Exogenous Signaling Molecules Released from Aptamer-Functionalized Hydrogels Promote the Survival of Mesenchymal Stem Cell Spheroids.

Mesenchymal stem cells (MSCs) have a very low survival rate after in vivo delivery, which limits their great promise for treating human diseases. Various strategies have been studied to overcome this challenge. However, an overlooked but important potential is to apply exogenous signaling molecules as biochemical cues to promote MSC survival, presumably because it is well-known that MSCs themselves can release a variety of potent signaling molecules. Thus, the purpose of this work was to examine and understand whether the release of exogenous signaling molecules from hydrogels can promote the survival of MSC spheroids. Our data show that more vascular endothelial growth factor (VEGF) but not platelet-derived growth factor BB (PDGF-BB) were released from MSC spheroids in comparison with 2D cultured MSCs. Aptamer-functionalized fibrin hydrogel (aFn) could release exogenous VEGF and PDGF-BB in a sustained manner. PDGF-BB-loaded aFn promoted MSC survival by ∼70% more than VEGF-loaded aFn under the hypoxic condition in vitro. Importantly, PDGF-BB-loaded aFn could double the survival rate of MSC spheroids in comparison with VEGF-loaded aFn during the one-week test in vivo. Therefore, this work demonstrated that defined exogenous signaling molecules (e.g., PDGF-BB) can function as biochemical cues for promoting the survival of MSC spheroids in vivo.

In†Situ Synthesis of an Aptamer-Based Polyvalent Antibody Mimic on the Cell Surface for Enhanced Interactions between Immune and Cancer Cells.

An ability to promote therapeutic immune cells to recognize cancer cells is important for the success of cell-based cancer immunotherapy. We present a synthetic method for functionalizing the surface of natural killer (NK) cells with a supramolecular aptamer-based polyvalent antibody mimic (PAM). The PAM is synthesized on the cell surface through nucleic acid assembly and hybridization. The data show that PAM has superiority over its monovalent counterpart in powering NKs to bind to cancer cells, and that PAM-engineered NK cells exhibit the capability of killing cancer cells more effectively. Notably, aptamers can, in principle, be discovered against any cell receptors; moreover, the aptamers can be replaced by any other ligands when developing a PAM. Thus, this work has successfully demonstrated a technology platform for promoting interactions between immune and cancer cells.

Development of hydrogel-like biomaterials via nanoparticle assembly and solid-hydrogel transformation.

Hydrogels for biomedical applications such as controlled drug release are usually synthesized with the chemical or physical crosslinking of monomers or macromers. In this work, we used gelatin to prepare hydrogel nanoparticles and studied whether gelatin nanoparticles (GNPs) could assemble to form a solid biomaterial and whether this solid biomaterial was capable of transforming into a hydrogel upon introduction to a hydrated environment. The data show that GNPs with or without aptamer functionalization could form a nanoparticle-assembled porous solid biomaterial after freezing and lyophilization treatment. This formation did not need any additional crosslinking reactions. More importantly, this solid biomaterial could undergo solid-to-hydrogel transition after contacting a solution and this transformation was tunable to match different shapes and geometries of defined molds. The formed hydrogel could also sequester and release growth factors for the promotion of skin wound healing. Thus, GNP-assembled solid biomaterials hold great potential as an off-the-shelf therapy for biomedical application such as drug delivery and regenerative medicine.

Prevention of suicidal behaviour: Results of a controlled community-based intervention study in four European countries.

The 'European Alliance Against Depression' community-based intervention approach simultaneously targets depression and suicidal behaviour by a multifaceted community based intervention and has been implemented in more than 115 regions worldwide. The two main aims of the European Union funded project "Optimizing Suicide Prevention Programmes and Their Implementation in Europe" were to optimise this approach and to evaluate its implementation and impact. This paper reports on the primary outcome of the intervention (the number of completed and attempted suicides combined as 'suicidal acts') and on results concerning process evaluation analysis. Interventions were implemented in four European cities in Germany, Hungary, Portugal and Ireland, with matched control sites. The intervention comprised activities with predefined minimal intensity at four levels: training of primary care providers, a public awareness campaign, training of community facilitators, support for patients and their relatives. Changes in frequency of suicidal acts with respect to a one-year baseline in the four intervention regions were compared to those in the four control regions (chi-square tests). The decrease in suicidal acts compared to baseline in the intervention regions (-58 cases, -3.26%) did not differ significantly (χ2 = 0.13; p = 0.72) from the decrease in the control regions (-18 cases, -1.40%). However, intervention effects differed between countries (χ2 = 8.59; p = 0.04), with significant effects on suicidal acts in Portugal (χ2 = 4.82; p = 0.03). The interviews and observations explored local circumstances in each site throughout the study. Hypothesised mechanisms of action for successful implementation were observed and drivers for 'added-value' were identified: local partnership working and 'in-kind' contributions; an approach which valued existing partnership strengths; and synergies operating across intervention levels. It can be assumed that significant events during the implementation phase had a certain impact on the observed outcomes. However, this impact was, of course, not proven.

Assembly of Bifunctional Aptamer-Fibrinogen Macromer for VEGF Delivery and Skin Wound Healing.

Macromolecular assembly has been studied for various applications. However, while macromolecules can recognize one another for assembly, their assembled structures usually lack the function of specific molecular recognition. We hypothesized that bifunctional aptamer-protein macromers would possess dual functions of molecular assembly and recognition. The data show that hybrid aptamer-fibrinogen macromers can assemble to form hydrogels. Moreover, the assembled hydrogels can recognize vascular endothelial growth factor (VEGF) for sustained release. When the VEGF-loaded hydrogels are implanted in vivo, they can promote angiogenesis and skin wound healing. Thus, this work has successfully demonstrated a promising macromolecular system for broad applications such as drug delivery and regenerative medicine.

DNA-templated synthesis of biomimetic cell wall for nanoencapsulation and protection of mammalian cells.

Mammalian cells are different from plant and microbial cells, having no exterior cell walls for protection. Environmental assaults can easily damage or destroy mammalian cells. Thus, the ability to develop a biomimetic cell wall (BCW) on their plasma membrane as a shield can advance various applications. Here we demonstrate the synthesis of BCW with a framing template and a crosslinked matrix for shielding live mammalian cells. The framing template is a supramolecular DNA structure. The crosslinked matrix is a polyelectrolyte complex made of alginate and polylysine. As the entire procedure of BCW synthesis is strictly operated under physiological conditions, BCW-covered mammalian cells can maintain high bioactivity. More importantly, the data show that BCW can shield live mammalian cells from not only physical assaults but also biological assaults. Thus, this study has successfully demonstrated the synthesis of BCW on live mammalian cells with great potential of shielding them from environmental assaults.

Dual Aptamer-Functionalized in Situ Injectable Fibrin Hydrogel for Promotion of Angiogenesis via Codelivery of Vascular Endothelial Growth Factor and Platelet-Derived Growth Factor-BB.

In situ injectable hydrogels hold great potential for in vivo applications such as drug delivery and regenerative medicine. However, it is challenging to ensure stable sequestration and sustained release of loaded biomolecules in these hydrogels. As aptamers have high binding affinities and specificities against target biomolecules, we studied the capability of aptamers in functionalizing in situ injectable fibrin (Fn) hydrogels for in vivo delivery of two growth factors including vascular endothelial growth factor (VEGF) and platelet-derived growth factor-BB (PDGF-BB). The results show that aptamer-functionalized fibrinogen (Fg) could form in situ injectable Fn hydrogels with porous structures. The aptamer-functionalized Fn hydrogels could sequester more VEGF and PDGF-BB than the native Fn and release these growth factors in a sustained manner with high bioactivity. After the aptamer-functionalized Fn hydrogels were subcutaneously injected into mice, the codelivery of VEGF and PDGF-BB could promote the growth of mature blood vessels. Therefore, this study has successfully demonstrated that aptamer-functionalized in situ injectable hydrogels hold great potential for in vivo codelivery of multiple growth factors and promotion of angiogenesis .

Does Twitter language reliably predict heart disease? A commentary on Eichstaedt et al. (2015a).

We comment on Eichstaedt et al.'s (2015a) claim to have shown that language patterns among Twitter users, aggregated at the level of US counties, predicted county-level mortality rates from atherosclerotic heart disease (AHD), with "negative" language being associated with higher rates of death from AHD and "positive" language associated with lower rates. First, we examine some of Eichstaedt et al.'s apparent assumptions about the nature of AHD, as well as some issues related to the secondary analysis of online data and to considering counties as communities. Next, using the data files supplied by Eichstaedt et al., we reproduce their regression- and correlation-based models, substituting mortality from an alternative cause of death-namely, suicide-as the outcome variable, and observe that the purported associations between "negative" and "positive" language and mortality are reversed when suicide is used as the outcome variable. We identify numerous other conceptual and methodological limitations that call into question the robustness and generalizability of Eichstaedt et al.'s claims, even when these are based on the results of their ridge regression/machine learning model. We conclude that there is no good evidence that analyzing Twitter data in bulk in this way can add anything useful to our ability to understand geographical variation in AHD mortality rates.

Polyvalent Display of Biomolecules on Live Cells.

Surface display of biomolecules on live cells offers new opportunities to treat human diseases and perform basic studies. Existing methods are primarily focused on monovalent functionalization, that is, the display of single biomolecules across the cell surface. Here we show that the surface of live cells can be functionalized to display polyvalent biomolecular structures through two-step reactions under physiological conditions. This polyvalent functionalization enables the cell surface to recognize the microenvironment one order of magnitude more effectively than with monovalent functionalization. Thus, polyvalent display of biomolecules on live cells holds great potential for various biological and biomedical applications.

One-year follow-up of a randomized controlled trial of sertraline and cognitive behavior group therapy in depressed primary care patients (MIND study).

BACKGROUND: The long-term course of symptoms in patients with mild-to-moderate depression is not well understood. A 12-month-follow-up analysis was performed on those participants from a randomized controlled 10-week trial (RCT, MIND-study), who had received either treatment with an antidepressant (sertraline) or a psychotherapeutic intervention (group cognitive-behavioral therapy (CBT)). METHODS: The longitudinal interval follow-up evaluation (LIFE) was applied to 77 patients with mild-to moderate depression. The primary outcome was the number of weeks in the one-year follow-up period spent completely recovered from all depressive symptoms. Functional outcome was measured with the Global Assessment of Functioning (GAF) scale. Further outcomes were relapse and remission rates based on weekly psychiatric rating scales (PSR) and the number of weeks in the follow-up period during which patients had a depressive disorder or subthreshold symptoms of depression. RESULTS: Patients with acute treatment (10 weeks) with SSRI and those with acute treatment with CBT (also 10 weeks) did not differ significantly concerning the number of weeks in the follow-up period in which they were completely recovered (primary outcome) (SSRI: 31.6 weeks (standard deviation (SD): 23.7), CBT: 27.8 weeks (SD: 24.3)). Sertraline was superior to CBT regarding GAF scores by trend (p = 0.06). LIMITATIONS: The generalizability of the findings is limited by the moderate sample size and missing values (LIFE). CONCLUSIONS: Sertraline and group CBT have similar anti-depressive effects in the long-term course of mild-to-moderate depression. Regarding long-term global functioning, sertraline seems to be slightly superior to CBT.

Dyadic psychological intervention for patients with cancer and caregivers in home-based specialized palliative care: The Domus model.

ABSTRACTObjective:Patients with incurable cancer and their informal caregivers have numerous psychological and psychosocial needs. Many of these patients wish to receive their care and die at home. Few home-based specialized palliative care (SPC) interventions systematically integrate psychological support. We present a psychological intervention for patient-caregiver dyads developed for an ongoing randomized controlled trial (RCT) of home-based SPC, known as Domus, as well as the results of an assessment of its acceptability and feasibility. METHOD: The Domus model of SPC for patients with incurable cancer and their caregivers offered systematic psychological assessment and dyadic intervention as part of interdisciplinary care. Through accelerated transition to SPC, the aim of the model was to enhance patients' chances of receiving care and dying at home. Integration of psychological support sought to facilitate this goal by alleviating distress in patients and caregivers. Psychologists provided needs-based sessions based on existential-phenomenological therapy. Feasibility and acceptability were investigated by examining enrollment, nonparticipation, and completion of psychological sessions. RESULTS: Enrollment in the RCT and uptake of the psychological intervention indicated that it was feasible and acceptable to patients and caregivers. The strengths of the intervention included its focus on dyads, psychological distress, and existential concerns, as well as interdisciplinary collaboration and psychological interventions offered according to need. Its main limitation was a lack of an intervention for other family members. SIGNIFICANCE OF RESULTS: Our results show that psychological intervention can be systematically integrated into SPC and that it appears feasible to provide dyadic needs-based sessions with an existential therapeutic approach. The Domus RCT will provide evidence of the efficacy of a novel model of multidisciplinary SPC.

Displacement and hybridization reactions in aptamer-functionalized hydrogels for biomimetic protein release and signal transduction.

A variety of hydrogels have been synthesized for controlling the release of signaling molecules in applications such as drug delivery and regenerative medicine. However, it remains challenging to synthesize hydrogels with the ability to control the release of signaling molecules sequentially or periodically under physiological conditions as living cells do in response to the variation of metabolism. The purpose of this work was to study a novel biomimetic hydrogel system with the ability of recapitulating the procedure of cellular signal transduction and controlling the sequential release of signaling molecules under physiological conditions. In the presence of a small chemical, the signaling molecule is regulated to change from a DNA-bound state to a free state and the freed signaling molecule is able to regulate intracellular signal transduction and cell migration. Moreover, periodic exposure of the hydrogel system to the small chemical leads to sequential protein release. Since signaling molecules are important for every activity of the cell, this hydrogel system holds potential as a metabolism-responsive platform for controlled release of signaling molecules and cell regulation in various applications.

Emodiversity: Robust predictor of outcomes or statistical artifact?

This article examines the concept of emodiversity, put forward by Quoidbach et al. (2014) as a novel source of information about "the health of the human emotional ecosystem" (p. 2057). Quoidbach et al. drew an analogy between emodiversity as a desirable property of a person's emotional make-up and biological diversity as a desirable property of an ecosystem. They claimed that emodiversity was an independent predictor of better mental and physical health outcomes in two large-scale studies. Here, we show that Quoidbach et al.'s construct of emodiversity suffers from several theoretical and practical deficiencies, which make these authors' use of Shannon's (1948) entropy formula to measure emodiversity highly questionable. Our reanalysis of Quoidbach et al.'s two studies shows that the apparently substantial effects that these authors reported are likely due to a failure to conduct appropriate hierarchical regression in one case and to suppression effects in the other. It appears that Quoidbach et al.'s claims about emodiversity may reduce to little more than a set of computational and statistical artifacts. (PsycINFO Database Record

Polymer Microneedle Mediated Local Aptamer Delivery for Blocking the Function of Vascular Endothelial Growth Factor.

Overexpression of proteins in the body can cause severe diseases and other physiological disturbances. The development of protein blockers and local delivery systems would offer opportunities for addressing the health problems caused by protein overexpression. Nucleic acid aptamers are an emerging class of ligands with the potential to block proteins effectively; however, little effort has been made in developing polymer systems for local aptamer delivery. In this work, polymer microneedles capable of delivering DNA aptamers locally to inhibit the function of vascular endothelial growth factor (VEGF) were developed and studied. The presence of anti-VEGF aptamer in the polymer matrix did not change the apparent mechanical strength of the microneedles. Once in contact with a physiological solution, the polymer microneedles quickly dissolved, generating a high concentration of anti-VEGF aptamer in the surrounding local microenvironment. Aptamer delivery by way of dissolving polymer microneedles in a tissue phantom reduced VEGF-mediated endothelial cell tube formation. Thus, aptamer-loaded polymer microneedles hold great potential as a therapeutic tool for the treatment of human diseases resulting from protein overexpression.

More Questions than Answers: Continued Critical Reanalysis of Fredrickson et al.'s Studies of Genomics and Well-Being.

We critically re-examine Fredrickson et al.'s renewed claims concerning the differential relationship between hedonic and eudaimonic forms of well-being and gene expression, namely that people who experience a preponderance of eudaimonic well-being have gene expression profiles that are associated with more favorable health outcomes. By means of an extensive reanalysis of their data, we identify several discrepancies between what these authors claimed and what their data support; we further show that their different analysis models produce mutually contradictory results. We then show how Fredrickson et al.'s most recent article on this topic not only fails to adequately address our previously published concerns about their earlier related work, but also introduces significant further problems, including inconsistency in their hypotheses. Additionally, we demonstrate that regardless of which statistical model is used to analyze their data, Fredrickson et al.'s method can be highly sensitive to the inclusion (or exclusion) of data from a single subject. We reiterate our previous conclusions, namely that there is no evidence that Fredrickson et al. have established a reliable empirical distinction between their two delineated forms of well-being, nor that eudaimonic well-being provides any overall health benefits over hedonic well-being.

Replication initiatives will not salvage the trustworthiness of psychology.

Replication initiatives in psychology continue to gather considerable attention from far outside the field, as well as controversy from within. Some accomplishments of these initiatives are noted, but this article focuses on why they do not provide a general solution for what ails psychology. There are inherent limitations to mass replications ever being conducted in many areas of psychology, both in terms of their practicality and their prospects for improving the science. Unnecessary compromises were built into the ground rules for design and publication of the Open Science Collaboration: Psychology that undermine its effectiveness. Some ground rules could actually be flipped into guidance for how not to conduct replications. Greater adherence to best publication practices, transparency in the design and publishing of research, strengthening of independent post-publication peer review and firmer enforcement of rules about data sharing and declarations of conflict of interest would make many replications unnecessary. Yet, it has been difficult to move beyond simple endorsement of these measures to consistent implementation. Given the strong institutional support for questionable publication practices, progress will depend on effective individual and collective use of social media to expose lapses and demand reform. Some recent incidents highlight the necessity of this.