A titanium dioxide/nitrogen-doped graphene quantum dot nanocomposite to mitigate cytotoxicity: synthesis, characterisation, and cell viability evaluation

Titanium dioxide nanoparticles (TiO2 NPs) have attracted tremendous interest owing to their unique physicochemical properties. However, the cytotoxic effect of TiO2 NPs remains an obstacle for their wide-scale applications, particularly in drug delivery systems and cancer therapies. In this study, the more biocompatible nitrogen-doped graphene quantum dots (N-GQDs) were successfully incorporated onto the surface of the TiO2 NPs resulting in a N-GQDs/TiO2 nanocomposites (NCs). The effects of the nanocomposite on the viability of the breast cancer cell line (MDA-MB-231) was evaluated. The N-GQDs and N-GQDs/TiO2 NCs were synthesised using a one- and two-pot hydrothermal method, respectively while the TiO2 NPs were fabricated using microwave-assisted synthesis in the aqueous phase. The synthesised compounds were characterised using Fourier transform infrared (FTIR) spectroscopy, high-resolution transmission electron microscopy (HRTEM), field emission scanning electron microscopy (FESEM) and UV-visible spectrophotometry. The cell viability of the MDA-MB-231 cell line was determined using a CellTiter 96® AQueous One Solution Cell Proliferation (MTS) assay. The obtained results indicated that a monodispersed solution of N-GQDs with particle size 4.40 ± 1.5 nm emitted intense blue luminescence in aqueous media. The HRTEM images clearly showed that the TiO2 particles (11.46 ± 2.8 nm) are square shaped. Meanwhile, TiO2 particles were located on the 2D graphene nanosheet surface in N-GQDs/TiO2 NCs (9.16 ± 2.4 nm). N-GQDs and N-GQDs/TiO2 NCs were not toxic to the breast cancer cells at 0.1 mg mL−1 and below. At higher concentrations (0.5 and 1 mg mL−1), the nanocomposite was significantly less cytotoxic compared to the pristine TiO2. In conclusion, this nanocomposite with reduced cytotoxicity warrants further exploration as a new TiO2-based nanomaterial for biomedical applications, especially as an anti-cancer strategy

Delayed retinal vein recovery responses indicate both non-adaptation to stress as well as increased risk for stroke: the SABPA study

OBJECTIVES: Low or high sympatho-adrenal-medullary axis (SAM) and hypothalamic-pituitary-adrenal axis (HPA) dysregulation reflect chronic stress. Retinal vessel dynamics may relate to SAM, HPA activity and stroke risk. Our objectives were therefore to assess the relationships between retinal vessel, SAM and HPA responses, and to determine stroke risk. METHODS: A prospective bi-ethnic gender cohort (n = 275, 45 ± 9 years) was included. Urine/serum/saliva samples for SAM [norepinephrine:creatinine ratio (u-NE)] and HPA [adrenocorticotrophic hormone (ACTH), cortisol] were obtained at baseline, three-year follow up and upon flicker light-induced provocation. Diastolic ocular perfusion pressure was measured as a marker of hypo-perfusion. Retinal arterial narrowing and venous widening calibres were quantified from digital images in the mydriatic eye. A validated stress and stroke risk score was applied. RESULTS: An interaction term was fitted for venous dilation in u-NE tertiles (p ≤ 0.05) and not in u-NE median/quartiles/quintiles. Independent of race or gender, tertile 1 (low u-NE) had a 112% increase in u-NE, decreases in cortisol, and no changes in ACTH over three years (positive feedback). Tertile 3 (high u-NE) contradictorily had decreases in u-NE and cortisol, and increases in ACTH (negative feedback). In tertile 1, reduced arterial dilation, and faster arterial vasoconstriction and narrowing were related to higher SAM activity and hypo-perfusion (p ≤ 0.05), whereas delayed venous dilation, recovery and widening were related to cortisol hypo-secretion (p ≤ 0.05). In tertile 1, delayed venous recovery responses predicted stress and stroke risk [odds ratio 4.8 (1.2-19.6); p = 0.03]. These associations were not found in u-NE tertiles 2 and 3. CONCLUSIONS: In response to low norepinephrine, a reflex increase in SAM activity occurred, enhancing arterial vasoconstriction and hypo-perfusion. Concomitant HPA dysregulation attenuated retinal vein vasoactivity and tone, reflecting delayed vein recovery responses and non-adaptation to stress. These constrained vein recovery responses are indicative of increased chronic stress and stroke risk

Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA)

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs

Early immune pressure initiated by tissue-resident memory T cells sculpts tumor evolution in non-small cell lung cancer

Tissue-resident memory T (TRM) cells provide immune defense against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and whether TRM cells existing in tissues before tumor onset influence cancer evolution in humans. We performed deep profiling of healthy lungs and lung cancers in never-smokers (NSs) and ever-smokers (ESs), finding evidence of enhanced immunosurveillance by cells with a TRM-like phenotype in ES lungs. In preclinical models, tumor-specific or bystander TRM-like cells present prior to tumor onset boosted immune cell recruitment, causing tumor immune evasion through loss of MHC class I protein expression and resistance to immune checkpoint inhibitors. In humans, only tumors arising in ES patients underwent clonal immune evasion, unrelated to tobacco-associated mutagenic signatures or oncogenic drivers. These data demonstrate that enhanced TRM-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes

CNS Recruitment of CD8+ T Lymphocytes Specific for a Peripheral Virus Infection Triggers Neuropathogenesis during Polymicrobial Challenge

Although viruses have been implicated in central nervous system (CNS) diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with both CNS-restricted measles virus (MV) and peripherally restricted lymphocytic choriomeningitis virus (LCMV). While infection with either virus alone resulted in no illness, infection with both viruses caused disease in all mice, with ∼50% dying following seizures. Co-infection resulted in a 12-fold increase in the number of CD8+ T cells in the brain as compared to MV infection alone. Tetramer analysis revealed that a substantial proportion (>35%) of these infiltrating CD8+ lymphocytes were LCMV-specific, despite no detectable LCMV in CNS tissues. Mechanistically, CNS disease was due to edema, induced in a CD8-dependent but perforin-independent manner, and brain herniation, similar to that observed in mice challenged intracerebrally with LCMV. These results indicate that T cell trafficking can be influenced by other ongoing immune challenges, and that CD8+ T cell recruitment to the brain can trigger CNS disease in the apparent absence of cognate antigen. By extrapolation, human CNS diseases of unknown etiology need not be associated with infection with any particular agent; rather, a condition that compromises and activates the blood-brain barrier and adjacent brain parenchyma can render the CNS susceptible to pathogen-independent immune attack

Positive and negative well-being and objectively measured sedentary behaviour in older adults: evidence from three cohorts

Background: Sedentary behaviour is related to poorer health independently of time spent in moderate to vigorous physical activity. The aim of this study was to investigate whether wellbeing or symptoms of anxiety or depression predict sedentary behaviour in older adults. Method: Participants were drawn from the Lothian Birth Cohort 1936 (LBC1936) (n = 271), and the West of Scotland Twenty-07 1950s (n = 309) and 1930s (n = 118) cohorts. Sedentary outcomes, sedentary time, and number of sit-to-stand transitions, were measured with a three-dimensional accelerometer (activPAL activity monitor) worn for 7 days. In the Twenty-07 cohorts, symptoms of anxiety and depression were assessed in 2008 and sedentary outcomes were assessed ~ 8 years later in 2015 and 2016. In the LBC1936 cohort, wellbeing and symptoms of anxiety and depression were assessed concurrently with sedentary behaviour in 2015 and 2016. We tested for an association between wellbeing, anxiety or depression and the sedentary outcomes using multivariate regression analysis. Results: We observed no association between wellbeing or symptoms of anxiety and the sedentary outcomes. Symptoms of depression were positively associated with sedentary time in the LBC1936 and Twenty-07 1950s cohort, and negatively associated with number of sit-to-stand transitions in the LBC1936. Meta-analytic estimates of the association between depressive symptoms and sedentary time or number of sit-to-stand transitions, adjusted for age, sex, BMI, long-standing illness, and education, were β = 0.11 (95% CI = 0.03, 0.18) and β = − 0.11 (95% CI = − 0.19, −0.03) respectively. Conclusion: Our findings indicate that depressive symptoms are positively associated with sedentary behavior. Future studies should investigate the causal direction of this association

Association of Sleep Duration with Chronic Diseases in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study

Background: In view of the reduced number of hours devoted to sleep in modern western societies the question arises what effects might result from sleep duration on occurrence of chronic diseases. Methods: Data from 23 620 middle-aged participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study, that were recruited between 1994–1998, were analyzed by using Cox proportional hazard regression to examine the association between self-reported sleep duration at baseline and incidence of chronic diseases, such as diabetes, myocardial infarction, stroke, and cancer. Results: During a mean follow-up period of 7.8 years 841 incident cases of type 2 diabetes, 197 cases of myocardial infarction, 169 incident strokes, and 846 tumor cases were observed. Compared to persons sleeping 7-,8 h/day, participants with sleep duration of,6 h had a significantly increased risk of stroke (Hazard Ratio (HR) = 2.06, 95

Early Life Events Carry Over to Influence Pre-Migratory Condition in a Free-Living Songbird

Conditions experienced during development can have long-term consequences for individual success. In migratory songbirds, the proximate mechanisms linking early life events and survival are not well understood because tracking individuals across stages of the annual cycle can be extremely challenging. In this paper, we first use a 13 year dataset to demonstrate a positive relationship between 1st year survival and nestling mass in migratory Savannah sparrows (Passerculus sandwichensis). We also use a brood manipulation experiment to show that nestlings from smaller broods have higher mass in the nest relative to individuals from larger broods. Having established these relationships, we then use three years of field data involving multiple captures of individuals throughout the pre-migratory period and a multi-level path model to examine the hypothesis that conditions during development limit survival during migration by affecting an individual's ability to accumulate sufficient lean tissue and fat mass prior to migration. We found a positive relationship between fat mass during the pre-migratory period (Sept–Oct) and nestling mass and a negative indirect relationship between pre-migratory fat mass and fledging date. Our results provide the first evidence that conditions during development limit survival during migration through their effect on fat stores. These results are particularly important given recent evidence showing that body condition of songbirds at fledging is affected by climate change and anthropogenic changes to landscape structure

Gene discovery for motile cilia disorders: Mutation spectrum in primary ciliary dyskinesia and discovery of mutations in CCDC151

We present a stratification of the genetic basis of primary ciliary dyskinesia (PCD), based on screening >230 individuals for gene mutations using various approaches including whole exome sequencing. PCD is a genetically heterogeneous recessive ciliopathy, characterized by chronic lung disease and laterality and fertility defects arising from cilia and sperm dysmotility. Most PCD is caused by loss of the ciliary outer dynein arm motors (ODA) essential for motility, arising from mutations in ODA subunits or ODA docking and targeting proteins. Gene panel resequencing of candidate ciliopathy genes in affected children from a consanguineous Bedouin-Arabic family has recently revealed a homozygous protein truncating variant in CCDC151 (c.925G>T; p.Glu308*). Parallel exome sequencing combined with autozygosity mapping in a consanguineous UK-Pakistani-origin family highlighted a large autozygous region on chr 19p13 harbouring a homozygous CCDC151 protein-truncating variant (c.1256C>T; pSer419*). Sanger sequencing of CCDC151 in 150 more PCD cases identified another individual carrying c.925G>T. Transmission electron microscopy of respiratory cilia from individuals carrying CCDC151 mutations showed loss of ODA. Consistent with laterality defects in these individuals, we find Ccdc151 expressed in vertebrate left-right organizers. Both homozygous zebrafish and mouse Ccdc151-deficient mutants display situs defects associated with complex heart defects. Immunofluorescence analysis in patients shows that CCDC151 mutations abolish assembly of CCDC151 into respiratory cilia, and furthermore cause a failure in assembly of the ODA component DNAH5 and ODA docking proteins CCDC114 and ARMC4. We conclude that CCDC151 mutations appear to cause PCD by disruption of the axonemal ODA docking complex machinery