The evolution of antibiotic resistance among bacteria threatens our continued ability to treat infectious diseases. The need for sustainable strategies to cure bacterial infections has never been greater. So far, all attempts to restore susceptibility after resistance has arisen have been unsuccessful, including restrictions on prescribing [1] and antibiotic cycling [2], [3]. Part of the problem may be that those efforts have implemented different classes of unrelated antibiotics, and relied on removal of resistance by random loss of resistance genes from bacterial populations (drift). Here, we show that alternating structurally similar antibiotics can restore susceptibility to antibiotics after resistance has evolved. We found that the resistance phenotypes conferred by variant alleles of the resistance gene encoding the TEM β-lactamase (bla TEM) varied greatly among 15 different β-lactam antibiotics. We captured those differences by characterizing complete adaptive landscapes for the resistance alleles bla TEM-50 and bla TEM-85, each of which differs from its ancestor bla TEM-1 by four mutations. We identified pathways through those landscapes where selection for increased resistance moved in a repeating cycle among a limited set of alleles as antibiotics were alternated. Our results showed that susceptibility to antibiotics can be sustainably renewed by cycling structurally similar antibiotics. We anticipate that these results may provide a conceptual framework for managing antibiotic resistance. This approach may also guide sustainable cycling of the drugs used to treat malaria and HIV.

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We report on multimodal coherent anti-Stokes Raman scattering ͑CARS͒ imaging with a source composed of a femtosecond fiber laser and a photonic crystal fiber ͑PCF͒-based optical parametric oscillator ͑FOPO͒. By switching between two PCFs with different zero dispersion wavelengths, a tunable signal beam from the FOPO covering the range from 840 to 930 nm was produced. By combining the femtosecond fiber laser and the FOPO output, simultaneous CARS imaging of a myelin sheath and two-photon excitation fluorescence imaging of a labeled axons in rat spinal cord have been demonstrated at the speed of 20 s per pixel.

Agradecimentos Ao Prof. Bremer pelas oportunidades e orientação. Ao Prof. Rozenfeld pela amizade e conselhos, ao Prof. João Fernando pelo exemplo de bom humor e de como tratar as pessoas e ao Prof. Silvio Pires pela atenção e conversa sobre algumas dúvidas conceituais. À Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) pela bolsa concedida. À todo o pessoal do Núcleo de Manufatura Avançada (NUMA) pelo convívio e troca de experiências. Em especial àqueles que participaram diretamente na realização deste trabalho (fosse dando sugestões, revendo o texto ou apenas escutando as minhas dúvidas e explicações

We explore the spectral effects due to cross-phase modulation and walk-off in picosecond fiber optical parametric oscillators. The output spectrum exhibits pump-power-dependent broadening, which can be quite asymmetric associated with a redshift or a blueshift depending on pump synchronization. By slightly increasing the cavity length, one obtains a blueshifted spectrum and a conversion efficiency as high as 15%.