Extra-Ribosomal Functions of the Ribosomal Protein, RPS3 as Predicted by In Silico Analysis

Products of ribosomal protein (RP) genes have been found to play extra-ribosomal roles that range from DNA repair to RNA splicing. Their association with congenital disorders or cancers has also been widely documented. However, the relatively large number of different RPs, each with perhaps unique biological roles, has compounded the comprehensive elucidation of the physiological functions of each RPs. Experimental functional studies on the many and variegated RPs are labour intensive, time-consuming and costly. Moreover, experimental studies unguided by theoretically insights entail inaccurate results. Therefore, knowledge on the actual roles of these proteins remains largely undefined. A valid alternative is the use of bioinformatics resources to computationally predict functional roles of these biomolecules. Findings from such in silico studies of the RPS3 are reported herein. We reveal an array of possible extra-ribosomal functions that includes regulation of transcription (including via NF-κB-mediated, POK-induced and DNA-dependent), regulation of p53 activities and its stabilisation, inflammatory immune response, modulation of nNOS activities, and anti-oxidative capabilities. Our findings provide computational prediction of de novo extra-ribosomal functions of RPS3. These results will enhance the theoretical basis for designing future experimental studies on elucidating its definitive physiological roles

Structure-to-Function Computational Prediction of a Subset of Ribosomal Proteins for the Small Ribosome Subunit

Extra-ribosomal functions of ribosomal proteins have been widely accepted albeit an incomplete understanding of these roles. Standard experimental studies have limited usefulness in defining the complete biological significance of ribosomal proteins. An alternative strategy is via in silico analysis. Here, we sought a sequence-to-structure-to-function approach to computationally predict the extra-ribosomal functions of a subset of ribosomal proteins of the small ribosome subunit, namely RPS12, RPS19, RPS20 and RPS24. Three-dimensional structure constructed from amino acid sequence was precisely matched with structural neighbours to extrapolate possible functions. Our analysis reveals new logical roles for these ribosomal proteins, of which represent important information for planning experimental and further in silico studies to elucidate their physiological roles

Spatial heterogeneity and peptide availability determine CTL killing efficiency in vivo

The rate at which a cytotoxic T lymphocyte (CTL) can survey for infected cells is a key ingredient of models of vertebrate immune responses to intracellular pathogens. Estimates have been obtained using in vivo cytotoxicity assays in which peptide-pulsed splenocytes are killed by CTL in the spleens of immunised mice. However the spleen is a heterogeneous environment and splenocytes comprise multiple cell types. Are some cell types intrinsically more susceptible to lysis than others? Quantitatively, what impacts are made by the spatial distribution of targets and effectors, and the level of peptide-MHC on the target cell surface? To address these questions we revisited the splenocyte killing assay, using CTL specific for an epitope of influenza virus. We found that at the cell population level T cell targets were killed more rapidly than B cells. Using modeling, quantitative imaging and in vitro killing assays we conclude that this difference in vivo likely reflects different migratory patterns of targets within the spleen and a heterogeneous distribution of CTL, with no detectable difference in the intrinsic susceptibilities of the two populations to lysis. Modeling of the stages involved in the detection and killing of peptide-pulsed targets in vitro revealed that peptide dose influenced the ability of CTL to form conjugates with targets but had no detectable effect on the probability that conjugation resulted in lysis, and that T cell targets took longer to lyse than B cells. We also infer that incomplete killing in vivo of cells pulsed with low doses of peptide may be due to a combination of heterogeneity in peptide uptake and the dissociation, but not internalisation, of peptide-MHC complexes. Our analyses demonstrate how population-averaged parameters in models of immune responses can be dissected to account for both spatial and cellular heterogeneity

Predictors of outcome of dream work for East Asian volunteer clients: Dream factors, attachment anxiety, Asian values, and therapist input

Eighty-eight East Asian volunteers were paired with 6 Eas

Papillary renal cell carcinoma with metastatic laparoscopic port site and vaginal involvement: a case report

10.1186/1752-1947-5-131Journal of Medical Case Reports513

Transplantation of canine olfactory ensheathing cells producing chondroitinase ABC promotes chondroitin sulphate proteoglycan digestion and axonal sprouting following spinal cord injury

Olfactory ensheathing cell (OEC) transplantation is a promising strategy for treating spinal cord injury (SCI), as has been demonstrated in experimental SCI models and naturally occurring SCI in dogs. However, the presence of chondroitin sulphate proteoglycans within the extracellular matrix of the glial scar can inhibit efficient axonal repair and limit the therapeutic potential of OECs. Here we have used lentiviral vectors to genetically modify canine OECs to continuously deliver mammalian chondroitinase ABC at the lesion site in order to degrade the inhibitory chondroitin sulphate proteoglycans in a rodent model of spinal cord injury. We demonstrate that these chondroitinase producing canine OECs survived at 4 weeks following transplantation into the spinal cord lesion and effectively digested chondroitin sulphate proteoglycans at the site of injury. There was evidence of sprouting within the corticospinal tract rostral to the lesion and an increase in the number of corticospinal axons caudal to the lesion, suggestive of axonal regeneration. Our results indicate that delivery of the chondroitinase enzyme can be achieved with the genetically modified OECs to increase axon growth following SCI. The combination of these two promising approaches is a potential strategy for promoting neural regeneration following SCI in veterinary practice and human patients

LOGISTICS IN CONTESTED ENVIRONMENTS

This report examines the transport and delivery of logistics in contested environments within the context of great-power competition (GPC). Across the Department of Defense (DOD), it is believed that GPC will strain our current supply lines beyond their capacity to maintain required warfighting capability. Current DOD efforts are underway to determine an appropriate range of platforms, platform quantities, and delivery tactics to meet the projected logistics demand in future conflicts. This report explores the effectiveness of various platforms and delivery methods through analysis in developed survivability, circulation, and network optimization models. Among other factors, platforms are discriminated by their radar cross-section (RCS), noise level, speed, cargo capacity, and self-defense capability. To maximize supply delivered and minimize the cost of losses, the results of this analysis indicate preference for utilization of well-defended convoys on supply routes where bulk supply is appropriate and smaller, and widely dispersed assets on shorter, more contested routes with less demand. Sensitivity analysis on these results indicates system survivability can be improved by applying RCS and noise-reduction measures to logistics assets.Director, Warfare Integration (OPNAV N9I)Major, Israel Defence ForcesCivilian, Singapore Technologies Engineering Ltd, SingaporeCommander, Republic of Singapore NavyCommander, United States NavyCaptain, Singapore ArmyLieutenant, United States NavyLieutenant, United States NavyMajor, Republic of Singapore Air ForceCaptain, United States Marine CorpsLieutenant, United States NavyLieutenant, United States NavyLieutenant, United States NavyLieutenant, United States NavyLieutenant, United States NavyCaptain, Singapore ArmyLieutenant Junior Grade, United States NavyCaptain, Singapore ArmyLieutenant Colonel, Republic of Singapore Air ForceApproved for public release. distribution is unlimite

Recruiting and retaining GPs and patients in intervention studies: the DEPS-GP project as a case study

Background: Recruiting and retaining GPs for research can prove difficult, and may result in sub-optimal patient participation where GPs are required to recruit patients. Low participation rates may affect the validity of research. This paper describes a multi-faceted approach to maximise participation of GPs and their patients in intervention studies, using an Australian randomised controlled trial of a depression/suicidality management intervention as a case study. The paper aims to outline experiences that may be of interest to others considering engaging GPs and/or their patients in primary care studies. Methods: A case study approach is used to describe strategies for: (a) recruiting GPs; (b) encouraging GPs to recruit patients to complete a postal questionnaire; and (c) encouraging GPs to recruit patients as part of a practice audit. Participant retention strategies are discussed in light of reasons for withdrawal. Results: The strategies described, led to the recruitment of a higher than expected number of GPs (n = 772). Three hundred and eighty three GPs (49.6%) followed through with the intent to participate by sending out a total of 77,820 postal questionnaires, 22,251 (28.6%) of which were returned. Three hundred and three GPs (37.0%) participated in the practice audit, which aimed to recruit 20 patients per participating GP (i.e., a total of 6,060 older adults). In total, 5,143 patients (84.9%) were represented in the audit. Conclusion: Inexpensive methods were chosen to identify and recruit GPs; these relied on an existing database, minor promotion and a letter of invitation. Anecdotally, participating GPs agreed to be involved because they had an interest in the topic, believed the study would not impinge too greatly on their time, and appreciated the professional recognition afforded by the Continuing Professional Development (CPD) points associated with study participation. The study team established a strong rapport with GPs and their reception staff, offered clear instructions, and were as flexible and helpful as possible to retain GP participants. Nonetheless, we experienced attrition due to GPs' competing demands, eligibility, personnel issues and the perceived impact of the study on patients. A summary of effective and ineffective methods for recruitment and retention is provided.Michelle K Williamson, Jane Pirkis, Jon J Pfaff, Orla Tyson, Moira Sim, Ngaire Kerse, Nicola T Lautenschlager, Nigel P Stocks and Osvaldo P Almeid

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Cumulative survival in early-onset unilateral and bilateral breast cancer: an analysis of 1907 Taiwanese women

As the epidemiological pattern of breast cancer in modernising Asian countries differs greatly from that in Western countries, it is worthwhile to investigate the long-term prognoses of unilateral and bilateral breast cancer in these nations. A retrospective cohort study composed of 1907 Taiwanese women was conducted to follow 1863 unilateral and 44 bilateral cases of breast cancer. Time-dependent Cox regression was used to assess the risk of breast cancer death by considering the time course of unilateral and bilateral tumour development. The 15-year survival rates were 68.37, 62.63, and 26.42% for unilateral, synchronous bilateral, and metachronous bilateral breast cancer, respectively. Differences among types were most apparent after 5 years of follow-up. After adjusting for significant prognostic factors, the risk of death for overall bilateral breast cancer was 2.50-fold greater (95% CI, 1.43–4.37) compared to unilateral breast cancer. The corresponding figures were 1.12-fold (95% CI, 0.42–3.02) and 6.11-fold (95% CI, 3.14–11.89) for synchronous and metachronous bilateral breast cancer, respectively. Taiwanese women, who are frequently diagnosed with breast cancer before 50 years of age, showed poorer survival for metachronous bilateral than for synchronous bilateral or unilateral breast cancer. Survival was markedly poorer compared to recent data from Sweden