Delivery of sTRAIL variants by MSCs in combination with cytotoxic drug treatment leads to p53-independent enhanced antitumor effects

Mesenchymal stem cells (MSCs) are able to infiltrate tumor tissues and thereby effectively deliver gene therapeutic payloads. Here, we engineered murine MSCs (mMSCs) to express a secreted form of the TNF-related apoptosis-inducing ligand (TRAIL), which is a potent inducer of apoptosis in tumor cells, and tested these MSCs, termed MSC.sTRAIL, in combination with conventional chemotherapeutic drug treatment in colon cancer models. When we pretreated human colorectal cancer HCT116 cells with low doses of 5-fluorouracil (5-FU) and added MSC.sTRAIL, we found significantly increased apoptosis as compared with single-agent treatment. Moreover, HCT116 xenografts, which were cotreated with 5-FU and systemically delivered MSC.sTRAIL, went into remission. Noteworthy, this effect was protein 53 (p53) independent and was mediated by TRAIL-receptor 2 (TRAIL-R2) upregulation, demonstrating the applicability of this approach in p53-defective tumors. Consequently, when we generated MSCs that secreted TRAIL-R2-specific variants of soluble TRAIL (sTRAIL), we found that such engineered MSCs, labeled MSC.sTRAIL DR5, had enhanced antitumor activity in combination with 5-FU when compared with MSC.sTRAIL. In contrast, TRAIL-resistant pancreatic carcinoma PancTu1 cells responded better to MSC.sTRAIL DR4 when the antiapoptotic protein XIAP (X-linked inhibitor of apoptosis protein) was silenced concomitantly. Taken together, our results demonstrate that TRAIL-receptor selective variants can potentially enhance the therapeutic efficacy of MSC-delivered TRAIL as part of individualized and tumor-specific combination treatments. © 2013 Macmillan Publishers Limited All rights reserved

“I don’t want to live too long!”: Successful ageing and the failure of longevity in Japan

This chapter examines ‘successful aging’ through its impacts on formal care workers in Japan. It is based on one year of fieldwork conducted in urban Japan and examines the affective, ethical, and cultural forces that result at times in resilience, compassion, and intimacy between carers and elderly clients, and at other times, in violence, abuse, and abandonment. I argue that locating the source of this divergence in individuals (i.e., adverse coping strategy) reproduces the same neoliberal model of success for care workers as it does for the elderly. Instead, care and abuse in formal care settings can be seen as symptoms of broader political and economic transformations that have been occurring in Japan since the 1990s

Shallow water marine sediment bacterial community shifts along a natural CO2 gradient in the Mediterranean Sea off Vulcano, Italy.

The effects of increasing atmospheric CO(2) on ocean ecosystems are a major environmental concern, as rapid shoaling of the carbonate saturation horizon is exposing vast areas of marine sediments to corrosive waters worldwide. Natural CO(2) gradients off Vulcano, Italy, have revealed profound ecosystem changes along rocky shore habitats as carbonate saturation levels decrease, but no investigations have yet been made of the sedimentary habitat. Here, we sampled the upper 2 cm of volcanic sand in three zones, ambient (median pCO(2) 419 μatm, minimum Ω(arag) 3.77), moderately CO(2)-enriched (median pCO(2) 592 μatm, minimum Ω(arag) 2.96), and highly CO(2)-enriched (median pCO(2) 1611 μatm, minimum Ω(arag) 0.35). We tested the hypothesis that increasing levels of seawater pCO(2) would cause significant shifts in sediment bacterial community composition, as shown recently in epilithic biofilms at the study site. In this study, 454 pyrosequencing of the V1 to V3 region of the 16S rRNA gene revealed a shift in community composition with increasing pCO(2). The relative abundances of most of the dominant genera were unaffected by the pCO(2) gradient, although there were significant differences for some 5 % of the genera present (viz. Georgenia, Lutibacter, Photobacterium, Acinetobacter, and Paenibacillus), and Shannon Diversity was greatest in sediments subject to long-term acidification (>100 years). Overall, this supports the view that globally increased ocean pCO(2) will be associated with changes in sediment bacterial community composition but that most of these organisms are resilient. However, further work is required to assess whether these results apply to other types of coastal sediments and whether the changes in relative abundance of bacterial taxa that we observed can significantly alter the biogeochemical functions of marine sediments

Background risk of breast cancer and the association between physical activity and mammographic density

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Sound Frequency and Aural Selectivity in Sound-Contingent Visual Motion Aftereffect

BACKGROUND: One possible strategy to evaluate whether signals in different modalities originate from a common external event or object is to form associations between inputs from different senses. This strategy would be quite effective because signals in different modalities from a common external event would then be aligned spatially and temporally. Indeed, it has been demonstrated that after adaptation to visual apparent motion paired with alternating auditory tones, the tones begin to trigger illusory motion perception to a static visual stimulus, where the perceived direction of visual lateral motion depends on the order in which the tones are replayed. The mechanisms underlying this phenomenon remain unclear. One important approach to understanding the mechanisms is to examine whether the effect has some selectivity in auditory processing. However, it has not yet been determined whether this aftereffect can be transferred across sound frequencies and between ears. METHODOLOGY/PRINCIPAL FINDINGS: Two circles placed side by side were presented in alternation, producing apparent motion perception, and each onset was accompanied by a tone burst of a specific and unique frequency. After exposure to this visual apparent motion with tones for a few minutes, the tones became drivers for illusory motion perception. However, the aftereffect was observed only when the adapter and test tones were presented at the same frequency and to the same ear. CONCLUSIONS/SIGNIFICANCE: These findings suggest that the auditory processing underlying the establishment of novel audiovisual associations is selective, potentially but not necessarily indicating that this processing occurs at an early stage

Effects of Noise Bandwidth and Amplitude Modulation on Masking in Frog Auditory Midbrain Neurons

Natural auditory scenes such as frog choruses consist of multiple sound sources (i.e., individual vocalizing males) producing sounds that overlap extensively in time and spectrum, often in the presence of other biotic and abiotic background noise. Detection of a signal in such environments is challenging, but it is facilitated when the noise shares common amplitude modulations across a wide frequency range, due to a phenomenon called comodulation masking release (CMR). Here, we examined how properties of the background noise, such as its bandwidth and amplitude modulation, influence the detection threshold of a target sound (pulsed amplitude modulated tones) by single neurons in the frog auditory midbrain. We found that for both modulated and unmodulated masking noise, masking was generally stronger with increasing bandwidth, but it was weakened for the widest bandwidths. Masking was less for modulated noise than for unmodulated noise for all bandwidths. However, responses were heterogeneous, and only for a subpopulation of neurons the detection of the probe was facilitated when the bandwidth of the modulated masker was increased beyond a certain bandwidth – such neurons might contribute to CMR. We observed evidence that suggests that the dips in the noise amplitude are exploited by TS neurons, and observed strong responses to target signals occurring during such dips. However, the interactions between the probe and masker responses were nonlinear, and other mechanisms, e.g., selective suppression of the response to the noise, may also be involved in the masking release

Organism-sediment interactions govern post-hypoxia recovery of ecosystem functioning

Hypoxia represents one of the major causes of biodiversity and ecosystem functioning loss for coastal waters. Since eutrophication-induced hypoxic events are becoming increasingly frequent and intense, understanding the response of ecosystems to hypoxia is of primary importance to understand and predict the stability of ecosystem functioning. Such ecological stability may greatly depend on the recovery patterns of communities and the return time of the system properties associated to these patterns. Here, we have examined how the reassembly of a benthic community contributed to the recovery of ecosystem functioning following experimentally-induced hypoxia in a tidal flat. We demonstrate that organism-sediment interactions that depend on organism size and relate to mobility traits and sediment reworking capacities are generally more important than recovering species richness to set the return time of the measured sediment processes and properties. Specifically, increasing macrofauna bioturbation potential during community reassembly significantly contributed to the recovery of sediment processes and properties such as denitrification, bedload sediment transport, primary production and deep pore water ammonium concentration. Such bioturbation potential was due to the replacement of the small-sized organisms that recolonised at early stages by large-sized bioturbating organisms, which had a disproportionately stronger influence on sediment. This study suggests that the complete recovery of organism-sediment interactions is a necessary condition for ecosystem functioning recovery, and that such process requires long periods after disturbance due to the slow growth of juveniles into adult stages involved in these interactions. Consequently, repeated episodes of disturbance at intervals smaller than the time needed for the system to fully recover organism-sediment interactions may greatly impair the resilience of ecosystem functioning.

The impact of mental health recovery narratives on recipients experiencing mental health problems: Qualitative analysis and change model.

BACKGROUND: Mental health recovery narratives are stories of recovery from mental health problems. Narratives may impact in helpful and harmful ways on those who receive them. The objective of this paper is to develop a change model identifying the range of possible impacts and how they occur. METHOD: Semi-structured interviews were conducted with adults with experience of mental health problems and recovery (n = 77). Participants were asked to share a mental health recovery narrative and to describe the impact of other people's recovery narratives on their own recovery. A change model was generated through iterative thematic analysis of transcripts. RESULTS: Change is initiated when a recipient develops a connection to a narrator or to the events descripted in their narrative. Change is mediated by the recipient recognising experiences shared with the narrator, noticing the achievements or difficulties of the narrator, learning how recovery happens, or experiencing emotional release. Helpful outcomes of receiving recovery narratives are connectedness, validation, hope, empowerment, appreciation, reference shift and stigma reduction. Harmful outcomes are a sense of inadequacy, disconnection, pessimism and burden. Impact is positively moderated by the perceived authenticity of the narrative, and can be reduced if the recipient is experiencing a crisis. CONCLUSIONS: Interventions that incorporate the use of recovery narratives, such as peer support, anti-stigma campaigns and bibliotherapy, can use the change model to maximise benefit and minimise harms from narratives. Interventions should incorporate a diverse range of narratives available through different mediums to enable a range of recipients to connect with and benefit from this material. Service providers using recovery narratives should preserve authenticity so as to maximise impact, for example by avoiding excessive editing

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition