Integrating Viral and Nonviral Vectors for Cystic Fibrosis Gene Therapy in the Airways

An important goal for cystic fibrosis (CF) gene therapy is to achieve long-term functional correction. While many vector options have been evaluated, integrating vectors have the greatest potential to maintain stable expression over time without a requirement for repeated administration. In this chapter, we discuss the importance of correcting the appropriate cell types, options for integrating vectors, animal models for CF gene therapy, and clinically relevant endpoint measurements. Lentiviral vectors are a promising option for CF gene therapy, as they integrate into the host genome and persistently express a transgene of interest. Airway cell tropism can be conferred by pseudotyping. Nonviral vectors such as DNA transposons can also integrate into the genome. Recent advances in hybrid viral/transposon vector technology improve the ability to deliver transposons to the airways in vivo. Integrating vector technology and new animal models have allowed considerable progress toward the goal of using gene therapy to correct life-long genetic diseases such as CF

Gene therapy potential for genetic disorders of surfactant dysfunction

Pulmonary surfactant is critically important to prevent atelectasis by lowering the surface tension of the alveolar lining liquid. While respiratory distress syndrome (RDS) is common in premature infants, severe RDS in term and late preterm infants suggests an underlying genetic etiology. Pathogenic variants in the genes encoding key components of pulmonary surfactant including surfactant protein B (SP-B

In vivo tomographic imaging based on bioluminescence

The most important task for bioluminescence imaging is to identify the emission source from the captured bioluminescent signal on the surface of a small tested animal. Quantitative information on the source location, geometry and intensity serves for in-vivo monitoring of infectious diseases, tumor growth, metastases in the small animal. In this paper, we present a point-spread function-based method for reconstructing the internal bioluminescent source from the surface light output flux signal. The method is evaluated for sensing the internal emission sources in nylon phantoms and within a live mouse. The surface bioluminescent signal is taken with a highly sensitive CCD camera. The results show the feasibility and efficiency of the proposed point-spread function-based method

Ferret and Pig Models of Cystic Fibrosis: Prospects and Promise for Gene Therapy

Large animal models of genetic diseases are rapidly becoming integral to biomedical research as technologies to manipulate the mammalian genome improve. The creation of cystic fibrosis (CF) ferrets and pigs is an example of such progress in animal modeling, with the disease phenotypes in the ferret and pig models more reflective of human CF disease than mouse models. The ferret and pig CF models also provide unique opportunities to develop and assess the effectiveness of gene and cell therapies to treat affected organs. In this review, we examine the organ disease phenotypes in these new CF models and the opportunities to test gene therapies at various stages of disease progression in affected organs. We then discuss the progress in developing recombinant replication-defective adenoviral, adeno-associated viral, and lentiviral vectors to target genes to the lung and pancreas in ferrets and pigs, the two most affected organs in CF. Through this review, we hope to convey the potential of these new animal models for developing CF gene and cell therapies

Capital inflows, crisis and recovery in small open economies

We compare two small open economics, Iceland and Ireland, that experienced a capital inflow through their banking systems in the period preceding the 2008 financial crises but differ in their currency arrangements. Both countries have mostly recovered from their respective crises, but the differences in the way their economies adjusted are interesting. The evidence suggests that changes in the real exchange rate served as the adjusting mechanism for Iceland’s current account while in Ireland domestic demand compression served as the main adjustment mechanism. We also explore the adjustment to the crisis in three other Eurozone economies and find that they were similar to the one in Ireland

In vivo tomographic imaging based on bioluminescence

The most important task for bioluminescence imaging is to identify the emission source from the captured bioluminescent signal on the surface of a small tested animal. Quantitative information on the source location, geometry and intensity serves for in-vivo monitoring of infectious diseases, tumor growth, metastases in the small animal. In this paper, we present a point-spread function-based method for reconstructing the internal bioluminescent source from the surface light output flux signal. The method is evaluated for sensing the internal emission sources in nylon phantoms and within a live mouse. The surface bioluminescent signal is taken with a highly sensitive CCD camera. The results show the feasibility and efficiency of the proposed point-spread function-based method

Cost analysis of nondeterministic probabilistic programs

We consider the problem of expected cost analysis over nondeterministic probabilistic programs, which aims at automated methods for analyzing the resource-usage of such programs. Previous approaches for this problem could only handle nonnegative bounded costs. However, in many scenarios, such as queuing networks or analysis of cryptocurrency protocols, both positive and negative costs are necessary and the costs are unbounded as well. In this work, we present a sound and efficient approach to obtain polynomial bounds on the expected accumulated cost of nondeterministic probabilistic programs. Our approach can handle (a) general positive and negative costs with bounded updates in variables; and (b) nonnegative costs with general updates to variables. We show that several natural examples which could not be handled by previous approaches are captured in our framework. Moreover, our approach leads to an efficient polynomial-time algorithm, while no previous approach for cost analysis of probabilistic programs could guarantee polynomial runtime. Finally, we show the effectiveness of our approach using experimental results on a variety of programs for which we efficiently synthesize tight resource-usage bounds

Cost Analysis of Nondeterministic Probabilistic Programs

We consider the problem of expected cost analysis over nondeterministic probabilistic programs, which aims at automated methods for analyzing the resource-usage of such programs. Previous approaches for this problem could only handle nonnegative bounded costs. However, in many scenarios, such as queuing networks or analysis of cryptocurrency protocols, both positive and negative costs are necessary and the costs are unbounded as well. In this work, we present a sound and efficient approach to obtain polynomial bounds on the expected accumulated cost of nondeterministic probabilistic programs. Our approach can handle (a) general positive and negative costs with bounded updates in variables; and (b) nonnegative costs with general updates to variables. We show that several natural examples which could not be handled by previous approaches are captured in our framework. Moreover, our approach leads to an efficient polynomial-time algorithm, while no previous approach for cost analysis of probabilistic programs could guarantee polynomial runtime. Finally, we show the effectiveness of our approach by presenting experimental results on a variety of programs, motivated by real-world applications, for which we efficiently synthesize tight resource-usage bounds.Comment: A conference version will appear in the 40th ACM Conference on Programming Language Design and Implementation (PLDI 2019

Who dares does not always win: risk-averse rockpool prawns are better at controlling a limited food resource

This is the author accepted manuscript. The final version is available from Elsevier Masson via the DOI in this record.Animal ‘personality’ – the phenomenon of consistent individual differences in behaviour within populations – has been documented widely, yet its functional significance and the reasons for its persistence remain unclear. One possibility is that among-individual behavioural variation is linked to fitness-determining traits via effects on resource acquisition. In this study, we test this idea, using rockpool prawns (Palaemon elegans) to test for a correlation between ‘high-risk exploration’ and the ability to monopolise a limited resource. Modified open field trials (OFTs) confirmed that consistent among-individual (co)variation in high-risk exploratory behaviours does exist in this species, and multivariate analysis shows trait variation is consistent with a major axis of personality variation. Subsequent feeding trials in size-matched groups where competition was possible revealed a high repeatability of feeding duration, used here as a proxy for RHP (resource holding potential). We found significant negative correlations between feeding duration and two ‘risky’ behaviours, such that individuals that took fewer risks fed more. Our results are not consistent with the widely hypothesised idea of a ‘proactive syndrome’ in which bolder, risk-taking personalities are positively associated with RHP. Rather they suggest the possibility of a trade-off, with some individuals successful at monopolising limited, high-value resources, while others are more willing to engage in potentially risky exploration (which may increase the likelihood of encountering novel resource patches). We speculate that alternative strategies for acquiring limited resources might thereby contribute to the maintenance of personality variation observed in wild populationsTH and AJW were supported by a grant from the Biotechnology and Biological Sciences Research Council awarded to AJW (BBSRC, grant BB/L022656/1)

AGO Recommendations for the surgical therapy of breast cancer: update 2022

The recommendations of the AGO Breast Committee on the surgical therapy of breast cancer were last updated in March 2022 (www.ago-online.de). Since surgical therapy is one of several partial steps in the treatment of breast cancer, extensive diagnostic and oncological expertise of a breast surgeon and good interdisciplinary cooperation with diagnostic radiologists is of great importance. The most important changes concern localization techniques, resection margins, axillary management in the neoadjuvant setting and the evaluation of the meshes in reconstructive surgery. Based on meta-analyses of randomized studies, the level of recommendation of an intraoperative breast ultrasound for the localization of non-palpable lesions was elevated to “++”. Thus, the technique is considered to be equivalent to wire localization, provided that it is a lesion which can be well represented by sonography, the surgeon has extensive experience in breast ultrasound and has access to a suitable ultrasound device during the operation. In invasive breast cancer, the aim is to reach negative resection margins (“no tumor on ink”), regardless of whether an extensive intraductal component is present or not. Oncoplastic operations can also replace a mastectomy in selected cases due to the large number of existing techniques, and are equivalent to segmental resection in terms of oncological safety at comparable rates of complications. Sentinel node excision is recommended for patients with cN0 status receiving neoadjuvant chemotherapy after completion of chemotherapy. Minimally invasive biopsy is recommended for initially suspect lymph nodes. After neoadjuvant chemotherapy, patients with initially 1 – 3 suspicious lymph nodes and a good response (ycN0) can receive the targeted axillary dissection and the axillary dissection as equivalent options