Therapeutic applications of ghrelin agonists in the treatment of gastroparesis

There remains an unmet need for effective pharmacologic treatments for gastroparesis. Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor and has been shown to regulate energy homeostasis and exert prokinetic effects on gastrointestinal motility. In recent years, several ghrelin receptor agonists have been studied in clinical trials of patients with diabetic gastroparesis. The intravenous macrocyclic peptidomimetic, TZP-101, initially suggested improvement in gastroparesis symptoms with intravenous administration when compared to placebo. However, in subsequent studies of oral preparations, TZP-102 failed to confirm these results. Another ghrelin receptor agonist, RM-131, was recently shown to significantly accelerate gastric emptying (GE) in patients with type 1 and type 2 diabetes and delayed GE. RM-131 reduced total Gastroparesis Cardinal Symptom Index-Daily Diary (GCSI-DD) and composite scores among type 1 diabetics. Continued development of ghrelin agonists should be explored in attempts to expand therapeutic options for the treatment of gastroparesis

On the exit statistics theorem of many particle quantum scattering

We review the foundations of the scattering formalism for one particle potential scattering and discuss the generalization to the simplest case of many non interacting particles. We point out that the "straight path motion" of the particles, which is achieved in the scattering regime, is at the heart of the crossing statistics of surfaces, which should be thought of as detector surfaces. We sketch a proof of the relevant version of the many particle flux across surfaces theorem and discuss what needs to be proven for the foundations of scattering theory in this context.Comment: 15 pages, 4 figures; to appear in the proceedings of the conference "Multiscale methods in Quantum Mechanics", Accademia dei Lincei, Rome, December 16-20, 200

Upper Airways Microbiota in Antibiotic-Naive Wheezing and Healthy Infants from the Tropics of Rural Ecuador

Background: Observations that the airway microbiome is disturbed in asthma may be confounded by the widespread use of antibiotics and inhaled steroids. We have therefore examined the oropharyngeal microbiome in early onset wheezinginfants from a rural area of tropical Ecuador where antibiotic usage is minimal and glucocorticoid usage is absent. Materials and Methods: We performed pyrosequencing of amplicons of the polymorphic bacterial 16S rRNA gene from oropharyngeal samples from 24 infants with non-infectious early onset wheezing and 24 healthy controls (average age 10.2 months). We analyzed microbial community structure and differences between cases and controls by QIIME software. Results: We obtained 76,627 high quality sequences classified into 182 operational taxonomic units (OTUs). Firmicutes was the most common and diverse phylum (71.22% of sequences) with Streptococcus being the most common genus (49.72%). Known pathogens were found significantly more often in cases of infantile wheeze compared to controls, exemplified by Haemophilus spp. (OR = 2.12, 95% Confidence Interval (CI) 1.82–2.47; P = 5.46610223) and Staphylococcus spp. (OR = 124.1, 95%CI 59.0–261.2; P = 1.876102241). Other OTUs were less common in cases than controls, notably Veillonella spp. (OR = 0.59, 95%CI = 0.56–0.62; P = 8.06610286). Discussion: The airway microbiota appeared to contain many more Streptococci than found in Western Europe and the USA. Comparisons between healthy and wheezing infants revealed a significant difference in several bacterial phylotypes that were not confounded by antibiotics or use of inhaled steroids. The increased prevalence of pathogens such as Haemophilus and Staphylococcus spp. in cases may contribute to wheezing illnesses in this age group

Survivin a radiogenetic promoter for glioblastoma viral gene therapy independently from CArG motifs

BACKGROUND: Radiogenetic therapy is a novel approach in the treatment of cancer, which employs genetic modification to alter the sensitivity of tumor cells to the effect of applied radiation. AIM: To select a potent radiation inducible promoter in the context of brain tumors and to investigate if CArG radio responsive motifs or other elements in the promoter nucleotide sequences can correlate to its response to radiation. METHODS: To select initial candidates for promoter inducible elements, the levels of mRNA expression of six different promoters were assessed using Quantitative RTPCR in D54 MG cells before and after radiation exposure. Recombinant Ad/reporter genes driven by five different promoters; CMV, VEGF, FLT-1, DR5 and survivin were constructed. Glioma cell lines were infected with different multiplicity of infection of the (promoter) Ad or CMV Ad. Cells were then exposed to a range of radiation (0–12 Gy) at single fraction. Fluorescent microscopy, Luc assay and X-gal staining was used to detect the level of expression of related genes. Different glioma cell lines and normal astrocytes were infected with Ad survivin and exposed to radiation. The promoters were analyzed for presence of CArG radio-responsive motifs and CCAAT box consensus using NCBI blast bioinformatics software. RESULTS: Radiotherapy increases the expression of gene expression by 1.25–2.5 fold in different promoters other than survivin after 2 h of radiation. RNA analysis was done and has shown an increase in copy number of tenfold for survivin. Most importantly cells treated with RT and Ad Luc driven by survivin promoter showed a fivefold increase in expression after 2 Gy of radiation in comparison to non-irradiated cells. Presence or absence of CArG motifs did not correlate with promoter response to radiation. Survivin with the best response to radiation had the lowest number of CCAAT box. CONCLUSION: Survivin is a selective potent radiation inducible promoter for glioblastoma viral gene therapy and this response to radiation could be independent of CArG motifs

Slightly generalized Generalized Contagion: Unifying simple models of biological and social spreading

We motivate and explore the basic features of generalized contagion, a model mechanism that unifies fundamental models of biological and social contagion. Generalized contagion builds on the elementary observation that spreading and contagion of all kinds involve some form of system memory. We discuss the three main classes of systems that generalized contagion affords, resembling: simple biological contagion; critical mass contagion of social phenomena; and an intermediate, and explosive, vanishing critical mass contagion. We also present a simple explanation of the global spreading condition in the context of a small seed of infected individuals.Comment: 8 pages, 5 figures; chapter to appear in "Spreading Dynamics in Social Systems"; Eds. Sune Lehmann and Yong-Yeol Ahn, Springer Natur

Genetic analysis of safflower domestication.

BackgroundSafflower (Carthamus tinctorius L.) is an oilseed crop in the Compositae (a.k.a. Asteraceae) that is valued for its oils rich in unsaturated fatty acids. Here, we present an analysis of the genetic architecture of safflower domestication and compare our findings to those from sunflower (Helianthus annuus L.), an independently domesticated oilseed crop within the same family.We mapped quantitative trait loci (QTL) underlying 24 domestication-related traits in progeny from a cross between safflower and its wild progenitor, Carthamus palaestinus Eig. Also, we compared QTL positions in safflower against those that have been previously identified in cultivated x wild sunflower crosses to identify instances of colocalization.ResultsWe mapped 61 QTL, the vast majority of which (59) exhibited minor or moderate phenotypic effects. The two large-effect QTL corresponded to one each for flower color and leaf spininess. A total of 14 safflower QTL colocalized with previously reported sunflower QTL for the same traits. Of these, QTL for three traits (days to flower, achene length, and number of selfed seed) had cultivar alleles that conferred effects in the same direction in both species.ConclusionsAs has been observed in sunflower, and unlike many other crops, our results suggest that the genetics of safflower domestication is quite complex. Moreover, our comparative mapping results indicate that safflower and sunflower exhibit numerous instances of QTL colocalization, suggesting that parallel trait transitions during domestication may have been driven, at least in part, by parallel genotypic evolution at some of the same underlying genes

Transcriptome profiling reveals significant changes in the gastric muscularis externa with obesity that partially overlap those that occur with idiopathic gastroparesis

BACKGROUND: Gastric emptying is impaired in patients with gastroparesis whereas it is either unchanged or accelerated in obese individuals. The goal of the current study was to identify changes in gene expression in the stomach muscularis that may be contributing to altered gastric motility in idiopathic gastroparesis and obesity. METHODS: Quantitative real time RT-PCR and whole transcriptome sequencing were used to compare the transcriptomes of lean individuals, obese individuals and either lean or obese individuals with idiopathic gastroparesis. RESULTS: Obesity leads to an increase in mRNAs associated with muscle contractility whereas idiopathic gastroparesis leads to a decrease in mRNAs associated with PDGF BB signaling. Both obesity and idiopathic gastroparesis were also associated with similar alterations in pathways associated with inflammation. CONCLUSIONS: Our findings show that obesity and idiopathic gastroparesis result in overlapping but distinct changes in the gastric muscularis transcriptome. Increased expression of mRNAs encoding smooth muscle contractile proteins may be contributing to the increased gastric motility observed in obese subjects, whereas decreased PDGF BB signaling may be contributing to the impaired motility seen in subjects with idiopathic gastroparesis

Gastroparesis is associated with decreased FOXF1 and FOXF2 in humans, and loss of FOXF1 and FOXF2 results in gastroparesis in mice

Background and Aims The transcription factors FOXF1 and FOXF2 have been implicated in the development of the gastrointestinal tract but their role in adults or in gastrointestinal diseases is poorly understood. We have recently shown that expression of serum response factor (SRF), a transcription factor whose activity is modulated by FOXF proteins, is decreased in the stomach muscularis of patients with gastroparesis. The aim of the current study was to determine whether FOXF expression is decreased in gastroparesis patients and whether loss of FOXF1 and/or FOXF2 from adult smooth muscle is sufficient to impair gastric emptying in mice. Methods Full‐thickness stomach biopsy samples were collected from control subjects and from patients with gastroparesis. mRNA was isolated from the muscularis externa, and FOXF mRNA expression levels were determined by quantitative reverse transcriptase (RT)‐PCR. Foxf1 and Foxf2 were knocked out together and separately from smooth muscle cells in adult mice, and the subsequent effect on liquid gastric emptying and contractile protein expression was determined. Key Results Expression of FOXF1 and FOXF2 is decreased in smooth muscle tissue from gastroparesis patients. Knockout of Foxf1 and Foxf2 together, but not alone, from mouse smooth muscle resulted in delayed liquid gastric emptying. Foxf1/2 double knockout mice had decreased expression of smooth muscle contractile proteins, SRF, and myocardin in stomach muscularis. Conclusions and Inferences Our findings suggest that decreased expression of FOXF1 and FOXF2 may be contributing to the impaired gastric emptying seen in gastroparesis patients

D^2PS: A Dependable Data Provisioning Service in Multi-tenant Cloud Environment

Software as a Service (SaaS) is a software delivery and business model widely used by Cloud computing. Instead of purchasing and maintaining a software suite permanently, customers only need to lease the software on-demand. The domain of high assurance distributed systems has focused greatly on the areas of fault tolerance and dependability. In a multi-tenant context, it is particularly important to store, manage and provision data services to customers in a highly efficient and dependable manner due to a large number of file operations involved in running such services. It is also desirable to allow a user group to share and cooperate (e.g., co-edit) on some specific data. In this paper we present a dependable data provisioning service in a multi-tenant Cloud environment. We describe a metadata management approach and leverage multiple replicated metadata caching to shorten the file access time, with the improved efficiency of data sharing. In order to reduce frequent data transmission and data access latency, we introduce a distributed cooperative disk cache mechanism that supports effective cache placement and pull-push cache synchronization. In addition, we use efficient component failover to enhance the service dependability whilst avoiding negative impact from system failures. Our experimental results show that our system can significantly reduce both unused data transmission and response latency. Specifically, over 50% network transmission and operational latency can be saved for random reads while 28.24% network traffic and 25% response latency can be reduced for random write operations. We believe that these findings are demonstrating positive results along the right direction of resolving storage-related challenges in a multi-tenant Cloud environment

Efectos de la sal sobre la solubilidad y las propiedades emulsionantes de la caseína y sus hidrolizados trípticos

This work reports an investigation about the effect of NaCl addition (0.02 mol/L) on some functional properties of casein(CA) and its tryptic hydrolysates (TH). The solubility, the emulsifying capacity (EC), the emulsifying activity index(EAI) and the emulsion stability (ES) were determined at two pH values (4.0 and 5.0). The results showed that thisprocedure was benefi cial for the solubility of CA and TH, being more intense at pH 5.0 and 4.0, respectively. Also, apositive effect of NaCl addition was observed for CA and TH, at both pH values, and the best results for both sampleswere achieved at pH 5.0. The ES was slightly affected by the presence of salt and only for some samples of CA andTH it was increased. Contrarily, the EAI values of casein were reduced with the addition of NaCl at pH 4.0 and 5.0,while those of TH were positively affected by this treatment at both pH values.En este trabajo se presentan los resultados de una investigación sobre los efectos de la adición de NaCl (0,02 mol/L)sobre algunas propiedades funcionales de la caseína (CA) y de sus hidrolizados trípticos (TH). Se determinaron lasolubilidad, la capacidad emulsionante (CE), el índice de actividad emulsionante (IAE) y la estabilidad de la emulsión(EE) con dos valores de pH (4,0 y 5,0). Los resultados demostraron que el procedimiento era benefi cioso parala solubilidad de CA y TH, siendo más intensa con pH 5,0 y 4,0, respectivamente. También se observó un efectopositivo de la adición de NaCl en CA y TH, con ambos valores de pH, consiguiéndose los mejores resultados conpH 5,0. La EE se vio ligeramente afectada por la presencia de sal, y sólo aumentó en algunas muestras de CA yTH. Por el contrario, los valores del IAE de la caseína se redujeron al añadir NaCl con pH 4,0 y 5,0, mientras quelas de TH se vieron afectadas positivamente por este tratamiento con ambos valores de pH