Design of dry powder formulations of pH responsive peptide/plasmid DNA complexes for pulmonary delivery

Poster Presentation: no. 13PS50Respiratory diseases are substantial public health problems around the world. Recently, nucleic acid was developed as a potential therapeutic strategy to tackle a series of lung diseases. Delivery still poses one of the major challenges for their clinical application. pH responsive peptides containing either histidine or derivatives of 2,3-diaminopropionic acid (Dap) can mediate effective DNA transfection in lung epithelial cells with the latter remaining effective even in the presence of lung surfactant containing bronchoalveolar fluid (BALF), which make them promising vectors for delivering therapeutic nucleic acid to the airways .....published_or_final_versio

Profiling biomolecules at cell-biomaterial interface by quantitative proteomics

Session: Controlling Microenvironment and Cell Fate: abstract no. 789INTRODUCTION: Implant surface structure and chemistry determines the contacting cell’s fate. Therefore, the fate of those cells directly affect bone-implant incorporation in clinical practice1-5. However, how these chemical and mechanical signals translating to cellular responses are not yet known. The major drawback is a lack of systematic study of cellbiomaterial interaction in terms of protein expression, specifically, at the attachment interface between the cell and biomaterial (adherence surface, AS). Therefore, we have proposed to unbiasedly identify the biomolecules at the interface by proteomics. This method combines the use of a subcellular fractionation with quantitative mass …postprintThe 2010 North America Conference of the Tissue Engineering and Regenerative Medicine International Society (TERMIS-NA 2010), Orlando, FL., 5-8 December 2010

Revealing heterogeneous nucleation of primary Si and eutectic Si by AlP in hypereutectic Al-Si alloys

The heterogeneous nucleation of primary Si and eutectic Si can be attributed to the presence of AlP. Although P, in the form of AlP particles, is usually observed in the centre of primary Si, there is still a lack of detailed investigations on the distribution of P within primary Si and eutectic Si in hypereutectic Al-Si alloys at the atomic scale. Here, we report an atomic-scale experimental investigation on the distribution of P in hypereutectic Al-Si alloys. P, in the form of AlP particles, was observed in the centre of primary Si. However, no significant amount of P was detected within primary Si, eutectic Si and the Al matrix. Instead, P was observed at the interface between the Al matrix and eutectic Si, strongly indicating that P, in the form of AlP particles (or AlP ‘patch’ dependent on the P concentration), may have nucleated on the surface of the Al matrix and thereby enhanced the heterogeneous nucleation of eutectic Si. The present investigation reveals some novel insights into heterogeneous nucleation of primary Si and eutectic Si by AlP in hypereutectic Al-Si alloys and can be used to further develop heterogeneous nucleation mechanisms based on adsorption

Spray freeze drying of small nucleic acids as inhaled powder for pulmonary delivery

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Health-related quality of life as measured with EQ-5D among populations with and without specific chronic conditions: A population-based survey in Shaanxi province, China

© 2013 Tan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Introduction: The aim of this study was to examine health-related quality of life (HRQoL) as measured by EQ-5D and to investigate the influence of chronic conditions and other risk factors on HRQoL based on a distributed sample located in Shaanxi Province, China. Methods: A multi-stage stratified cluster sampling method was performed to select subjects. EQ-5D was employed to measure the HRQoL. The likelihood that individuals with selected chronic diseases would report any problem in the EQ-5D dimensions was calculated and tested relative to that of each of the two reference groups. Multivariable linear regression models were used to investigate factors associated with EQ VAS. Results: The most frequently reported problems involved pain/discomfort (8.8%) and anxiety/depression (7.6%). Nearly half of the respondents who reported problems in any of the five dimensions were chronic patients. Higher EQ VAS scores were associated with the male gender, higher level of education, employment, younger age, an urban area of residence, access to free medical service and higher levels of physical activity. Except for anemia, all the selected chronic diseases were indicative of a negative EQ VAS score. The three leading risk factors were cerebrovascular disease, cancer and mental disease. Increases in age, number of chronic conditions and frequency of physical activity were found to have a gradient effect. Conclusion: The results of the present work add to the volume of knowledge regarding population health status in this area, apart from the known health status using mortality and morbidity data. Medical, policy, social and individual attention should be given to the management of chronic diseases and improvement of HRQoL. Longitudinal studies must be performed to monitor changes in HRQoL and to permit evaluation of the outcomes of chronic disease intervention programs. © 2013 Tan et al.National Nature Science Foundation (No. 8107239

Lateral Gene Expression in Drosophila Early Embryos Is Supported by Grainyhead-Mediated Activation and Tiers of Dorsally-Localized Repression

The general consensus in the field is that limiting amounts of the transcription factor Dorsal establish dorsal boundaries of genes expressed along the dorsal-ventral (DV) axis of early Drosophila embryos, while repressors establish ventral boundaries. Yet recent studies have provided evidence that repressors act to specify the dorsal boundary of intermediate neuroblasts defective (ind), a gene expressed in a stripe along the DV axis in lateral regions of the embryo. Here we show that a short 12 base pair sequence (“the A-box”) present twice within the ind CRM is both necessary and sufficient to support transcriptional repression in dorsal regions of embryos. To identify binding factors, we conducted affinity chromatography using the A-box element and found a number of DNA-binding proteins and chromatin-associated factors using mass spectroscopy. Only Grainyhead (Grh), a CP2 transcription factor with a unique DNA-binding domain, was found to bind the A-box sequence. Our results suggest that Grh acts as an activator to support expression of ind, which was surprising as we identified this factor using an element that mediates dorsally-localized repression. Grh and Dorsal both contribute to ind transcriptional activation. However, another recent study found that the repressor Capicua (Cic) also binds to the A-box sequence. While Cic was not identified through our A-box affinity chromatography, utilization of the same site, the A-box, by both factors Grh (activator) and Cic (repressor) may also support a “switch-like” response that helps to sharpen the ind dorsal boundary. Furthermore, our results also demonstrate that TGF-β signaling acts to refine ind CRM expression in an A-box independent manner in dorsal-most regions, suggesting that tiers of repression act in dorsal regions of the embryo

Proteomics: in pursuit of effective traumatic brain injury therapeutics

Effective traumatic brain injury (TBI) therapeutics remain stubbornly elusive. Efforts in the field have been challenged by the heterogeneity of clinical TBI, with greater complexity among underlying molecular phenotypes than initially conceived. Future research must confront the multitude of factors comprising this heterogeneity, representing a big data challenge befitting the coming informatics age. Proteomics is poised to serve a central role in prescriptive therapeutic development, as it offers an efficient endpoint within which to assess post-TBI biochemistry. We examine rationale for multifactor TBI proteomic studies and the particular importance of temporal profiling in defining biochemical sequences and guiding therapeutic development. Lastly, we offer perspective on repurposing biofluid proteomics to develop theragnostic assays with which to prescribe, monitor and assess pharmaceutics for improved translation and outcome for TBI patients

Learning Contextualized Document Representations for Healthcare Answer Retrieval

We present Contextual Discourse Vectors (CDV), a distributed document representation for efficient answer retrieval from long healthcare documents. Our approach is based on structured query tuples of entities and aspects from free text and medical taxonomies. Our model leverages a dual encoder architecture with hierarchical LSTM layers and multi-task training to encode the position of clinical entities and aspects alongside the document discourse. We use our continuous representations to resolve queries with short latency using approximate nearest neighbor search on sentence level. We apply the CDV model for retrieving coherent answer passages from nine English public health resources from the Web, addressing both patients and medical professionals. Because there is no end-to-end training data available for all application scenarios, we train our model with self-supervised data from Wikipedia. We show that our generalized model significantly outperforms several state-of-the-art baselines for healthcare passage ranking and is able to adapt to heterogeneous domains without additional fine-tuning.Comment: The Web Conference 2020 (WWW '20

Morphologically and immunohistochemically undifferentiated gastric neoplasia in a patient with multiple metastatic malignant melanomas: a case report

Introduction: Malignant melanoma is a neoplasia which frequently involves the gastrointestinal tract (GIT). GIT metastases are difficult to diagnose because they often recur many years after treatment of the primary cutaneous lesion and also manifest clinically at an advanced stage of the neoplasia. Furthermore, GIT metastases can appear in various morphological forms, and therefore immunohistochemistry is often useful in distinguishing between a malignant melanoma and other malignancies. Case presentation: We report the case of a 60-year-old man with a multiple metastatic melanoma who underwent an upper endoscopy to clarify the possible involvement of the gastric wall with a mass localized in the upper abdomen involving the pancreas and various lymph nodes, which was previously described with computed tomography. Clinically, the patient reported a progressive loss of appetite, nausea and vomiting. The upper endoscopy and histological examination revealed a gastric location of an undifferentiated neoplasm with an absence of immunohistochemical characteristics referable to the skin malignant melanoma that was removed previously. Conclusion: The present case report shows the difficulty in diagnosing a metastatic melanoma in the GIT and therefore, it seems worthwhile to consider metastatic malignant melanoma in the differential diagnosis of undifferentiated neoplasia. © 2008 Alghisi et al; licensee BioMed Central Ltd

Cross-Species Analyses Identify the BNIP-2 and Cdc42GAP Homology (BCH) Domain as a Distinct Functional Subclass of the CRAL_TRIO/Sec14 Superfamily

The CRAL_TRIO protein domain, which is unique to the Sec14 protein superfamily, binds to a diverse set of small lipophilic ligands. Similar domains are found in a range of different proteins including neurofibromatosis type-1, a Ras GTPase-activating Protein (RasGAP) and Rho guanine nucleotide exchange factors (RhoGEFs). Proteins containing this structural protein domain exhibit a low sequence similarity and ligand specificity while maintaining an overall characteristic three-dimensional structure. We have previously demonstrated that the BNIP-2 and Cdc42GAP Homology (BCH) protein domain, which shares a low sequence homology with the CRAL_TRIO domain, can serve as a regulatory scaffold that binds to Rho, RhoGEFs and RhoGAPs to control various cell signalling processes. In this work, we investigate 175 BCH domain-containing proteins from a wide range of different organisms. A phylogenetic analysis with ∼100 CRAL_TRIO and similar domains from eight representative species indicates a clear distinction of BCH-containing proteins as a novel subclass within the CRAL_TRIO/Sec14 superfamily. BCH-containing proteins contain a hallmark sequence motif R(R/K)h(R/K)(R/K)NL(R/K)xhhhhHPs (‘h’ is large and hydrophobic residue and ‘s’ is small and weekly polar residue) and can be further subdivided into three unique subtypes associated with BNIP-2-N, macro- and RhoGAP-type protein domains. A previously unknown group of genes encoding ‘BCH-only’ domains is also identified in plants and arthropod species. Based on an analysis of their gene-structure and their protein domain context we hypothesize that BCH domain-containing genes evolved through gene duplication, intron insertions and domain swapping events. Furthermore, we explore the point of divergence between BCH and CRAL-TRIO proteins in relation to their ability to bind small GTPases, GAPs and GEFs and lipid ligands. Our study suggests a need for a more extensive analysis of previously uncharacterized BCH, ‘BCH-like’ and CRAL_TRIO-containing proteins and their significance in regulating signaling events involving small GTPases