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CD8 virtual memory T (TVM) cells are Ag-naive CD8 T cells that have undergone partial differentiation in response to common γ-chain cytokines, particularly IL-15 and IL-4. TVM cells from young individuals are highly proliferative in response to TCR and cytokine stimulation but, with age, they lose TCR-mediated proliferative capacity and exhibit hallmarks of senescence. Helminth infection can drive an increase in TVM cells, which is associated with improved pathogen clearance during subsequent infectious challenge in young mice. Given the cytokine-dependent profile of TVM cells and their age-associated dysfunction, we traced proliferative and functional changes in TVM cells, compared with true naive CD8 T cells, after helminth infection of young and aged C57BL/6 mice. We show that IL-15 is essential for the helminth-induced increase in TVM cells, which is driven only by proliferation of existing TVM cells, with negligible contribution from true naive cell differentiation. Additionally, TVM cells showed the greatest proliferation in response to helminth infection and IL-15 compared with other CD8 T cells. Furthermore, TVM cells from aged mice did not undergo expansion after helminth infection due to both TVM cell–intrinsic and –extrinsic changes associated with aging.

SUMMARYThe differentiation of naïve CD8+cytotoxic T lymphocytes (CTLs) into effector and memory states results in large scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organisation reflect or underpin these transcriptional programs. We utilised Hi-C to map changes in the spatial organisation of long-range genome contacts within naïve, effector and memory virus-specific CD8+T cells. We observed that the architecture of the naive CD8+T cell genome was distinct from effector and memory genome configurations with extensive changes within discrete functional chromatin domains. However, deletion of the BACH2 or SATB1 transcription factors was sufficient to remodel the naïve chromatin architecture and engage transcriptional programs characteristic of differentiated cells. This suggests that the chromatin architecture within naïve CD8+T cells is preconfigured to undergo autonomous remodelling upon activation, with key transcription factors restraining differentiation by actively enforcing the unique naïve chromatin state.One Sentence SummaryCD8+T cell naïvety is actively maintained by transcription factors that enforce a distinct, naïve chromatin architecture.HighlightsCD8+T cell differentiation states are underscored by distinct chromatin looping architectures.Chromatin loops juxtapose CTL state appropriate enhancers, transcription factors and genes.Effector and memory CTLs have similar genome architectures, explaining rapid memory recall.CTL differentiation is restrained by BACH2 and SATB1, which enforce a naïve loop architecture.

Cytokines that signal via STAT1 and STAT3 transcription factors instruct decisions affecting tissue homeostasis, anti-microbial host defense, and inflammation-induced tissue injury. To understand the coordination of these activities, we applied RNA-seq, ChIP-seq, and ATAC-seq to identify the transcriptional output of STAT1 and STAT3 in peritoneal tissues during acute resolving inflammation and inflammation primed to drive fibrosis. Bioinformatics focussed on the transcriptional signature of the immuno-modulatory cytokine IL-6 in both settings and examined how pro-fibrotic IFNγ-secreting CD4+T-cells altered the interpretation of STAT1 and STAT3 cytokine cues. In resolving inflammation, STAT1 and STAT3 cooperated to drive stromal gene expression affecting anti-microbial immunity and tissue homeostasis. The introduction of IFNγ-secreting CD4+T-cells altered this transcriptional program and channeled STAT1 and STAT3 to a previously latent GAS motif inAlu-like elements. STAT1 and STAT3 binding to this conserved sequence revealed evidence of reciprocal cross-regulation and gene signatures relevant to pathophysiology. Thus, we propose that effector T-cells re-tune the transcriptional output of IL-6 by shaping a regulatory interplay between STAT1 and STAT3 in inflammation.

Objective: This study assesses the prevalence of musculoskeletal (MSK) pain in patients attending primary care clinics in a medium-sized town in Malaysia and examines the interventions given for the symptoms and the level of the associated disabilities. Method: This investigation comprises a cross-sectional descriptive study of all patients visiting two primary care clinics aged 18 years and above. Patients presenting with joint pain answered a questionnaire assessing demographic data, disabilities (measured by the Stanford HAQ-DI), and treatment options. Results: Of 1,074 patients surveyed, 202 (18.8%) had MSK complaints. The mean age of those with MSK pain was 56.1 years. Incidence increased with age, reaching 78.8% of those over 48 years of age. The knee was the most common site of MSK pain (52.2%), with 20.3% requiring referral for specialist assessment. The median HAQ score was 0.375 and 89.6% of those surveyed had mild disability. Conclusion: MSK pain is a common problem among patients visiting primary care clinics. The most common site of MSK pain was the knee. On formal assessment, the majority of these patients exhibited mild disability. A significant proportion of patients still required specialist referral. This finding would suggest a need for further training on the management of MSK disease at the primary care level to avoid over-burdening the secondary care services.

The Functional ANnoTation Of the Mammalian genome (FANTOM) Consortium has continued to provide extensive resources in the pursuit of understanding the transcriptome, and transcriptional regulation, of mammalian genomes for the last 20 years. To share these resources with the research community, the FANTOM web-interfaces and databases are being regularly updated, enhanced and expanded with new data types. In recent years, the FANTOM Consortium's efforts have been mainly focused on creating new non-coding RNA datasets and resources. The existing FANTOM5 human and mouse miRNA atlas was supplemented with rat, dog, and chicken datasets. The sixth (latest) edition of the FANTOM project was launched to assess the function of human long non-coding RNAs (lncRNAs). From its creation until 2020, FANTOM6 has contributed to the research community a large dataset generated from the knock-down of 285 lncRNAs in human dermal fibroblasts; this is followed with extensive expression profiling and cellular phenotyping. Other updates to the FANTOM resource includes the reprocessing of the miRNA and promoter atlases of human, mouse and chicken with the latest reference genome assemblies. To facilitate the use and accessibility of all above resources we further enhanced FANTOM data viewers and web interfaces. The updated FANTOM web resource is publicly available at https://fantom.gsc.riken.jp/.

The micronucleus (MN) assay is widely used as part of a battery of tests applied to evaluate the genotoxic potential of chemicals, including new food additives and novel food ingredients. Micronucleus assays typically utilise homogenous in vitro cell lines which poorly recapitulate the physiology, biochemistry and genomic events in the gut, the site of first contact for ingested materials. Here we have adapted and validated the MN endpoint assay protocol for use with complex 3D reconstructed intestinal microtissues; we have named this new protocol the reconstructed intestine micronucleus cytome (RICyt) assay. Our data suggest the commercial 3D microtissues replicate the physiological, biochemical and genomic responses of native human small intestine to exogenous compounds. Tissues were shown to maintain log-phase proliferation throughout the period of exposure and expressed low background MN. Analysis using the RICyt assay protocol revealed the presence of diverse cell types and nuclear anomalies (cytome) in addition to MN, indicating evidence for comprehensive DNA damage and mode(s) of cell death reported by the assay. The assay correctly identified and discriminated direct-acting clastogen, aneugen and clastogen requiring exogenous metabolic activation, and a non-genotoxic chemical. We are confident that the genotoxic response in the 3D microtissues more closely resembles the native tissues due to the inherent tissue architecture, surface area, barrier effects and tissue matrix interactions. This proof-of-concept study highlights the RICyt MN cytome assay in 3D reconstructed intestinal microtissues is a promising tool for applications in predictive toxicology. Agency for Science, Technology and Research (A*STAR) National Research Foundation (NRF) Published version This study is supported by Industry Alignment Fund (Pre-Positioning) (IAF-PP-H18/01/a0/G14), Biomedical Research Council (BMRC, A*STAR). BPC Smith was also supported by a National Research Foundation Singapore Whitespace Grant (W20W3D0002) administered by A*STAR.

Naive CD8+ T cell survival in the periphery is critically dependent on tonic TCR signaling through peptide + MHC class I (MHCI) recognition; however, little is known about how natural variation in MHCI levels impacts the naive CD8+ T cell repertoire. Using mice that are hemizygous or homozygous for a single MHCI allele, we showed that despite a reduction in peripheral CD8+ T cell numbers of ∼50% in MHCI hemizygous mice, MHCI levels had no notable impact on the rate of thymic generation or emigration of CD8 single-positive T cells. Moreover, the peripheral T cell repertoire in hemizygous mice showed selective retention of T cell clonotypes with a greater competitive advantage as evidenced by increased expression of CD5 and IL-7Rα. The qualitative superiority of CD8+ T cells retained in hemizygous mice was also seen during influenza A virus infection, in which epitope-specific CD8+ T cells from hemizygous mice had a higher avidity for pMHCI and increased cytokine polyfunctionality, despite a reduced response magnitude. Collectively, this study suggests that natural variation in MHCI expression levels has a notable and biologically relevant impact on the maintenance, but not generation, of the naive CD8+ T cell repertoire.

The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor samples. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment., Mucosal-associated invariant T (MAIT) cells facilitate anti-microbial responses, but their functions in cancer protection is unclear. Here the authors show that activated MAIT cells induce an IFN-γ transcriptome in natural killer (NK) cells and enhance NK-dependent anti-cancer immunity in mice, thereby hinting a new avenue for cancer therapy.

BackgroundSurgical treatment of full-thickness rotator cuff (RC) tears is associated with generally good results. There is no consensus regarding treatment of partial thickness tears that fail conservative treatment. The purpose of this study was to look at the efficacy and confirm the safety of dual injection PRP into the shoulder of patients with rotator cuff pathology who have failed conservative treatment with followup to two years.MethodsSeventy-one shoulders with MRI confirmed, rotator cuff pathology who failed conservative treatment, had dual PRP injection into the rotator cuff. Global improvement, Quick DASH and VAS scores were collected at 6, 12, and 24 months after treatment and comparison of means was used to analyze changes.ResultsNo adverse events were seen in any patient. Based on global rating scores positive results were seen in 77.9 % of patients at 6 months, 71.6 % at 1 year, and 68.8 % of patients at 2 years. Mean VAS scores improved from 50.2 [CI 44.4–56.0] pre-injection to 26.2 [CI 19.5–32.9] at 6 months, 22.4[CI 16.1–28.7] at 1 year and 18.2 [CI 12.3–24.1] at 2 years (p 50 % partial tear group had the best overall improvement based on Global Rating scores while those in the tendinitis group had the poorest outcomes.ConclusionsPRP injection is a safe and effective treatment for RC cuff injury in patients who have failed conservative treatment of activity modification and physical therapy without deterioration of results two years after treatment. Better results are obtained with greater structural tendon damage than in shoulders with inflammation without structural damage.Trial registrationThis is not a clinical trial.

The cytokine IL-6 controls the survival, proliferation and effector characteristics of lymphocytes through activation of the transcription factors STAT1 and STAT3. While STAT3 activity is an ever-present feature of IL-6 signaling in CD4 + T cells, prior activation via the T cell antigen receptor limits IL-6’s control of STAT1 in effector and memory populations. Here we found that phosphorylation of STAT1 in response to IL-6 was regulated by the tyrosine phosphatases PTPN2 and PTPN22 expressed in response to the activation of naïve CD4 + T cells. Transcriptomics and chromatin immunoprecipitation–sequencing (ChIP-seq) of IL-6 responses in naïve and effector memory CD4 + T cells showed how the suppression of STAT1 activation shaped the functional identity and effector characteristics of memory CD4 + T cells. Thus, tyrosine phosphatases induced by the activation of naïve T cells determine the way activated or memory CD4 + T cells sense and interpret cytokine signals.

Potential adverse effects of gold nanoparticles (AuNPs) are gaining attention due to their wide industrial, consumer, and biomedical applications. This may give rise to possible health risks from direct exposure to the NPs. Excessive inflammatory response is known to be one of the main effects induced by NPs. In this study, inflammatory and miRNA expression changes in lung tissues were evaluated in rats following intravenous administration of AuNPs. AuNPs (20 nm) at a mass concentration of 256 μg/mL were intravenously injected into 6-8 week old male Wistar rats at single doses of 0.025, 0.05, 0.1, and 0.2 mg/kg and sacrificed at 1 week, 1 month, and 2 months, respectively. The biodistribution of AuNPs in the lungs of the rats was determined by inductively coupled plasma mass spectrometry. There were no apparent changes observed in the body weight of the experimental rats. Histopathological examination revealed the presence of infiltrating lymphocytes in lung interstitial tissues and enhanced IL-1α immunostaining in the lung tissues. Out of 84 rat microRNAs (miRNAs) analyzed, the expression of three miRNAs in rat lungs were dysregulated by more than 2-fold in the 0.1 and 0.2 mg/kg AuNP-treated rats 1 week after exposure. In particular, miR-327 was significantly down-regulated in both groups of treated rats. Taken together, it would seem that miRNAs may regulate inflammatory changes in the lungs after exposure to AuNPs

Making sense of TCR–pMHC topology Most T cells use a T cell receptor (TCR) that recognizes major histocompatibility complex molecules bound to peptides (pMHCs) derived from both self- and foreign antigens. Although there is great variability in the interface because of the diversity of both partners, this interaction displays a canonical docking topology for reasons that remain contested. Zareie et al. tested an assortment of both canonical and reversed-polarity TCRs that were all specific for the same cognate pMHC-I bearing a peptide derived from influenza A virus (IAV) (see the Perspective by Horkova and Stepanek). The authors determined that docking topology was the primary driver of in vivo T cell activation and recruitment when mice were infected with IAV. The canonical topology was required for the formation of a functional signaling complex, suggesting that T cell signaling constraints dictate how TCR and pMHC meet. Science , abe9124, this issue p. eabe9124 ; see also abj2937, p. 1038

Mucosal-associated invariant T (MAIT) cells are an innate-like population of unconventional T cells that respond rapidly to microbial metabolite Ags or cytokine stimulation. Because of this reactivity and surface expression of CD45RO+, CD45RA−, and CD127+, they are described as effector memory cells. Yet, there is heterogeneity in MAIT cell effector response. It is unclear what factors control MAIT cell effector capacity, whether it is fixed or can be modified and if this differs based on whether activation is TCR dependent or independent. To address this, we have taken a systematic approach to examine human MAIT cell effector capacity across healthy individuals in response to ligand and cytokine stimulation. We demonstrate the heterogenous nature of MAIT cell effector capacity and that the ability to produce an effector response is not directly attributable to TCR clonotype or coreceptor expression. Global gene transcription analysis revealed that the MAIT cell effector capacity produced in response to TCR stimulation is associated with increased expression of the epigenetic regulator lysine demethylase 6B (KDM6B). Addition of a KDM6B inhibitor did not alter MAIT cell effector function to Ag or cytokine stimulation. However, addition of the KDM6B cofactor α-ketoglutarate greatly enhanced MAIT cell effector capacity to TCR-dependent stimulation in a partially KDM6B-dependent manner. These results demonstrate that the TCR-dependent effector response of MAIT cells is epigenetically regulated and dependent on the availability of metabolic cofactors.

Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-to-date lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2., Genome Research, 30 (7), ISSN:1088-9051, ISSN:1549-5469

Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-to-date lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.

Liver resident-memory CD8+ T cells (TRM cells) can kill liver-stage Plasmodium-infected cells and prevent malaria, but simple vaccines for generating this important immune population are lacking. Here, we report the development of a fully synthetic self-adjuvanting glycolipid-peptide conjugate vaccine designed to efficiently induce liver TRM cells. Upon cleavage in vivo, the glycolipid-peptide conjugate vaccine releases an MHC I-restricted peptide epitope (to stimulate Plasmodium-specific CD8+ T cells) and an adjuvant component, the NKT cell agonist α-galactosylceramide (α-GalCer). A single dose of this vaccine in mice induced substantial numbers of intrahepatic malaria-specific CD8+ T cells expressing canonical markers of liver TRM cells (CD69, CXCR6, and CD101), and these cells could be further increased in number upon vaccine boosting. We show that modifications to the peptide, such as addition of proteasomal-cleavage sequences or epitope-flanking sequences, or the use of alternative conjugation methods to link the peptide to the glycolipid improved liver TRM cell generation and led to the development of a vaccine able to induce sterile protection in C57BL/6 mice against Plasmodium berghei sporozoite challenge after a single dose. Furthermore, this vaccine induced endogenous liver TRM cells that were long-lived (half-life of ~425 days) and were able to maintain >90% sterile protection to day 200. Our findings describe an ideal synthetic vaccine platform for generating large numbers of liver TRM cells for effective control of liver-stage malaria and, potentially, a variety of other hepatotropic infections.

Retroviral nucleocapsid (NC) proteins are nucleic acid chaperones that play distinct roles in the viral life cycle. During reverse transcription, HIV-1 NC facilitates the rearrangement of nucleic acid secondary structures, allowing the transactivation response (TAR) RNA hairpin to be transiently destabilized and annealed to a complementary RNA hairpin. In contrast, during viral assembly, NC, as a domain of the group-specific antigen (Gag) polyprotein, binds the genomic RNA and facilitates packaging into new virions. It is not clear how the same protein, alone or as part of Gag, performs such different RNA binding functions in the viral life cycle. By combining single-molecule optical tweezers measurements with a quantitative mfold-based model, we characterize the equilibrium stability and unfolding barrier for TAR RNA. Comparing measured results with a model of discrete protein binding allows us to localize affected binding sites, in addition to quantifying hairpin stability. We find that, while both NCp7 and Gag∆p6 destabilize the TAR hairpin, Gag∆p6 binding is localized to two sites in the stem, while NCp7 targets sites near the top loop. Unlike Gag∆p6, NCp7 destabilizes this loop, shifting the location of the reaction barrier toward the folded state and increasing the natural rate of hairpin opening by ~104. Thus, our results explain why Gag cleavage and NC release is an essential prerequisite for reverse transcription within the virion.

Naive CD8

SUMMARYNaive CD8+ T cell activation results in an autonomous program of cellular proliferation and differentiation. However, the mechanisms that underpin this process are unclear. Here we profiled genome-wide changes in chromatin accessibility, gene transcription and the deposition of a key chromatin modification (H3K27me3) early after naive CD8+ T cell activation. Rapid upregulation of the histone demethylase, KDM6B, prior to first cell division was required for initiating H3K27me3 removal at genes essential for subsequent T cell differentiation and proliferation. Inhibition of KDM6B-dependent H3K27me3 demethylation limited the magnitude of an effective primary virus-specific CD8+ T cell response and the formation of memory CD8+ T cell populations. Accordingly, we define the early spatio-temporal events underpinning early lineage-specific epigenetic reprogramming that is necessary for autonomous CD8+ T cell proliferation and differentiation.

BACKGROUND Several studies suggest that systemic magnesium reduces postoperative opioid consumption and the intensity of pain, but others report conflicting results. The efficacy and safety profile of intravenous magnesium in noncardiac surgery remain uncertain. OBJECTIVES The aim of this review was to investigate the effect of intravenous magnesium on the consumption of postoperative morphine in the first 24 h in adults undergoing noncardiac surgery. DESIGN Systematic review and meta-analysis with trial sequential analysis. DATA SOURCES MEDLINE, EMBASE, CENTRAL from their inception until January 2019. ELIGIBILITY CRITERIA All randomised clinical trials comparing intravenous magnesium versus placebo in noncardiac surgery were systematically searched in the databases. Observational studies, case reports, case series and nonsystematic reviews were excluded. RESULTS Fifty-one trials (n=3311) were included for quantitative meta-analysis. In comparison with placebo, postoperative morphine consumption at 24-h was significantly reduced in the magnesium group, with a mean difference [95% confidence interval (CI)] of -5.6 mg (-7.54 to -3.66, P

A cardinal feature of adaptive T-cell responses to infection is the initiation of a largely autonomous differentiation program that results in proliferation and acquisition of lineage-specific T-cell functions. Moreover, upon clearance of infection, immunological memory is established whereby memory T cells retain the functional capacity acquired during the initial primary response. This enables pathogen specific T cells to respond more rapidly and robustly without the need for further differentiation. It has long been appreciated that changes in chromatin architecture and histone biochemical modifications play a role in the establishment of transcriptionally permissive structures at T-cell lineage effector gene loci. The advent of new technologies is now providing new insights into how epigenetic regulation not only impacts acquisition and maintenance of effector function, but also the maintenance of this functional capacity into memory, and how epigenetics regulates cell fate decisions that drive both effector and memory T-cell responses. This chapter will cover these topics.

Naive CD8+ T cell activation results in an autonomous program of cellular proliferation and differentiation. However, the mechanisms that underpin this process are unclear. Here we profiled genome-wide changes in chromatin accessibility, gene transcription and the deposition of a key chromatin modification (H3K27me3) early after naive CD8+ T cell activation. Rapid upregulation of the histone demethylase, KDM6B, prior to first cell division was required for initiating H3K27me3 removal at genes essential for subsequent T cell differentiation and proliferation. Inhibition of KDM6B-dependent H3K27me3 demethylation limited the magnitude of an effective primary virus-specific CD8+ T cell response and the formation of memory CD8+ T cell populations. Accordingly, we define the early spatio-temporal events underpinning early lineage-specific epigenetic reprogramming that is necessary for autonomous CD8+ T cell proliferation and differentiation.

Background Low level of fibrinogen is a risk factor of perioperative bleeding, which is a major complication in surgical patients. However, the safety and efficacy of fibrinogen supplementation with fibrinogen concentrate to minimize postoperative bleeding remains unclear. Objectives The primary aim of this review was to investigate the effect of fibrinogen concentrate in postoperative blood loss in adult surgical patients. Design Systematic review and meta-analysis. Data sources Databases of MEDLINE, EMBASE and CENTRAL were searched from their start date until July 2019. Eligibility criteria All randomized clinical trials comparing intravenous fibrinogen concentrate and placebo in adult surgical patients were included, regardless of type of surgery. Observational studies, case reports, case series and non-systematic reviews were excluded. Results Thirteen trials (n = 900) were included in this review. In comparison to placebo, fibrinogen concentrate significantly reduced the first 12-hour postoperative blood loss, with a mean difference of −134.6 ml (95% CI −181.9 to −87.4). It also significantly increased clot firmness in thromboelastometry (FIBTEM) with a mean difference of 2.5 mm (95%CI 1.1 to 3.8). No significant differences were demonstrated in the adverse events associated with fibrinogen concentrate use, namely incidence of thromboembolism, myocardial infarction and acute kidney injury. Conclusions In this meta-analysis of 13 randomized trials, low level of evidence and substantial heterogeneity with small sample size limit strong recommendation on the use of fibrinogen concentrate in adult surgical patients. However, its use is tolerable without any notable adverse events. Trial registration CRD42019149164.

Objectives While complementary and alternative medicine (CAM) is used by more than half of Australians, its role in dentistry is rarely covered in the curricula of Australian dental schools. This study aimed to investigate dental students’ knowledge of and attitudes towards CAM. Design Australian dental students in the final two years of their study were invited to undertake a survey. These questions consisted of five clinically relevant case vignettes, for which there was only one correct answer amongst four possible options and seven self-reported perspective-based questions. Results were analysed using descriptive statistics. Results Of the 185 students that participated, the mean correct response rate for the five clinical scenarios was 3.46 ± 0.95 (range: 0–5 out of 5). Of 185 students, 157 (85 %) answered more than half of the questions correctly. All five questions were answered correctly by 19 (10 %) students. Most (74 %) students self-reported to have little to no knowledge. More than two-thirds of dental students reported an interest in and belief in the effectiveness of CAM. A similar proportion expressed a desire for the integration of CAM content into their undergraduate curriculum. Conclusions Despite approximately three out of four of dental students in this study having little to no knowledge on CAM, attitudes towards CAM therapies, and the need to integrate them into the dental curriculum, were generally positive. Future research into identifying specific knowledge gaps could help to redesign improved dental curricula.

Purpose/objectives Prescribing medicine is integral to clinical dentistry. Future dental practitioners need to have a thorough knowledge of how to prescribe safely and effectively. To date, medication knowledge among dental students in Australia has not been assessed at a national scale. Methods Australian dental students were invited to undertake the survey comprising 12 multiple choice questions to investigate their medication knowledge. A total of 185 responses were received. The questions were 11 clinically relevant questions and 1 opinion-based question with 4 options from which to select. Results were analyzed using descriptive statistics. Results The 185 respondents had a mean correct response of 6.77 ± 1.8 (range: 2-11 out of 11). Out of 185 students, 142 students (77%) answered more than half of the questions correctly. Only 1 student (1%) answered all 11 questions correctly. There were 135 students (73%) who either agreed or strongly agreed that they would feel confident to prescribe safe and effective medication for their patients after having completed dental school. Conclusion Most respondents answered more than half, but not all, of the clinical questions correctly. Despite this, many reported confidence in their prescribing skills. Future research needs to further investigate pharmacotherapeutic knowledge to determine detailed knowledge gaps in prescribing.

Liver resident-memory CD8

Age-associated decreases in primary CD8+ T cell responses occur, in part, due to direct effects on naive CD8+ T cells to reduce intrinsic functionality, but the precise nature of this defect remains undefined. Aging also causes accumulation of antigen-naive but semi-differentiated "virtual memory" (TVM) cells, but their contribution to age-related functional decline is unclear. Here, we show that TVM cells are poorly proliferative in aged mice and humans, despite being highly proliferative in young individuals, while conventional naive T cells (TN cells) retain proliferative capacity in both aged mice and humans. Adoptive transfer experiments in mice illustrated that naive CD8 T cells can acquire a proliferative defect imposed by the aged environment but age-related proliferative dysfunction could not be rescued by a young environment. Molecular analyses demonstrate that aged TVM cells exhibit a profile consistent with senescence, marking an observation of senescence in an antigenically naive T cell population.

Nanomaterials and nanoparticles are regarded as promising candidates for various biomedical applications due to their unique physicochemical properties. In this study, three types of carbon-encapsulated iron nanoparticles (CEINs) were synthesized and their impact on cellular changes was investigated by atomic force microscopy (AFM). The AFM experiment was additionally compared with conventional methods, such as colorimetric assay and other microscopic techniques. A significant difference of reduced Young’s modulus of the cells was revealed, even at low concentration of nanoparticles in the culture medium. The AFM measurement proved to be a useful tool not only for visualization, but also for identification of local cellular changes at the nanoscale after exposure to carbon-encapsulated iron nanoparticles.