A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia

Metabolic reprogramming has emerged as a crucial regulator of immune cell activation, but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic, and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2-mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function

Reduced Diversity and High Sponge Abundance on a Sedimented Indo-Pacific Reef System: Implications for Future Changes in Environmental Quality

Although coral reef health across the globe is declining as a result of anthropogenic impacts, relatively little is known of how environmental variability influences reef organisms other than corals and fish. Sponges are an important component of coral reef fauna that perform many important functional roles and changes in their abundance and diversity as a result of environmental change has the potential to affect overall reef ecosystem functioning. In this study, we examined patterns of sponge biodiversity and abundance across a range of environments to assess the potential key drivers of differences in benthic community structure. We found that sponge assemblages were significantly different across the study sites, but were dominated by one species Lamellodysidea herbacea (42% of all sponges patches recorded) and that the differential rate of sediment deposition was the most important variable driving differences in abundance patterns. Lamellodysidea herbacea abundance was positively associated with sedimentation rates, while total sponge abundance excluding Lamellodysidea herbacea was negatively associated with rates of sedimentation. Overall variation in sponge assemblage composition was correlated with a number of variables although each variable explained only a small amount of the overall variation. Although sponge abundance remained similar across environments, diversity was negatively affected by sedimentation, with the most sedimented sites being dominated by a single sponge species. Our study shows how some sponge species are able to tolerate high levels of sediment and that any transition of coral reefs to more sedimented states may result in a shift to a low diversity sponge dominated system, which is likely to have subsequent effects on ecosystem functioning. © 2014 Powell et al

Silicon vacancy in SiC as a promising quantum system for single-defect and single-photon spectroscopy

Results of experiments are presented that suggest that the Si vacancy in SiC is a promising quantum system for single-defect and single-photon spectroscopy in the infrared region. The investigation was carried out with electron paramagnetic resonance (EPR), zero-field optically detected magnetic resonance (ODMR), direct-detection EPR (DD-EPR), and high-resolution fluorescence-excitation spectroscopy. Depending on the temperature, crystal polytype, and crystal position, two opposite schemes have been observed for the optical alignment of the populations of the spin sublevels of the high-spin ground state of the Si vacancy in SiC upon irradiation with unpolarized light at the zero-phonon lines (ZPLs). A giant change has been found in the luminescence intensity of the ZPLs in zero magnetic field upon the application of resonant microwaves which induce transitions between the spin sublevels of the vacancy ground state thus opening the possibility for magnetic-resonance detection of a single vacancy. The optical alignment of the populations of the spin sublevels in the ground state of the Si vacancy was shown with DD-EPR. Surprisingly narrow ZPLs of Si vacancies with a width less than 0.05 meV have been observed which seem to be the narrowest detected so far in SiC. © 2011 American Physical Society

De ketenbenadering in de AWB

Volgens de opstellers van de Algemene wet bestuursrecht (Awb) moet de gang van zaken met betrekking tot een besluit als één keten worden beschouwd. Hoe hoger de kwaliteit in de beginfase, hoe groter de kans dat vervolgfasen achterwege kunnen blijven. In het onderhavige onderzoek is nagegaan in hoeverre die ketenbenadering in de praktijk uit de verf komt. Geconstateerd wordt dat de termijnen frequent worden overschreden en dat bestuursorganen de mogelijkheden van het horen nog onvoldoende benutten. De zeeffunctie van de bezwaarfase komt onvoldoende tot zijn recht, omdat de juridische component daarin te veel nadruk krijgt. De rechter wordt nogal eens geconfronteerd met kwesties die eigenlijk in de bezwaarfase hadden moeten worden afgedaan. In hoger beroep worden rechters met een groot aantal kansloze zaken geconfronteerd. Het rapport bevat aanbevelingen die aan deze knelpunten een einde kunnen maken

The GFAP proteoform puzzle: How to advance GFAP as a fluid biomarker in neurological diseases

Glial fibrillary acidic protein (GFAP) is a well-established biomarker of reactive astrogliosis in the central nervous system because of its elevated levels following brain injury and various neurological disorders. The advent of ultra-sensitive methods for measuring low-abundant proteins has significantly enhanced our understanding of GFAP levels in the serum or plasma of patients with diverse neurological diseases. Clinical studies have demonstrated that GFAP holds promise both as a diagnostic and prognostic biomarker, including but not limited to individuals with Alzheimer's disease. GFAP exhibits diverse forms and structures, herein referred to as its proteoform complexity, encompassing conformational dynamics, isoforms and post-translational modifications (PTMs). In this review, we explore how the proteoform complexity of GFAP influences its detection, which may affect the differential diagnostic performance of GFAP in different biological fluids and can provide valuable insights into underlying biological processes. Additionally, proteoforms are often disease-specific, and our review provides suggestions and highlights areas to focus on for the development of new assays for measuring GFAP, including isoforms, PTMs, discharge mechanisms, breakdown products, higher-order species and interacting partners. By addressing the knowledge gaps highlighted in this review, we aim to support the clinical translation and interpretation of GFAP in both CSF and blood and the development of reliable, reproducible and specific prognostic and diagnostic tests. To enhance disease pathology comprehension and optimise GFAP as a biomarker, a thorough understanding of detected proteoforms in biofluids is essential. (Figure presented.)

Neurofilament light protein as a biomarker for spinal muscular atrophy:A review and reference ranges

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by progressive neuromuscular degeneration resulting from mutations in the survival motor neuron (SMN1) gene. The availability of disease-modifying therapies for SMA therapies highlights the pressing need for easily accessible and cost-effective blood biomarkers to monitor treatment response and for better disease management. Additionally, the wide implementation of newborn genetic screening programs in Western countries enables presymptomatic diagnosis of SMA and immediate treatment administration. However, the absence of monitoring and prognostic blood biomarkers for neurodegeneration in SMA hinders effective disease management. Neurofilament light protein (NfL) is a promising biomarker of neuroaxonal damage in SMA and reflects disease progression in children with SMA undergoing treatment. Recently, the European Medicines Agency issued a letter of support endorsing the potential utilization of NfL as a biomarker of pediatric neurological diseases, including SMA. Within this review, we comprehensively assess the potential applications of NfL as a monitoring biomarker for disease severity and treatment response in pediatric-onset SMA. We provide reference ranges for normal levels of serum based NfL in neurologically healthy children aged 0-18 years. These reference ranges enable accurate interpretation of NfL levels in children and can accelerate the implementation of NfL into clinical practice.</p

Individual patient data meta-analysis of self-monitoring of blood pressure (BP-SMART): a protocol

Self-monitoring of blood pressure is effective in reducing blood pressure in hypertension. However previous meta-analyses have shown a considerable amount of heterogeneity between studies, only part of which can be accounted for by meta-regression. This may be due to differences in design, recruited populations, intervention components or results among patient subgroups. To further investigate these differences, an individual patient data (IPD) meta-analysis of self-monitoring of blood pressure will be performed. We will identify randomised trials that have compared patients with hypertension who are self-monitoring blood pressure with those who are not and invite trialists to provide IPD including clinic and/or ambulatory systolic and diastolic blood pressure at baseline and all follow-up points where both intervention and control groups were measured. Other data requested will include measurement methodology, length of follow-up, cointerventions, baseline demographic (age, gender) and psychosocial factors (deprivation, quality of life), setting, intensity of self-monitoring, self-monitored blood pressure, comorbidities, lifestyle factors (weight, smoking) and presence or not of antihypertensive treatment. Data on all available patients will be included in order to take an intention-to-treat approach. A two-stage procedure for IPD meta-analysis, stratified by trial and taking into account age, sex, diabetes and baseline systolic BP will be used. Exploratory subgroup analyses will further investigate non-linear relationships between the prespecified variables. Sensitivity analyses will assess the impact of trials which have and have not provided IPD.This study does not include identifiable data. Results will be disseminated in a peer-reviewed publication and by international conference presentations. IPD analysis should help the understanding of which self-monitoring interventions for which patient groups are most effective in the control of blood pressure

Depressive Symptoms and Plasma Markers of Alzheimer's Disease and Neurodegeneration:A Coordinated Meta-Analysis of 8 Cohort Studies

Background: Depressive symptoms are associated with an increased risk of Alzheimer's disease (AD). There has been a recent emergence in plasma biomarkers for AD pathophysiology, such as amyloid-beta (Aβ) and phosphorylated tau (p-tau), as well as for axonal damage (neurofilament light, NfL) and astrocytic activation (glial fibrillary acidic protein, GFAP). Hypothesizing that depressive symptoms may occur along the AD process, we investigated associations between plasma biomarkers of AD with depressive symptoms in individuals without dementia. Methods: A two-stage meta-analysis was performed on 2 clinic-based and 6 population-based cohorts (N = 7210) as part of the Netherlands Consortium of Dementia Cohorts. Plasma markers (Aβ42/40, p-tau181, NfL, and GFAP) were measured using Single Molecular Array (Simoa; Quanterix) assays. Depressive symptoms were measured with validated questionnaires. We estimated the cross-sectional association of each standardized plasma marker (determinants) with standardized depressive symptoms (outcome) using linear regressions, correcting for age, sex, education, and APOE ε4 allele presence, as well as subgrouping by sex and APOE ε4 allele. Effect estimates were entered into a random-effects meta-analysis. Results: Mean age of participants was 71 years. The prevalence of clinically relevant depressive symptoms ranged from 1% to 22%. None of the plasma markers were associated with depressive symptoms in the meta-analyses. However, NfL was associated with depressive symptoms only in APOE ε4 carriers (β 0.11; 95% CI: 0.05–0.17). Conclusions: Late-life depressive symptoms did not show an association to plasma biomarkers of AD pathology. However, in APOE ε4 allele carriers, a more profound role of neurodegeneration was suggested with depressive symptoms.</p

Slachtofferhulp en herstelbemiddeling

ARTIKELEN: Y.H. Heslinga - De professionalisering van slachtofferhulp; activiteiten en ontwikkelingen J. van Erp en M. Verberk - Evaluatie regelgeving Terwee; bevindingen van slachtoffers P. van Dijk - Slachtoffers in de strafrechtspleging; enige recente ontwikkelingen M.E.I. Brienen en E.H. Hoegen - Het Nederlandse slachtofferbeleid; een rechtsvergelijkend perspectief E. Rassin - Het getraumatiseerde slachtoffer; behandeling, verhoor en hiaten in de herinnering A.C. Spapens - Bemiddeling in relatie tot het strafproces J. Frijns - Herstelbemiddeling in de praktijk; uitzicht door inzicht L. Walgrave - Herstelrecht en strafrecht; duet of duel? I. Wijers - Family group conferencing; kanttekeningen bij herstelrecht voor jeugdige delinquenten C.P.M. Cleiren - De andere kant van het gelijk; strafgeding of mediation? Bijlage: de International Victimology Website SAMENVATTING: De ontwikkelingen binnen slachtofferzorg en -rechten staan centraal in het eerste gedeelte van dit nummer. In het tweede gedeelte wordt ingezoemd op een andere maatschappelijk trend die nadrukkelijk tegemoet komt aan slachtofferbelangen: herstelbemiddeling. Hoewel de vooralsnog schaarse experimenten in Nederland worden toegejuicht, resteren er veel vragen. In welke fase is herstelbemiddeling het meest geëigend: voor, tijdens of na de zitting? Welke risico's brengt een mislukte mediation voor slachtoffers en daders met zich mee? Is hun rechtszekerheid voldoende gewaarborgd en in hoeverre is de herstelrechtelijke sanctie proportioneel

Probing and controlling fluorescence blinking of single semiconductor nanoparticles

In this review we present an overview of the experimental and theoretical development on fluorescence intermittency (blinking) and the roles of electron transfer in semiconductor crystalline nanoparticles. Blinking is a very interesting phenomenon commonly observed in single molecule/particle experiments. Under continuous laser illumination, the fluorescence time trace of these single nanoparticles exhibit random light and dark periods. Since its first observation in the mid-1990s, this intriguing phenomenon has attracted wide attention among researchers from many disciplines. We will first present the historical background of the discovery and the observation of unusual inverse power-law dependence for the waiting time distributions of light and dark periods. Then, we will describe our theoretical modeling efforts to elucidate the causes for the power-law behavior, to probe the roles of electron transfer in blinking, and eventually to control blinking and to achieve complete suppression of the blinking, which is an annoying feature in many applications of quantum dots as light sources and fluorescence labels for biomedical imaging