Screening of Oligomeric (Meth)acrylate Vaccine Adjuvants Synthesized via Catalytic Chain Transfer Polymerization.

This report details the first systematic screening of free-radical-produced methacrylate oligomer reaction mixtures as alternative vaccine adjuvant components to replace the current benchmark compound squalene, which is unsustainably sourced from shark livers. Homo-/co-oligomer mixtures of methyl, butyl, lauryl, and stearyl methacrylate were successfully synthesized using catalytic chain transfer control, where the use of microwave heating was shown to promote propagation over chain transfer. Controlling the mixture material properties allowed the correct viscosity to be achieved, enabling the mixtures to be effectively used in vaccine formulations. Emulsions of selected oligomers stimulated comparable cytokine levels to squalene emulsion when incubated with human whole blood and elicited an antigen-specific cellular immune response when administered with an inactivated influenza vaccine, indicating the potential utility of the compounds as vaccine adjuvant components. Furthermore, the oligomers' molecular sizes were demonstrated to be large enough to enable greater emulsion stability than squalene, especially at high temperatures, but are predicted to be small enough to allow for rapid clearance from the body.

Poor power quality is a major barrier to providing optimal care in special neonatal care units (SNCU) in Central India.

Background: Approximately 25% of all neonatal deaths worldwide occur in India. The Indian Government has established Special Neonatal Care Units (SNCUs) in district and sub-district level hospitals to reduce neonatal mortality, but mortality rates have stagnated. Reasons include lack of personnel and training and sub-optimal quality of care. The role of medical equipment is critical for the care of babies, but its role in improving neonatal outcomes has not been well studied.  Methods: In a qualitative study, we conducted seven focus group discussions with SNCU nurses and pediatric residents and thirty-five key informant interviews and with pediatricians, residents, nurses, annual equipment maintenance contractors, equipment manufacturers, and Ministry of Health personnel in Maharashtra between December 2019 and November 2020. The goal of the study was to understand challenges to SNCU care. In this paper, we focus on current gaps and future needs for SNCU equipment, quality of the power supply, and use of SNCU equipment. Results: Respondents described a range of issues but highlighted poor power quality as an important cause of equipment malfunction. Other concerns were lack of timely repair that resulted in needed equipment being unavailable for neonatal care. Participants recommended procuring uninterrupted power supply (UPS) to protect equipment, improving quality/durability of equipment to withstand constant use, ensuring regular proactive maintenance for SNCU equipment, and conducting local power audits to discern and address the causes of power fluctuations. Conclusions: Poor power quality and its negative impact on equipment function are major unaddressed concerns of those responsible for the care and safety of babies in SNCUs in Central India. Further research on the power supply and protection of neonatal equipment is needed to determine a cost-effective way to improve access to supportive care in SNCUs and desired improvements in neonatal mortality rates.

Lithium chloride protects retinal neurocytes from nutrient deprivation by promoting DNA non-homologous end-joining.

Lithium chloride is a therapeutic agent for treatment of bipolar affective disorders. Increasing numbers of studies have indicated that lithium has neuroprotective effects. However, the molecular mechanisms underlying the actions of lithium have not been fully elucidated. This study aimed to investigate whether lithium chloride produces neuroprotective function by improving DNA repair pathway in retinal neurocyte. In vitro, the primary cultured retinal neurocytes (85.7% are MAP-2 positive cells) were treated with lithium chloride, then cultured with serum-free media to simulate the nutrient deprived state resulting from ischemic insult. The neurite outgrowth of the cultured cells increased significantly in a dose-dependent manner when exposed to different levels of lithium chloride. Genomic DNA electrophoresis demonstrated greater DNA integrity of retinal neurocytes when treated with lithium chloride as compared to the control. Moreover, mRNA and protein levels of Ligase IV (involved in DNA non-homologous end-joining (NHEJ) pathway) in retinal neurocytes increased with lithium chloride. The end joining activity assay was performed to determine the role of lithium on NHEJ in the presence of extract from retinal neurocytes. The rejoining levels in retinal neurocytes treated with lithium were significantly increased as compared to the control. Furthermore, XRCC4, the Ligase IV partner, and the transcriptional factor, CREB and CTCF, were up-regulated in retinal cells after treating with 1.0mM lithium chloride. Therefore, our data suggest that lithium chloride protects the retinal neural cells from nutrient deprivation in vitro, which may be similar to the mechanism of cell death in glaucoma. The improvement in DNA repair pathway involving in Ligase IV might have an important role in lithium neuroprotection. This study provides new insights into the neural protective mechanisms of lithium chloride.

Ecotherapy - A Forgotten Ecosystem Service: A Review.

Natural ecosystems provide important services upon which humans depend. Unfortunately, some people tend to believe that these services are provided by nature for free; therefore, the services have little or no value. One nearly forgotten ecosystem service is ecotherapy - the ability of interaction with nature to enhance healing and growth. While we do not pay for this service, its loss can result in a cost to humans resulting in slower recovery times, greater distress and reduced well-being. Losses in these images of nature can diminish our basic happiness. Little is understood or, at least, appreciated concerning the potential ecotherapy benefits of the natural environment and its ecosystem services. The complex and interactive relationship of ecosystems, their services and human well-being is poorly acknowledged in the broad social, philosophical, psychological and economic well-being literature. In this article, we examine the role of nature and its ecosystem services in ecotherapy and its associated enhancement of recovery from physical and mental illness through a review of studies evaluating this ecosystem service-recovery connection.

Site-directed genome modification: nucleic acid and protein modules for targeted integration and gene correction.

A variety of technological advances in recent years have made permanent genetic manipulation of an organism a technical possibility. As the details of natural biological processes for genome modification are elucidated, the enzymes catalyzing these events (transposases, recombinases, integrases and DNA repair enzymes) are being harnessed or modified for the purpose of intentional gene modification. Targeted integration and gene repair can be mediated by the DNA-targeting specificity inherent to a particular enzyme, or rely on user-designed specificities. Integration sites can be defined by using DNA base-pairing or protein-DNA interaction as a means of targeting. This review will describe recent progress in the development of 'user-targetable' systems, particularly highlighting the application of custom DNA-binding proteins or nucleic acid homology to confer specificity.

Site-directed genome modification: derivatives of DNA-modifying enzymes as targeting tools.

The modification of mammalian genomes is an important goal in gene therapy and animal transgenesis. To generate stable genetic and biochemical changes, the therapeutic genes or transgenes need to be incorporated into the host genome. Ideally, the integration of the foreign gene should occur at sites that ensure their continual expression in the absence of any unwanted side effects on cellular metabolism. In this article, we discuss the opportunities provided by natural DNA-modifying enzymes, such as transposases, recombinases and integrases, to mediate the stable integration of foreign genes into host genomes. In addition, we discuss the approaches that have been taken to improve the efficiency and to modify the site-specificity of these enzymes.

The controversial abscopal effect.

The abscopal effect is potentially important for tumor control and is mediated through cytokines and/or the immune system, mainly cell-mediated immunity. It results from loss of growth stimulatory and/or immunosuppressive factors from the tumor. Until recently, the abscopal effect referred to the distant effects seen after local radiation therapy. However, the term should now be used interchangeably with distant bystander effect. Through analysis of distant bystander effects of other local therapies, we discuss the poorly understood and researched radiation-induced abscopal effect. Although the abscopal effect has been described in various malignancies, it is a rarely recognized clinical event. The abscopal effect is still extremely controversial with known data that both support and refute the concept.

Design of a nonviral vector for site-selective, efficient integration into the human genome.

Gene therapy in eukaryotes has met many obstacles. Research into the design of suitable nonviral vectors has been slow. To our knowledge, no nonviral vector has been proposed that allows for the possibility of highly efficient, site-selective integration into the genome of mammalian cells. On the basis of prior studies investigating the components necessary for transposon, retrovirus-like retrotransposon, and retroviral integration, we propose a nonviral system that would potentially allow for site-selective, efficient integration into the mammalian genome. Transposons have been developed that can transform a variety of cell lines. For example, the Sleeping Beauty transposon (SB) can transform a wide range of vertebrate cells from fish to human, and it mediates stable integration and long-term transgene expression in mice. However, the efficiency of transposition varies significantly among cell lines, suggesting the possible involvement of host factors in SB transposition. Here, we propose the use of a chimeric transposase (i.e., transposase-host DNA binding domain) to bypass the potential requirement of a host DNA-directing factor (or factors) for efficient, site-selective integration. We also discuss another potential method of docking the transposon-based vector adjacent to the host DNA, utilizing repetitive sequences for homologous recombination to promote efficient site-selective integration, as well as other site-selective nonviral approaches.

Immunotherapy and prostate cancer.

Prostate cancer is the second leading cause of cancer death in the US, largely because of the limitations of our current therapeutic options, especially once the cancer has metastasized. Investigators have long sought new therapeutic modalities such as angiogenesis inhibitors, vaccines, and gene therapy, among others. It appears that a combination approach will be required to cure the majority of malignancies. Immunotherapy for prostate cancer appears feasible and a likely therapeutic modality in the armamentarium. Unfortunately, further research in basic immunology and the interaction of the immune system with other forms of therapy is needed. Many obstacles exist in immunotherapy, including vector design, tumouricidal specificity, and tumor evasion, which will have to be overcome in order to realize the maximum therapeutic benefit from this treatment modality.

Strain reactions to perceived entitlement behavior by others as a contextual stressor: Moderating role of political skill in three samples.

Observing others entitlement behavior can create a stressful work context fraught with accompanying strain consequences. The present investigation examined the interactive effects of perceived entitlement behavior by others and political skill on job tension in three samples (N = 440, 167, and 140, respectively) designed to establish a consistent pattern of results. Specifically, perceived entitlement behavior by others was hypothesized to predict heightened levels of job tension in the absence of political skill. Conversely, for those with high levels of political skill, perceived entitlement behavior by others was predicted to demonstrate little relationship with job tension. Across samples, hypothesized relationships received support, as political skill was found to be a significant moderator of the perceived entitlement behavior by others--job tension relationship. Scholarly and practical implications, strengths and limitations, and future research directions are discussed.