Intracellular Targeting Specificity of Novel Phthalocyanines Assessed in a Host-Parasite Model for Developing Potential Photodynamic Medicine

Photodynamic therapy, unlikely to elicit drug-resistance, deserves attention as a strategy to counter this outstanding problem common to the chemotherapy of all diseases. Previously, we have broadened the applicability of this modality to photodynamic vaccination by exploiting the unusual properties of the trypanosomatid protozoa, Leishmania, i.e., their innate ability of homing to the phagolysosomes of the antigen-presenting cells and their selective photolysis therein, using transgenic mutants endogenously inducible for porphyrin accumulation. Here, we extended the utility of this host-parasite model for in vitro photodynamic therapy and vaccination by exploring exogenously supplied photosensitizers. Seventeen novel phthalocyanines (Pcs) were screened in vitro for their photolytic activity against cultured Leishmania. Pcs rendered cationic and soluble (csPcs) for cellular uptake were phototoxic to both parasite and host cells, i.e., macrophages and dendritic cells. The csPcs that targeted to mitochondria were more photolytic than those restricted to the endocytic compartments. Treatment of infected cells with endocytic csPcs resulted in their accumulation in Leishmania-containing phagolysosomes, indicative of reaching their target for photodynamic therapy, although their parasite versus host specificity is limited to a narrow range of csPc concentrations. In contrast, Leishmania pre-loaded with csPc were selectively photolyzed intracellularly, leaving host cells viable. Pre-illumination of such csPc-loaded Leishmania did not hinder their infectivity, but ensured their intracellular lysis. Ovalbumin (OVA) so delivered by photo-inactivated OVA transfectants to mouse macrophages and dendritic cells were co-presented with MHC Class I molecules by these antigen presenting cells to activate OVA epitope-specific CD8+T cells. The in vitro evidence presented here demonstrates for the first time not only the potential of endocytic csPcs for effective photodynamic therapy against Leishmania but also their utility in photo-inactivation of Leishmania to produce a safe carrier to express and deliver a defined antigen with enhanced cell-mediated immunity

Kin Selection and the Evolution of Social Information Use in Animal Conflict

Animals often use social information about conspecifics in making decisions about cooperation and conflict. While the importance of kin selection in the evolution of intraspecific cooperation and conflict is widely acknowledged, few studies have examined how relatedness influences the evolution of social information use. Here we specifically examine how relatedness affects the evolution of a stylised form of social information use known as eavesdropping. Eavesdropping involves individuals escalating conflicts with rivals observed to have lost their last encounter and avoiding fights with those seen to have won. We use a game theoretical model to examine how relatedness affects the evolution of eavesdropping, both when strategies are discrete and when they are continuous or mixed. We show that relatedness influences the evolution of eavesdropping, such that information use peaks at intermediate relatedness. Our study highlights the importance of considering kin selection when exploring the evolution of complex forms of information use

Patient experiences of psychological therapy for depression: a qualitative metasynthesis

Background Globally, national guidelines for depression have prioritised evidence from randomised controlled trials and quantitative meta-analyses, omitting qualitative research concerning patient experience of treatments. A review of patient experience research can provide a comprehensive overview of this important form of evidence and thus enable the voices and subjectivities of those affected by depression to have an impact on the treatments and services they are offered. This review aims to seek a comprehensive understanding of patient experiences of psychological therapies for depression using a systematic and rigorous approach to review and synthesis of qualitative research. Method PsychINFO, PsychARTICLES, MEDLINE, and CINAHL were searched for published articles using a qualitative approach to examine experiences of psychological therapies for depression. All types of psychological therapy were included irrespective of model or modes of delivery (e.g. remote or in person; group or individual). Each article was assessed following guidance provided by the Critical Appraisal Skill Programme tool. Articles were entered in full into NVIVO and themes were extracted and synthesized following inductive thematic analysis. Results Thirty-seven studies, representing 671 patients were included. Three main themes are described; the role of therapy features and setting; therapy processes and how they impact on outcomes; and therapy outcomes (benefits and limitations). Subthemes are described within these themes and include discussion of what works and what’s unhelpful; issues integrating therapy with real life; patient preferences and individual difference; challenges of undertaking therapy; influence of the therapist; benefits of therapy; limits of therapy and what happens when therapy ends. Conclusions Findings point to the importance of common factors in psychotherapies; highlight the need to assess negative outcomes; and indicate the need for patients to be more involved in discussions and decisions about therapy, including tailoring therapy to individual needs and taking social and cultural contexts into account

Altitudinal variation in soil organic carbon stock in coniferous subtropical and broadleaf temperate forests in Garhwal Himalaya

<p>Abstract</p> <p>Background</p> <p>The Himalayan zones, with dense forest vegetation, cover a fifth part of India and store a third part of the country reserves of soil organic carbon (SOC). However, the details of altitudinal distribution of these carbon stocks, which are vulnerable to forest management and climate change impacts, are not well known.</p> <p>Results</p> <p>This article reports the results of measuring the stocks of SOC along altitudinal gradients. The study was carried out in the coniferous subtropical and broadleaf temperate forests of Garhwal Himalaya. The stocks of SOC were found to be decreasing with altitude: from 185.6 to 160.8 t C ha^-1and from 141.6 to 124.8 t C ha^-1in temperature (<it>Quercus leucotrichophora</it>) and subtropical (<it>Pinus roxburghii</it>) forests, respectively.</p> <p>Conclusion</p> <p>The results of this study lead to conclusion that the ability of soil to stabilize soil organic matter depends negatively on altitude and call for comprehensive theoretical explanation</p

Localized induction of gene expression in embryonic stem cell aggregates using holographic optical tweezers to create biochemical gradients

Three-dimensional (3D) cell models that mimic the structure and function of native tissues are enabling more detailed study of physiological and pathological mechanisms in vitro. We have previously demonstrated the ability to build and manipulate 3D multicellular microscopic structures using holographic optical tweezers (HOTs). Here, we show the construction of a precisely patterned 3D microenvironment and biochemical gradient model consisting of mouse embryoid bodies (mEBs) and polymer microparticles loaded with retinoic acid (RA), embedded in a hydrogel. We demonstrate discrete, zonal expression of the RA-inducible protein Stra8 within mEBs in response to release of RA from polymer microparticles, corresponding directly to the defined 3D positioning of the microparticles using HOTs. These results demonstrate the ability of this technology to create chemical microgradients at definable length scales and to elicit, with fidelity and precision, specific biological responses. This technique can be used in the study of in vitro microenvironments to enable new insights on 3D cell models, their cellular assembly, and the delivery of drug or biochemical molecules for engineering and interrogation of functional and morphogenic responses