Induction of WNT16 via peptide-mRNA nanoparticle-based delivery maintains cartilage homeostasis

Osteoarthritis (OA) is a progressive joint disease that causes significant disability and pain and for which there are limited treatment options. We posit that delivery of anabolic factors that protect and maintain cartilage homeostasis will halt or retard OA progression. We employ a peptide-based nanoplatform to deliver Wingless and the name Int-1 (WNT) 16 messenger RNA (mRNA) to human cartilage explants. The peptide forms a self-assembled nanocomplex of approximately 65 nm in size when incubated with WNT16 mRNA. The complex is further stabilized with hyaluronic acid (HA) for enhanced cellular uptake. Delivery of peptide-WNT16 mRNA nanocomplex to human cartilage explants antagonizes canonical β-catenin/WNT3a signaling, leading to increased lubricin production and decreased chondrocyte apoptosis. This is a proof-of-concept study showing that mRNA can be efficiently delivered to articular cartilage, an avascular tissue that is poorly accessible even when drugs are intra-articularly (IA) administered. The ability to accommodate a wide range of oligonucleotides suggests that this platform may find use in a broad range of clinical applications

Authentication of Electronic Records: Limitations of Indian Legal Approach

Paper based documents have inherent authenticity and high evidentiary value for obvious reasons. The documents are permanent record of the contractual relationship of the parties and their contents cannot be so easily altered, modified or changed and even if any change is effected that can be easily detected. This is the reason that the Indian Evidence Act, 1872 excludes oral evidence in presence of documentary evidence. The moot point is that can an electronic record be treated equivalent to paper based record? In other words, can an electronic record have all the properties of the physical document appended with the hand written signature? This is necessitated by the fact that there are different laws in India providing that a contract is not valid unless it is in writing and signed by the parties. An attempt is made in this paper to analyze the provisions prescribing authentication of electronic records in India to demonstrate inherent limitations in them. To overcome these limitations, a new model of authentication is proposed which is based on digital signature combined with time stamping service

Development of a peptide-siRNA nanocomplex targeting NF- κB for efficient cartilage delivery

Abstract Delivery of therapeutic small interfering RNAs (siRNAs) in an effective dose to articular cartilage is very challenging as the cartilage dense extracellular matrix renders the chondrocytes inaccessible, even to intra-articular injections. Herein, we used a self-assembling peptidic nanoparticle (NP) platform featuring a cell penetrating peptide complexed to NF-κB p65 siRNA. We show that it efficiently and deeply penetrated human cartilage to deliver its siRNA cargo up to a depth of at least 700 μm. To simulate osteoarthritis in vitro, human articular cartilage explants were placed in culture and treated with IL-1β, a cytokine with known cartilage catabolic and pro-inflammatory effects. Exposure of peptide-siRNA NP to cartilage explants markedly suppressed p65 activation, an effect that persisted up to 3 weeks after an initial 48 h exposure to NP and in the presence of continuous IL-1β stimulation. Suppression of IL-1β-induced p65 activity attenuated chondrocyte apoptosis and maintained cartilage homeostasis. These findings confirm our previous in vivo studies in a murine model of post-traumatic osteoarthritis and suggest that the ability of peptide-siRNA NP to specifically modulate NF-κB pathway, a central regulator of the inflammatory responses in chondrocytes, may potentially mitigate the progression of cartilage degeneration

Protecting and sharing of semantically-enabled, user-orientated electronic laboratory notebook focusing on a case study in the e-science domain

We discuss the addition to an existing Electronic Laboratory Notebook (ELN) system, a means to permit the sharing of modelling data. One advantage is that sharing of such data is a means of assisting the publication process. This is done by presenting the modelling data and the reasoning behind its creation. This sharing of data is managed in a user sensitive fashion by restricting the release of data based upon the role someone performs. Further sensitivity is shown by fine-grained access control, which permits only part of the ELN to be shown. The performance of the solution presented is reviewed via quantitative analysis that showed a reasonable degree of end-user acceptance of the proposed approach

Mortality in dementia with Lewy bodies compared with Alzheimer's dementia: a retrospective naturalistic cohort study.

OBJECTIVES: To use routine clinical data to investigate survival in dementia with Lewy bodies (DLB) compared with Alzheimer's dementia (AD). DLB is the second most common dementia subtype after AD, accounting for around 7% of dementia diagnoses in secondary care, though studies suggest that it is underdiagnosed by up to 50%. Most previous studies of DLB have been based on select research cohorts, so little is known about the outcome of the disease in routine healthcare settings. SETTING: Cambridgeshire & Peterborough NHS Foundation Trust, a mental health trust providing secondary mental health care in England. SAMPLE: 251 DLB and 222 AD identified from an anonymised database derived from electronic clinical case records across an 8-year period (2005-2012), with mortality data updated to May 2015. RESULTS: Raw (uncorrected) median survival was 3.72 years for DLB (95% CI 3.33 to 4.14) and 6.95 years for AD (95% CI 5.78 to 8.12). Controlling for age at diagnosis, comorbidity and antipsychotic prescribing the model predicted median survival for DLB was 3.3 years (95% CI 2.88 to 3.83) for males and 4.0 years (95% CI 3.55 to 5.00) for females, while median survival for AD was 6.7 years (95% CI 5.27 to 8.51) for males and 7.0 years (95% CI 5.92 to 8.73) for females. CONCLUSION: Survival from first presentation with cognitive impairment was markedly shorter in DLB compared with AD, independent of age, sex, physical comorbidity or antipsychotic prescribing. This finding, in one of the largest clinical cohorts of DLB cases assembled to date, adds to existing evidence for poorer survival for DLB versus AD. There is an urgent need for further research to understand possible mechanisms accounting for this finding

Modified Chaplygin Gas and Solvable F-essence Cosmologies

The Modified Chaplygin Gas (MCG) model belongs to the class of a unified models of dark energy and dark matter. In this paper, we have modeled MCG in the framework of f-essence cosmology. By constructing an equation connecting the MCG and the f-essence, we solve it to obtain explicitly the pressure and energy density of MCG. As special cases, we obtain both positive and negative pressure solutions for suitable choices of free parameters. We also calculate the state parameter which describes the phantom crossing.Comment: 12 pages, (Invited Review), accepted for publication in "Astrophysics and Space Science" DOI: 10.1007/s10509-011-0870-

The ArgoNeuT Detector in the NuMI Low-Energy beam line at Fermilab

The ArgoNeuT liquid argon time projection chamber has collected thousands of neutrino and antineutrino events during an extended run period in the NuMI beam-line at Fermilab. This paper focuses on the main aspects of the detector layout and related technical features, including the cryogenic equipment, time projection chamber, read-out electronics, and off-line data treatment. The detector commissioning phase, physics run, and first neutrino event displays are also reported. The characterization of the main working parameters of the detector during data-taking, the ionization electron drift velocity and lifetime in liquid argon, as obtained from through-going muon data complete the present report.Comment: 43 pages, 27 figures, 5 tables - update referenc