Alterations in the composition of the intestinal microbiota have been correlated with aging and measures of frailty in the elderly. However, the relationships between microbial dynamics, age-related ...changes in intestinal physiology, and organismal health remain poorly understood. Here, we show that dysbiosis of the intestinal microbiota, characterized by an expansion of the Gammaproteobacteria, is tightly linked to age-onset intestinal barrier dysfunction in Drosophila. Indeed, alterations in the microbiota precede and predict the onset of intestinal barrier dysfunction in aged flies. Changes in microbial composition occurring prior to intestinal barrier dysfunction contribute to changes in excretory function and immune gene activation in the aging intestine. In addition, we show that a distinct shift in microbiota composition follows intestinal barrier dysfunction, leading to systemic immune activation and organismal death. Our results indicate that alterations in microbiota dynamics could contribute to and also predict varying rates of health decline during aging in mammals.
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•Age-related dysbiosis in Drosophila is characterized by Gammaproteobacteria expansion•Dysbiosis predicts age-onset intestinal barrier dysfunction and rapid health decline•Age-related dysbiosis drives changes in excretory function•Loss of commensal control following intestinal barrier dysfunction drives mortality
The relationship between microbiota dynamics and age-related changes in organismal health are poorly understood. Using Drosophila, Clark et al. show that dysbiosis of the intestinal microbiota precedes and predicts age-related intestinal barrier dysfunction. Age-related alterations in the microbiota contribute to intestinal immune activation, modulate excretory function, and ultimately lead to mortality.
We demonstrate efficient generation of correlated photon pairs by spontaneous four wave mixing in a 5 μm radius silicon ring resonator in the telecom band around 1550 nm. By optically pumping our ...device with a 200 μW continuous wave laser, we obtain a pair generation rate of 0.2 MHz and demonstrate photon time correlations with a coincidence-to-accidental ratio as high as 250. The results are in good agreement with theoretical predictions and show the potential of silicon micro-ring resonators as room temperature sources for integrated quantum optics applications.
The ability to rapidly switch between orbital angular momentum modes of light has important implications for future classical and quantum systems. In general, orbital angular momentum beams are ...generated using free-space bulk optical components where the fastest reconfiguration of such systems is around a millisecond using spatial light modulators. In this work, an extremely compact optical vortex emitter is demonstrated with the ability to actively tune between different orbital angular momentum modes. The emitter is tuned using a single electrically contacted thermo-optical control, maintaining device simplicity and micron scale footprint. On-off keying and orbital angular momentum mode switching are achieved at rates of 10 μs and 20 μs respectively.
A transfer printing (TP) method is presented for the micro-assembly of integrated photonic devices from suspended membrane components. Ultra thin membranes with thickness of 150nm are directly ...printed without the use of mechanical support and adhesion layers. By using a correlation alignment scheme vertical integration of single-mode silicon waveguides is achieved with an average placement accuracy of 100±70nm. Silicon (Si) μ-ring resonators are also fabricated and show controllable optical coupling by varying the lateral absolute position to an underlying Si bus waveguide.
X-linked hyper-immunoglobulin M (hyper-IgM) syndrome (XHIM) is a primary immunodeficiency due to mutations in CD40 ligand that affect immunoglobulin class-switch recombination and somatic ...hypermutation. The disease is amenable to gene therapy using retroviral vectors, but dysregulated gene expression results in abnormal lymphoproliferation in mouse models, highlighting the need for alternative strategies. Here, we demonstrate the ability of both the transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) platforms to efficiently drive integration of a normal copy of the CD40L cDNA delivered by Adeno-Associated Virus. Site-specific insertion of the donor sequence downstream of the endogenous CD40L promoter maintained physiologic expression of CD40L while overriding all reported downstream mutations. High levels of gene modification were achieved in primary human hematopoietic stem cells (HSCs), as well as in cell lines and XHIM-patient-derived T cells. Notably, gene-corrected HSCs engrafted in immunodeficient mice at clinically relevant frequencies. These studies provide the foundation for a permanent curative therapy in XHIM.
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•TALENs and CRISPRs allow targeted gene insertion at CD40LG in hematopoietic stem cells•Adenoviral helper proteins augment rates of gene modification in vitro, but not in vivo•Gene-modified HSCs engraft in mice at clinically relevant frequencies
Kuo et al. demonstrate that both TALEN and CRISPR/Cas9 platforms combined with a corrective AAV donor can mediate site-specific gene editing at the CD40 ligand locus. High levels of gene modification were achieved in human hematopoietic stem cells, which engraft in immunodeficient mice at clinically relevant frequencies.
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