Identifying the cellular targets of drug action in the central nervous system following corticosteroid therapy

Corticosteroid (CS) therapy is used widely in the treatment of a range of pathologies, but can delay production of myelin, the insulating sheath around central nervous system nerve fibers. The cellular targets of CS action are not fully understood, that is, "direct" action on cells involved in myelin genesis [oligodendrocytes and their progenitors the oligodendrocyte precursor cells (OPCs)] versus "indirect" action on other neural cells. We evaluated the effects of the widely used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes, employing complementary histological and transcriptional analyses. Histological assessments showed no DEX effects on OPC proliferation or oligodendrocyte genesis/maturation (key processes underpinning myelin genesis). Immunostaining and RT-PCR analyses show that both cell types express glucocorticoid receptor (GR; the target for DEX action), ruling out receptor expression as a causal factor in the lack of DEX-responsiveness. GRs function as ligand-activated transcription factors, so we simultaneously analyzed DEX-induced transcriptional responses using microarray analyses; these substantiated the histological findings, with limited gene expression changes in DEX-treated OPCs and oligodendrocytes. With identical treatment, microglial cells showed profound and global changes post-DEX addition; an unexpected finding was the identification of the transcription factor Olig1, a master regulator of myelination, as a DEX responsive gene in microglia. Our data indicate that CS-induced myelination delays are unlikely to be due to direct drug action on OPCs or oligodendrocytes, and may occur secondary to alterations in other neural cells, such as the immune component. To the best of our knowledge, this is the first comparative molecular and cellular analysis of CS effects in glial cells, to investigate the targets of this major class of anti-inflammatory drugs as a basis for myelination deficits

Crystal Structures of Dense Lithium: A Metal-Semiconductor-Metal Transition

Ab initio random structure searching and single-crystal x-ray diffraction have been used to determine the full structures of three phases of lithium, recently discovered at low temperature above 60 GPa. A structure with C2mb symmetry, calculated to be a poor metal, is proposed for the oC88 phase (60-65 GPa). The oC40 phase (65-95 GPa) is found to have a lowest-enthalpy structure with C2cb symmetry, in excellent agreement with the x-ray data. It is calculated to be a semiconductor with a band gap of similar to 1 eV at 90 GPa. oC24, stable above 95 GPa, has the space group Cmca, and refined atomic coordinates are in excellent agreement with previous calculations

Green tea polyphenols supplementation and Tai Chi exercise for postmenopausal osteopenic women: safety and quality of life report

<p>Abstract</p> <p>Background</p> <p>Evidence suggests that both green tea polyphenols (GTP) and Tai Chi (TC) exercise may benefit bone health in osteopenic women. However, their safety in this population has never been systematically investigated. In particular, there have been hepatotoxicity concerns related to green tea extract. This study was to evaluate the safety of 24 weeks of GTP supplementation combined with TC exercise in postmenopausal osteopenic women, along with effects on quality of life in this population.</p> <p>Methods</p> <p>171 postmenopausal women with osteopenia were randomly assigned to 4 treatment arms for 24 weeks: (1) Placebo (500 mg starch/day), (2) GTP (500 mg GTP/day), (3) Placebo + TC (placebo plus TC training at 60 min/session, 3 sessions/week), and (4) GTP + TC (GTP plus TC training). Safety was examined by assessing liver enzymes (aspartate aminotransferase, alanine aminotransferase), alkaline phosphatase, and total bilirubin at baseline and every 4 weeks. Kidney function (urea nitrogen and creatinine), calcium, and inorganic phosphorus were also assessed at the same times. Qualify of life using SF-36 questionnaire was evaluated at baseline, 12, and 24 weeks. A mixed model of repeated measures ANOVA was applied for analysis.</p> <p>Results</p> <p>150 subjects completed the study (12% attrition rate). The compliance rates for study agents and TC exercise were 89% and 83%, respectively. Neither GTP supplementation nor TC exercise affected liver or kidney function parameters throughout the study. No adverse event due to study treatment was reported by the participants. TC exercise significantly improved the scores for role-emotional and mental health of subjects, while no effect on quality of life was observed due to GTP supplementation.</p> <p>Conclusions</p> <p>GTP at a dose of 500 mg/day and/or TC exercise at 3 hr/week for 24 weeks appear to be safe in postmenopausal osteopenic women, particularly in terms of liver and kidney functions. TC exercise for 24 weeks (3 hr/wk) significantly improved quality of life in terms of role-emotional and mental health in these subjects. ClinicalTrials.gov identifier: NCT00625391.</p

Thinking about Later Life: Insights from the Capability Approach

A major criticism of mainstream gerontological frameworks is the inability of such frameworks to appreciate and incorporate issues of diversity and difference in engaging with experiences of aging. Given the prevailing socially structured nature of inequalities, such differences matter greatly in shaping experiences, as well as social constructions, of aging. I argue that Amartya Sen’s capability approach (2009) potentially offers gerontological scholars a broad conceptual framework that places at its core consideration of human beings (their values) and centrality of human diversity. As well as identifying these key features of the capability approach, I discuss and demonstrate their relevance to thinking about old age and aging. I maintain that in the context of complex and emerging identities in later life that shape and are shaped by shifting people-place and people-people relationships, Sen’s capability approach offers significant possibilities for gerontological research

Immune responses following 3rd and 4th doses of heterologous and homologous COVID-19 vaccines in kidney transplant recipients

Background Solid organ transplant recipients have attenuated immune responses to SARS-CoV-2 vaccines. In this study, we report on immune responses to 3rd- (V3) and 4th- (V4) doses of heterologous and homologous vaccines in a kidney transplant population. Methods We undertook a single centre cohort study of 724 kidney transplant recipients prospectively screened for serological responses following 3 primary doses of a SARS-CoV2 vaccine. 322 patients were sampled post-V4 for anti-spike (anti-S), with 69 undergoing assessment of SARS-CoV-2 T-cell responses. All vaccine doses were received post-transplant, only mRNA vaccines were used for V3 and V4 dosing. All participants had serological testing performed post-V2 and at least once prior to their first dose of vaccine. Findings 586/724 (80.9%) patients were infection-naïve post-V3; 141/2586 (24.1%) remained seronegative at 31 (21-51) days post-V3. Timing of vaccination in relation to transplantation, OR: 0.28 (0.15-0.54), p=0.0001; immunosuppression burden, OR: 0.22 (0.13-0.37), p<0.0001, and a diagnosis of diabetes, OR: 0.49 (0.32-0.75), p=0.001, remained independent risk factors for non-seroconversion. Seropositive patients post-V3 had greater anti-S if primed with BNT162b2 compared with ChAdOx1, p=0.001. Post-V4, 45/239 (18.8%) infection-naïve patients remained seronegative. De novo seroconversion post-V4 occurred in 15/60 (25.0%) patients. There was no difference in anti-S post-V4 by vaccine combination, p=0.50. T-cell responses were poor, with only 11/54 (20.4%) infection-naive patients having detectable T-cell responses post-V4, with no difference seen by vaccine type. Interpretation A significant proportion of transplant recipients remain seronegative following 3- and 4- doses of SARS-CoV-2 vaccines, with poor T-cell responses, and are likely to have inadequate protection against infection. As such alternative strategies are required to provide protection to this vulnerable group. Funding MW/PK received study support from Oxford Immunotec

A Comparison of Stress Levels, Coping Styles and Psychological Morbidity Between Graduate-entry and Traditional Undergraduate Medical Students During the First 2 Years at a UK Medical School.

Background: Stress levels and psychological morbidity are high among undergraduate medical students (UGs), but there is a lack of research into the psychological health of UK graduate-entry medical students (GEs). GEs are likely to experience different (perhaps more severe) stressors and to cope with stress differently. We compared stress levels, psychological morbidity and coping styles in GE versus UG medical students studying at the same UK medical school in the same academic year. Method: A cross-sectional self-rated questionnaire study of all first- and second-year GE and UG medical students. Perceived stress, psychological morbidity, recent adverse life events, stress-related personality traits and coping styles were assessed using standard questionnaires. Results: 75% GEs and 46% UGs responded to the questionnaire. Both groups reported equally high levels, and similar profiles of, perceived stress and psychological morbidity. Levels of recent adverse life events and stress-related personality traits were similar in both groups. Compared to UGs, GEs were more likely to use active coping (p = 0.02) and positive reframing (p = 0.03), but were also more likely to use substances (alcohol and other drugs; p < 0.001) to help them cope. Unlike UGs, second-year GEs showed less perceived stress (p = 0.007) and psychological morbidity (p = 0.006) than first-year GEs although levels of both were still high. Conclusion: Our results show that both GE students and their younger UG counterparts on a traditional medical course have similar profiles of stress symptoms. They do, however, cope with stress differently. GEs are more likely to use active problem-focused coping strategies, and they are also more likely to cope by using substances (alcohol or other drugs). GE students need interventions to prevent maladaptive coping styles and encourage adaptive coping that are tailored to their needs. Such interventions should be targeted at first-year students. It is vital that these students develop positive coping skills to benefit them during training and in a future career that is inherently stressful

The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design.

The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitors. In addition, we report a novel PKA-S6K1 chimeric protein with five mutations in or near its ATP-binding site, which was used to determine the binding mode of two of the three inhibitor series, and provided a robust system to aid the optimisation of the oxadiazole-substituted benzimidazole inhibitor series. We show that the resulting oxadiazole-substituted aza-benzimidazole is a potent and ligand efficient S6 kinase inhibitor, which blocks the phosphorylation of RPS6 at Ser235/236 in TSC negative HCV29 human bladder cancer cells by inhibiting S6 kinase activity and thus provides a useful tool compound to investigate the function of S6 kinases

Australian Library Job Advertisements: Seeking Inclusion and Diversity

A growing body of literature is drawing our attention to on diversity in librarianship, arguing for improved diversity through better recruitment, retention, and career advancement of minority professionals. While much of the discussion about diversity in libraries is taking place in United States, this article attempts to extend the discussion, bringing attention to diversity in Australian librarianship through analysis of Australian library job ads. This article uses content analysis of 96 Australian job ads posted from 22 January to 3 February 2018 in key Australian library job search engines. The analysis focuses on how diversity is reflected in these ads, with a content analysis of wording focused on inviting diversity in terms of ability/disability, ethnicity and language, and gender and sexuality