Bright light increases alertness and not cortisol in healthy men:A forced desynchrony study under dim and bright light (I)

Light-induced improvements in alertness are more prominent during nighttime than during the day, suggesting that alerting effects of light may depend on internal clock time or wake duration. Relative contributions of both factors can be quantified using a forced desynchrony (FD) designs. FD designs have only been conducted under dim light conditions (<10 lux) since light above this amount can induce non-uniform phase progression of the circadian pacemaker (also called relative coordination). This complicates the mathematical separation of circadian clock phase from homeostatic sleep pressure effects. Here we investigate alerting effects of light in a novel 4 × 18 h FD protocol (5 h sleep, 13 h wake) under dim (6 lux) and bright light (1300 lux) conditions. Hourly saliva samples (melatonin and cortisol assessment) and 2-hourly test sessions were used to assess effects of bright light on subjective and objective alertness (electroencephalography and performance). Results reveal (1) stable free-running cortisol rhythms with uniform phase progression under both light conditions, suggesting that FD designs can be conducted under bright light conditions (1300 lux), (2) subjective alerting effects of light depend on elapsed time awake but not circadian clock phase, while (3) light consistently improves objective alertness independent of time awake or circadian clock phase. Reconstructing the daily time course by combining circadian clock phase and wake duration effects indicates that performance is improved during daytime, while subjective alertness remains unchanged. This suggests that high-intensity indoor lighting during the regular day might be beneficial for mental performance, even though this may not be perceived as such

Bright light decreases peripheral skin temperature in healthy men:A forced desynchrony study under dim and bright light (II)

Human thermoregulation is strictly regulated by the preoptic area of the hypothalamus, which is directly influenced by the suprachiasmatic nucleus (SCN). The main input pathway of the SCN is light. Here, thermoregulatory effects of light were assessed in humans in a forced desynchrony (FD) design. The FD experiment was performed in dim light (DL, 6 lux) and bright white light (BL, 1300 lux) in 8 men in a semi-randomized within-subject design. A 4 × 18 h FD protocol (5 h sleep, 13 h wake) was applied, with continuous core body temperature (CBT) and skin temperature measurements at the forehead, clavicles, navel, palms, foot soles and toes. Skin temperature parameters indicated sleep-wake modulations as well as internal clock variations. All distal skin temperature parameters increased during sleep, when CBT decreased. Light significantly affected temperature levels during the wake phase, with decreased temperature measured at the forehead and toes and increased navel and clavicular skin temperatures. These effects persisted when the lights were turned off for sleep. Circadian amplitude of CBT and all skin temperature parameters decreased significantly during BL exposure. Circadian proximal skin temperatures cycled in phase with CBT, while distal skin temperatures cycled in anti-phase, confirming the idea that distal skin regions reflect heat dissipation and proximal regions approximate CBT. In general, we find that increased light intensity exposure may have decreased heat loss in humans, especially at times when the circadian system promotes sleep

Bright light during wakefulness improves sleep quality in healthy men:A forced desynchrony study under dim and bright light (III)

Under real-life conditions, increased light exposure during wakefulness seems associated with improved sleep quality, quantified as reduced time awake during bed time, increased time spent in non-rapid eye movement (NREM) sleep, or increased power of the electroencephalogram delta band (0.5-4 Hz). The causality of these important relationships and their dependency on circadian phase and/or time awake has not been studied in depth. To disentangle possible circadian and homeostatic interactions, we employed a forced desynchrony protocol under dim light (6 lux) and under bright light (1300 lux) during wakefulness. Our protocol consisted of a fast cycling sleep-wake schedule (13 h wakefulness-5 h sleep; 4 cycles), followed by 3 h recovery sleep in a within-subject cross-over design. Individuals (8 men) were equipped with 10 polysomnography electrodes. Subjective sleep quality was measured immediately after wakening with a questionnaire. Results indicated that circadian variation in delta power was only detected under dim light. Circadian variation in time in rapid eye movement (REM) sleep and wakefulness were uninfluenced by light. Prior light exposure increased accumulation of delta power and time in NREM sleep, while it decreased wakefulness, especially during the circadian wake phase (biological day). Subjective sleep quality scores showed that participants rated their sleep quality better after bright light exposure while sleeping when the circadian system promoted wakefulness. These results suggest that high environmental light intensity either increases sleep pressure buildup during wakefulness or prevents the occurrence of micro-sleep, leading to improved quality of subsequent sleep

Increased Prevalence of Autoimmune Gastritis in Patients with a Gastric Precancerous Lesion

Background: Autoimmune gastritis (AIG), characterized with the presence of anti-parietal-cell antibodies (APCA), is a risk factor for gastric cancer. However, AIG may go underdiagnosed, especially in the case of H. pylori infection and the presence of gastric precancerous lesions (GPL), due to the ambiguous pathology and delayed symptom onset. Aim: Investigate the prevalence and characteristics of AIG in GPL patients. Methods:Prevalence of AIG was determined with the presence of APCA in patients with GPL (n = 256) and the control group (n = 70). Pathological characteristics and levels of gastrin 17 (G17), pepsinogen (PG) I and II and anti-Helicobacter pylori IgG were assessed in GPL cases, and the severity of intestinal metaplasia and gastric atrophy was scored by expert pathologists. Results: APCA positivity was observed in 18% of cases vs. 7% of controls (p = 0.033). Only 3/256 patients were previously diagnosed with AIG. The presence of APCA was associated with corpus-limited and extended GPL. A receiver operating curve analysis demonstrated that the G17 and PGI/II ratio could identify APCA-positive patients within GPL cases (AUC: 0.884). Conclusions: The prevalence of AIG is higher in patients with GPL but goes undiagnosed. Using G17 and PG I/II as diagnostic markers can help to identify patients with AIG and improve surveillance programs for patients with GPL.</p

Kinome-wide analysis of the effect of statins in colorectal cancer

Background Epidemiological studies and meta-analyses show an association between statin use and a reduced incidence of colorectal cancer (CRC). We have shown that statins act on CRC through bone morphogenetic protein (BMP) signalling, but the exact cellular targets and underlying mechanism of statin action remain elusive. In this study, we set out to assess the influence of statins on global cancer cell signalling by performing an array-based kinase assay using immobilised kinase substrates spanning the entire human kinome. Methods CRC cells with or without Lovastatin treatment were used for kinome analysis. Findings on kinome arrays were further confirmed by immunoblotting with activity-specific antibodies. Experiments in different CRC cell lines using immunoblotting, siRNA-mediated knockdown and treatment with specific BMP inhibitor Noggin were performed. The relevance of in vitro findings was confirmed in xenografts and in CRC patients treated with Simvastatin. Results Kinome analysis can distinguish between non-specific, toxic effects caused by 10 mu M of Lovastatin and specific effects on cell signalling caused by 2 mu M Lovastatin. Statins induce upregulation of PTEN activity leading to downregulation of the PI3K/Akt/mTOR signalling. Treatment of cells with the specific BMP inhibitor Noggin as well as PTEN knockdown and transfection of cells with a constitutively active form of AKT abolishes the effect of Lovastatin on mTOR phosphorylation. Experiments in xenografts and in patients treated with Simvastatin confirm statin-mediated BMP pathway activation, activation of PTEN and downregulation of mTOR signalling. Conclusions Statins induce BMP-specific activation of PTEN and inhibition of PI3K/Akt/mTOR signalling in CRC

Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits

Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNA methyltransferase 3A (DNMT3A), a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a Dnmt3

Cytotoxicity of apigenin on leukemia cell lines: implications for prevention and therapy

Natural-food-based compounds show substantial promise for prevention and biotherapy of cancers including leukemia. In general, their mechanism of action remains unclear, hampering rational use of these compounds. Herein we show that the common dietary flavonoid apigenin has anticancer activity, but also may decrease chemotherapy sensitivity, depending on the cell type. We analyzed the molecular consequences of apigenin treatment in two types of leukemia, the myeloid and erythroid subtypes. Apigenin blocked proliferation in both lineages through cell-cycle arrest in G2/M phase for myeloid HL60 and G0/G1 phase for erythroid TF1 cells. In both cell lines the JAK/STAT pathway was one of major targets of apigenin. Apigenin inhibited PI3K/PKB pathway in HL60 and induced caspase-dependent apoptosis. In contrast, no apoptosis was detected in TF1 cells, but initiation of autophagy was observed. The block in cell cycle and induction of autophagy observed in this erythroleukemia cell line resulted in a reduced susceptibility toward the commonly used therapeutic agent vincristine. Thus, this study shows that although apigenin is a potential chemopreventive agent due to the induction of leukemia cell-cycle arrest, caution in dietary intake of apigenin should be taken during disease as it potentially interferes with cancer treatment

Quantitative Phosphoproteomics of CXCL12 (SDF-1) Signaling

CXCL12 (SDF-1) is a chemokine that binds to and signals through the seven transmembrane receptor CXCR4. The CXCL12/CXCR4 signaling axis has been implicated in both cancer metastases and human immunodeficiency virus type 1 (HIV-1) infection and a more complete understanding of CXCL12/CXCR4 signaling pathways may support efforts to develop therapeutics for these diseases. Mass spectrometry-based phosphoproteomics has emerged as an important tool in studying signaling networks in an unbiased fashion. We employed stable isotope labeling with amino acids in cell culture (SILAC) quantitative phosphoproteomics to examine the CXCL12/CXCR4 signaling axis in the human lymphoblastic CEM cell line. We quantified 4,074 unique SILAC pairs from 1,673 proteins and 89 phosphopeptides were deemed CXCL12-responsive in biological replicates. Several well established CXCL12-responsive phosphosites such as AKT (pS473) and ERK2 (pY204) were confirmed in our study. We also validated two novel CXCL12-responsive phosphosites, stathmin (pS16) and AKT1S1 (pT246) by Western blot. Pathway analysis and comparisons with other phosphoproteomic datasets revealed that genes from CXCL12-responsive phosphosites are enriched for cellular pathways such as T cell activation, epidermal growth factor and mammalian target of rapamycin (mTOR) signaling, pathways which have previously been linked to CXCL12/CXCR4 signaling. Several of the novel CXCL12-responsive phosphoproteins from our study have also been implicated with cellular migration and HIV-1 infection, thus providing an attractive list of potential targets for the development of cancer metastasis and HIV-1 therapeutics and for furthering our understanding of chemokine signaling regulation by reversible phosphorylation

Systems medicine approaches for peptide array-based protein kinase profiling: progress and prospects

Introduction: Pharmacological manipulation of signalling pathways is becoming an increasingly important avenue for the rational clinical management of disease but is hampered by a lack of technologies that allow the generation of comprehensive descriptions of cellular signalling.Areas covered: Herein, the authors discuss the potential of peptide array-based kinome profiling for evaluating cellular signalling in the context of drug discovery.Expert commentary: Genomic and proteomic approaches have been of significant value to our elucidation of the molecular mechanisms that govern physiology. However, an equally, if not more important goal, is to define those proteins that participate in signalling pathways that ultimately control cell fate, especially kinases. Traditional genetic and biochemical approaches can certainly provide answers here, but for technical and practical reasons, are typically pursued one gene or pathway at a time. A more comprehensive approach is one in which peptide arrays of kinase-specific substrates are incubated with cell lysates and P-33-ATP generating comprehensive descriptions, or where arrays are interrogated with phosphospecific antibodies. Both approaches allow analysis of cellular signalling without a priori assumptions to possibly influenced pathways