to the neuronal Nogo-66 receptor (NgR) and inhibit axon growth. The NgR antagonist, soluble NgR1-Fc protein (sNgR-Fc), facilitates axon regeneration by neutralizing the inhibitory effects of myelin proteins in experimental models of CNS injury. Here we aim to investigate the effect of sNgR-Fc on the proliferation of neural progenitor cells (NPCs). The hippocampus cells of embryonic rats were isolated and cultured in vitro. The expression of nestin, βIII-Tubulin, GFAP and Nogo-A on these cells was observed using immunocytochemistry. In order to investigate the effect on proliferation of NPCs, sNgR-Fc, MAG-Fc chimera and Notch1 blocker were added respectively. The total cell number for the proliferated NPCs was counted. BrdU was applied and the rate of proliferating cells was examined. The level of Notch1 was analyzed using Western blotting. We identified that NogoA is expressed in NPCs. sNgR-Fc significantly enhanced the proliferation of NPCs in vitro as indicated by BrdU labeling and total cell count. This proliferation effect was abolished by the administration of MAG suggesting specificity. In addition, we demonstrate that sNgR-Fc is a potent activator for Notch1 and Notch1 antagonist reversed the effect of sNgR-Fc on NPC proliferation. Our results suggest that sNgR-Fc may modulate Nogo activity to induce NPC proliferation via the Notch pathway

Sortilin Participates in Light-dependent Photoreceptor Degeneration in Vivo

Both proNGF and the neurotrophin receptor p75 (p75NTR) are known to regulate photoreceptor cell death caused by exposure of albino mice to intense illumination. ProNGF-induced apoptosis requires the participation of sortilin as a necessary p75NTR co-receptor, suggesting that sortilin may participate in the photoreceptor degeneration triggered by intense lighting. We report here that light-exposed albino mice showed sortilin, p75NTR, and proNGF expression in the outer nuclear layer, the retinal layer where photoreceptor cell bodies are located. In addition, cone progenitor-derived 661W cells subjected to intense illumination expressed sortilin and p75NTR and released proNGF into the culture medium. Pharmacological blockade of sortilin with either neurotensin or the “pro” domain of proNGF (pro-peptide) favored the survival of 661W cells subjected to intense light. In vivo, the pro-peptide attenuated retinal cell death in light-exposed albino mice. We propose that an auto/paracrine proapoptotic mechanism based on the interaction of proNGF with the receptor complex p75NTR/sortilin participates in intense light-dependent photoreceptor cell death. We therefore propose sortilin as a putative target for intervention in hereditary retinal dystrophies

Developmentally Regulated Impediments to Skin Reinnervation by Injured Peripheral Sensory Axon Terminals

SummaryThe structural plasticity of neurites in the central nervous system (CNS) diminishes dramatically after initial development, but the peripheral nervous system (PNS) retains substantial plasticity into adulthood. Nevertheless, functional reinnervation by injured peripheral sensory neurons is often incomplete [1–6]. To investigate the developmental control of skin reinnervation, we imaged the regeneration of trigeminal sensory axon terminals in live zebrafish larvae following laser axotomy. When axons were injured during early stages of outgrowth, regenerating and uninjured axons grew into denervated skin and competed with one another for territory. At later stages, after the establishment of peripheral arbor territories, the ability of uninjured neighbors to sprout diminished severely, and although injured axons reinitiated growth, they were repelled by denervated skin. Regenerating axons were repelled specifically by their former territories, suggesting that local inhibitory factors persist in these regions. Antagonizing the function of several members of the Nogo receptor (NgR)/RhoA pathway improved the capacity of injured axons to grow into denervated skin. Thus, as in the CNS, impediments to reinnervation in the PNS arise after initial establishment of axon arbor structure

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Efeitos de ensino envolvendo equivalência entre palavra ditada, palavra escrita e objeto sobre a inteligibilidade da fala em adolescente com hipoplasia cerebelar

Dentre as muitas estruturas cerebrais envolvidas na linguagem, o ceberelo cumpre um papel importante na coordenação dos movimentos responsáveis pela fala, de modo que qualquer alteração nesta estrutura pode comprometer o desenvolvimento da linguagem oral. Considerando o planejamento do ensino e as intervenções enquanto um fator que pode alterar as expressões fenotípicas impostas pela hipoplasia cerebelar, este estudo de caso teve como objetivo verificar os efeitos de um programa de ensino (envolvendo equivalência entre palavra ditada, palavra escrita e objeto) sobre a inteligibilidade da fala de um adolescente com doze anos, gênero masculino, com hipoplasia cerebelar. As sessões foram conduzidas em contexto clínico e com uso de brinquedos de preferência do participante. O programa consistiu em etapas de avaliação, ensino, pós-testes e retenção, no qual eram apresentadas tarefas de seleção, vocalização, escrita e composição de palavras. Durante a avaliação, observou-se um baixo desempenho em todas as tarefas, especialmente na nomeação de objetos; no decorrer do ensino, as vocalizações foram monitoradas, constatando-se uma gradativa melhora na inteligibilidade da fala quando o participante nomeava objetos, chegando à precisão no pós-testes e retenção. Pode-se concluir que, para o caso apresentado, o fortalecimento da rede de relações entre estímulos e estímulos-ações verbais promovido pelo programa de ensino, favoreceu melhorias na inteligibilidade da fala