Transcutaneous immunization with a novel lipid-based adjuvant protects against Chlamydia genital and respiratory infections

Mucosal adjuvants are important to overcome the state of immune tolerance normally associated with mucosal delivery and to enhance adaptive immunity to often-weakly immunogenic subunit vaccine antigens. Unfortunately, adverse side effects of many experimental adjuvants limit the number of adjuvants approved for vaccination. Lipid C is a novel, non-toxic, lipid oral vaccine-delivery formulation, developed originally for oral delivery of the live Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccine. In the present study, murine models of chlamydial respiratory and genital tract infections were used to determine whether transcutaneous immunization (TCI) with Lipid C-incorporated protein antigens could elicit protective immunity at the genital and respiratory mucosae. BALB/c mice were immunized transcutaneously with Lipid C containing the chlamydial major outer membrane protein (MOMP), with and without addition of cholera toxin and CpG-ODN 1826 (CT/CpG). Both vaccine combinations induced mixed cell-mediated and mucosal antibody immune responses. Immunization with Lipid C-incorporated MOMP (Lipid C/MOMP), either alone or with CT/CpG resulted in partial protection following live challenge with Chlamydia muridarum as evidenced by a significant reduction in recoverable Chlamydia from both the genital secretions and lung tissue. Protection induced by immunization with Lipid C/MOMP alone was not further enhanced by the addition of CT/CpG. These results highlight the potential of Lipid C as a novel mucosal adjuvant capable of targeting multiple mucosal surfaces following TCI. Protection at both the respiratory and genital mucosae was achieved without the requirement for potentially toxic adjuvants, suggesting that Lipid C may provide a safe effective mucosal adjuvant for human vaccination.

Role of Human Topoisomerase I in DNA Repair and Apoptosis

Human topoisomerase I (htopoI) is an enzyme that up to now was believed to function mainly in the removal of torsional stress generated during transcription and replication. In 1998, it was found that htopoI might play another important role in the cellular response to DNA damage -- the so-called htopoI damage response. Since this initial discovery, many studies have suggested that the htopoI damage response is involved in DNA repair as well as in apoptosis. Here we discuss the earliest as well as the latest results in this field. Combining all of the published and as yet unpublished results, we suggest and discuss a model of how htopoI may function during DNA repair and apoptosis. Furthermore, numerous results show that the htopoI damage response is not a spontaneous event, but is strictly regulated by cellular signalling pathways. We discuss which pathways may be involved and how the htopoI damage response is activated. Although the htopoI damage response was discovered several years ago, research in this area is just beginning. The future will surely bring more clarity regarding the precise mechanism behind the involvement of htopoI in DNA repair and apoptosis, as well as its implications for a broader understanding of how the human organism ensures genomic stability.

The human topoisomerase I damage response plays a role in apoptosis

Previous studies have shown that human topoisomerase I cleavage complexes form as a response to various DNA damages in vivo, the so called human topoisomerase I “damage response”. It was suggested that this damage response may play a role in DNA repair as well as in apoptosis, but only very few investigations have been done and the significance of the damage response still remains unclear. Here we demonstrate that human topoisomerase I cleavage complexes induced by high doses of UV irradiation are highly stable for up to 48 h. Furthermore, we show that human topoisomerase I cleavage complexes correlate with apoptosis. However, at low UV doses the cleavage complex level was very low and the complexes were repaired. Surprisingly, we found that high levels of stable cleavage complexes were not only found in UV-irradiated cells but also in untreated cells that underwent apoptosis. A possible role of human topoisomerase I in apoptosis is discussed.

Dispelling ageing myths in technology design

We present a review of literature from the fields of gerontology, gerontechnology, HCI and government policy that deals with social and technical solutions for the ageing population. We highlight common assumptions about ageing people, which we argue are still embedded in much of the research related to the domain of ageing. This paper challenges six common assumptions across four broad themes that we identified in the literature. It aims to provide a reminder and resource for designers to eschew assumptions during designing technology for 'older' users.

A randomized controlled trial of a correspondence-based intervention for carers of relatives with psychosis

Background Family members play a crucial role in supporting the recovery of loved ones with psychosis. The journey of recovery is not only traversed by the person experiencing the mental illness but also by their family. Interventions to support these families have traditionally either focused on psychoeducation or addressed problematic interactions or expressed emotion. Family programmes have far less frequently emphasized supporting family members' adjustment to the challenges posed by their relative's disorder or their recovery from associated distress. The study compared a control condition that received only a psychoeducational booklet (Information) and a condition also receiving a correspondence-based interactive recovery-oriented intervention (Connections). The Connections group was expected to show greater improvements in recovery knowledge, well-being, experiences of caregiving, hopefulness and distress. Method A randomized controlled trial was conducted to evaluate the effectiveness of two correspondence-based family interventions delivered to 81 carers of relatives with psychosis. Results Intent-to-treat analyses showed no differential outcomes between conditions, but an analysis of participants who substantially completed their allocated treatment showed that carers receiving Connections had significantly more improvements in well-being, positive experiences of caregiving and distress. Conclusions Correspondence interventions that support carer's recovery may result in more positive mental health for those who complete key elements of the programme compared with information alone. However, many carers do not complete a correspondence programme and this may limit its impact.

2. Contact lens care and ocular surface homeostasis

Moderator Opening The early focus of contact lens wear and ocular health was on oxygen delivery. However, as we learn more about how the eye works, and investigate how the contact lens interacts with the cornea, the role of the tear film has risen in prominence. A healthy tear film is critical for normal ocular homeostasis, and abnormalities of the tear film are the primary cause of dry eye. In order to improve patient eye health and comfort during lens wear, we need to further elucidate the relationship among contact lenses, contact lens solutions, the tear film, and the corneal epithelium, and find ways to maintain homeostasis of the ocular surface. In this section, we review the latest data and opinions on this complex relationship between contact lenses and lens care solutions

The science behind the “stain”

It has been almost fi ve years since I fi rst published the article entitled “Much Ado About Staining” in Review of Optometry, which explored what we really knew in 2006 about the relationship between “corneal staining” and contact lens multipurpose solutions (MPS). This was published just prior to the controversial “staining grid.” While the Grid showed MPS-associated hyperfl uorescence under the slitlamp at two hours, it did not explain the “what” or “why” behind it; even so, many proponents of the Grid continue to suggest that it shows us which solution/lens combinations are “biocompatible” and which are not. New evidence suggests that the preservative-associated transient hyperfl uorescence (or PATH) observed at two hours after lens insertion is a benign phenomenon due to an interaction between fl uorescein, MPS preservatives, and corneal cell membranes. The misinterpretation of PATH as “real” corneal staining, like that observed in pathological conditions, may be due in part to the fact that there is not a lot of teaching regarding the true properties of fl uorescein and what is actually occurring when we see either PATH or corneal staining. To discuss the science of fl uorescein, corneal staining, and PATH, I have asked some of the preeminent research experts in the study of fl uorescence spectroscopy and corneal staining from around the world to share their new research and personal opinions on these topics...

Perspectives on research in project management : the nine schools

This paper demonstrates that project management is a developing field of academic study in management, of considerable diversity and richness, which can make a valuable contribution to the development of management knowledge, as well as being of considerable economic importance. The paper reviews the substantial progress and trends of research in the subject, which has been grouped into nine major schools of thought: optimization, modelling, governance, behaviour, success, decision, process, contingency, and marketing. The paper addresses interactions between the different schools and with other related management fields, and provides insights into current and potential research in each and across these schools.

Habituated interaction and social objects

In this position paper we draw from critical approaches to the concept of habit from cultural theory to argue that considering the sociality of everyday objects might be productive for understanding and designing for habituated interaction within the emerging Internet of Things.

The reduced expression of the HADH2 protein causes X-linked mental retardation, choreoathetosis, and abnormal behavior

Recently, we defined a new syndromic form of X-linked mental retardation in a 4-generation family with a unique clinical phenotype characterized by mild mental retardation, choreoathetosis, and abnormal behavior (MRXS10). Linkage analysis in this family revealed a candidate region of 13.4 Mb between markers DXS1201 and DXS991 on Xp11; therefore, mutation analysis was performed by direct sequencing in most of the 135 annotated genes located in the region. The gene (HADH2) encoding L-3-hydroxyacyl-CoA dehydrogenase II displayed a sequence alteration (c.574 C-->A; p.R192R) in all patients and carrier females that was absent in unaffected male family members and could not be found in 2,500 control X chromosomes, including in those of 500 healthy males. The silent C-->A substitution is located in exon 5 and was shown by western blot to reduce the amount of HADH2 protein by 60%-70% in the patient. Quantitative in vivo and in vitro expression studies revealed a ratio of splicing transcript amounts different from those normally seen in controls. Apparently, the reduced expression of the wild-type fragment, which results in the decreased protein expression, rather than the increased amount of aberrant splicing fragments of the HADH2 gene, is pathogenic. Our data therefore strongly suggest that reduced expression of the HADH2 protein causes MRXS10, a phenotype different from that caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, which is a neurodegenerative disorder caused by missense mutations in this multifunctional protein.

Time kinetics of bone defect healing in response to BMP-2 and GDF-5 characterised by in vivo biomechanics

This study reports that treatment of osseous defects with different growth factors initiates distinct rates of repair. We developed a new method for monitoring the progression of repair, based upon measuring the in vivo mechanical properties of healing bone. Two different members of the bone morphogenetic protein (BMP) family were chosen to initiate defect healing: BMP-2 to induce osteogenesis, and growth-and-differentiation factor (GDF)-5 to induce chondrogenesis. To evaluate bone healing, BMPs were implanted into stabilised 5 mm bone defects in rat femurs and compared to controls. During the first two weeks, in vivo biomechanical measurements showed similar values regardless of the treatment used. However, 2 weeks after surgery, the rhBMP-2 group had a substantial increase in stiffness, which was supported by the imaging modalities. Although the rhGDF-5 group showed comparable mechanical properties at 6 weeks as the rhBMP-2 group, the temporal development of regenerating tissues appeared different with rhGDF-5, resulting in a smaller callus and delayed tissue mineralisation. Moreover, histology showed the presence of cartilage in the rhGDF-5 group whereas the rhBMP-2 group had no cartilaginous tissue. Therefore, this study shows that rhBMP-2 and rhGDF-5 treated defects, under the same conditions, use distinct rates of bone healing as shown by the tissue mechanical properties. Furthermore, results showed that in vivo biomechanical method is capable of detecting differences in healing rate by means of change in callus stiffness due to tissue mineralisation.

What information is necessary to assess the environmental impacts of deconstruction?

4D modeling - the simulation and visualisation of the construction process - is now a common method used during the building construction process with reasonable support from existing software. The goal of this paper is to examine the information needs required to model the deconstruction/demolition process of a building. The motivation is the need to reduce the impacts on the local environment during the deconstruction process. The focus is on the definition and description of the activities to remove building components and on the assessment of the noise, dust and vibration implications of these activities on the surrounding environment. The outcomes of the research are: i. requirements specification for BIM models to support operational deconstruction process planning, ii. algorithms for augmenting the BIM with the derived information necessary to automate planning of the deconstruction process with respect to impacts on the surrounding environment, iii. algorithms to build naive deconstruction activity schedules.

Transcript and metabolite profiling for the evaluation of tobacco tree and poplar as feedstock for the bio-based industry

The global demand for food, feed, energy and water poses extraordinary challenges for future generations. It is evident that robust platforms for the exploration of renewable resources are necessary to overcome these challenges. Within the multinational framework MultiBioPro we are developing biorefinery pipelines to maximize the use of plant biomass. More specifically, we use poplar and tobacco tree (Nicotiana glauca) as target crop species for improving saccharification, isoprenoid, long chain hydrocarbon contents, fiber quality, and suberin and lignin contents. The methods used to obtain these outputs include GC-MS, LC-MS and RNA sequencing platforms. The metabolite pipelines are well established tools to generate these types of data, but also have the limitations in that only well characterized metabolites can be used. The deep sequencing will allow us to include all transcripts present during the developmental stages of the tobacco tree leaf, but has to be mapped back to the sequence of Nicotiana tabacum. With these set-ups, we aim at a basic understanding for underlying processes and at establishing an industrial framework to exploit the outcomes. In a more long term perspective, we believe that data generated here will provide means for a sustainable biorefinery process using poplar and tobacco tree as raw material. To date the basal level of metabolites in the samples have been analyzed and the protocols utilized are provided in this article.

Never too old : engaging retired people inventing the future with MaKey MaKey

Within HCI, aging is often viewed in terms of designing assistive technologies to improve the lives of older people, such as those who are suffering from frailty or memory loss. Our research adopts a very different approach, reframing the relationship in terms of wisdom, creativity and invention. We ran a series of workshops where groups of retirees, aged between early 60s and late 80s, used the MaKey MaKey inventor's toolkit. We asked them to think about inventing the future and suggest ideas for new technologies. Our findings showed that they not only rose to the challenge but also mastered the technology, collaborated intensely together while using it and freely and at length discussed their own, their family's and others' relationship with technology. We discuss the value of empowering people in this way and consider what else could be invented to enable more people to be involved in the design and use of creative technologies.

Invisible connections : investigating older people's emotions and social relations around objects

The advent of the Internet of Things creates an interest in how people might interrelate through and with networks of internet enabled objects. With an emphasis on fostering social connection and physical activity among older people, this preliminary study investigated objects that people over the age of 65 years viewed as significant to them. We conducted contextual interviews in people's homes about their significant objects in order to understand the role of the objects in their lives, the extent to which they fostered emotional and social connections and physical activity, and how they might be augmented through internet connection. Discussion of significant objects generated considerable emotion in the participants. We identified objects of comfort and routine, objects that exhibited status, those that fostered independence and connection, and those that symbolized relationships with loved ones. These findings lead us to consider implications for the design of interconnected objects.