Single molecule tracking fluorescence microscopy in mitochondria reveals highly dynamic but confined movement of Tom40

Tom40 is an integral protein of the mitochondrial outer membrane, which as the central component of the Translocase of the Outer Membrane (TOM) complex forms a channel for protein import. We characterize the diffusion properties of individual Tom40 molecules fused to the photoconvertable fluorescent protein Dendra2 with millisecond temporal resolution. By imaging individual Tom40 molecules in intact isolated yeast mitochondria using photoactivated localization microscopy with sub-diffraction limited spatial precision, we demonstrate that Tom40 movement in the outer mitochondrial membrane is highly dynamic but confined in nature, suggesting anchoring of the TOM complex as a whole

Mitogen-Activated Protein Kinases Regulate Susceptibility to Ventilator-Induced Lung Injury

Background: Mechanical ventilation causes ventilator-induced lung injury in animals and humans. Mitogen-activated protein kinases have been implicated in ventilator-induced lung injury though their functional significance remains incomplete. We characterize the role of p38 mitogen-activated protein kinase/mitogen activated protein kinase kinase-3 and c-jun-NH2-terminal kinase-1 in ventilator-induced lung injury and investigate novel independent mechanisms contributing to lung injury during mechanical ventilation. Methodology and Principle Findings: C57/BL6 wild-type mice and mice genetically deleted for mitogen-activated protein kinase kinase-3 (mkk-3-/-) or c-Jun-NH2-terminal kinase-1 (jnk1-/-) were ventilated, and lung injury parameters were assessed. We demonstrate that mkk3-/- or jnk1-/- mice displayed significantly reduced inflammatory lung injury and apoptosis relative to wild-type mice. Since jnk1-/- mice were highly resistant to ventilator-induced lung injury, we performed comprehensive gene expression profiling of ventilated wild-type or jnk1-/- mice to identify novel candidate genes which may play critical roles in the pathogenesis of ventilator-induced lung injury. Microarray analysis revealed many novel genes differentially expressed by ventilation including matrix metalloproteinase-8 (MMP8) and GAFF45α. Functional characterization of MMP8 revealed that mmp8-/- mice were sensitized to ventilator-induced lung injury with increased lung vascular permeability. Conclusion: We demonstrate that mitogen-activated protein kinase pathways mediate inflammatory lung injury during ventilator-induced lung injury. C-Jun-NH2-terminal kinase was also involved in alveolo-capillary leakage and edema formation, whereas MMP8 inhibited alveolo-capillary protein leakage. © 2008 Dolinay et al

Analysis of LhcSR3, a Protein Essential for Feedback De-Excitation in the Green Alga Chlamydomonas reinhardtii

To prevent photodamage by excess light, plants use different proteins to sense pH changes and to dissipate excited energy states. In green microalgae, however, the LhcSR3 gene product is able to perform both pH sensing and energy quenching functions

Diagnostic tools in Rhinology EAACI position paper

This EAACI Task Force document aims at providing the readers with a comprehensive and complete overview of the currently available tools for diagnosis of nasal and sino-nasal disease. We have tried to logically order the different important issues related to history taking, clinical examination and additional investigative tools for evaluation of the severity of sinonasal disease into a consensus document. A panel of European experts in the field of Rhinology has contributed to this consensus document on Diagnostic Tools in Rhinology

EAACI position paper on occupational rhinitis

The present document is the result of a consensus reached by a panel of experts from European and non-European countries on Occupational Rhinitis (OR), a disease of emerging relevance which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored on that of occupational asthma, as well as a diagnostic algorithm based on steps allowing for different levels of diagnostic evidence are proposed. The needs for future research are pointed out. Key messages are issued for each item

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy

peer reviewedBackground: The phase IIIb, randomized, parallel-group, placebo-controlled ANDHI double-blind (DB) study extended understanding of the efficacy of benralizumab for patients with severe eosinophilic asthma. Patients from ANDHI DB could join the 56-week ANDHI in Practice (IP) single-arm, open-label extension substudy. Objective: Assess potential for standard-of-care background medication reductions while maintaining asthma control with benralizumab. Methods: Following ANDHI DB completion, eligible adults were enrolled in ANDHI IP. After an 8-week run-in with benralizumab, there were 5 visits to potentially reduce background asthma medications for patients achieving and maintaining protocol-defined asthma control with benralizumab. Main outcome measures for non–oral corticosteroid (OCS)-dependent patients were the proportions with at least 1 background medication reduction (ie, lower inhaled corticosteroid dose, background medication discontinuation) and the number of adapted Global Initiative for Asthma (GINA) step reductions at end of treatment (EOT). Main outcomes for OCS-dependent patients were reductions in daily OCS dosage and proportion achieving OCS dosage of 5 mg or lower at EOT. Results: For non–OCS-dependent patients, 53.3% (n = 208 of 390) achieved at least 1 background medication reduction, increasing to 72.6% (n = 130 of 179) for patients who maintained protocol-defined asthma control at EOT. A total of 41.9% (n = 163 of 389) achieved at least 1 adapted GINA step reduction, increasing to 61.8% (n = 110 of 178) for patients with protocol-defined EOT asthma control. At ANDHI IP baseline, OCS dosages were 5 mg or lower for 40.4% (n = 40 of 99) of OCS-dependent patients. Of OCS-dependent patients, 50.5% (n = 50 of 99) eliminated OCS and 74.7% (n = 74 of 99) achieved dosages of 5 mg or lower at EOT. Conclusions: These findings demonstrate benralizumab's ability to improve asthma control, thereby allowing background medication reduction. © 202

Models and measurements of energy-dependent quenching

Energy-dependent quenching (qE) in photosystem II (PSII) is a pH-dependent response that enables plants to regulate light harvesting in response to rapid fluctuations in light intensity. In this review, we aim to provide a physical picture for understanding the interplay between the triggering of qE by a pH gradient across the thylakoid membrane and subsequent changes in PSII. We discuss how these changes alter the energy transfer network of chlorophyll in the grana membrane and allow it to switch between an unquenched and quenched state. Within this conceptual framework, we describe the biochemical and spectroscopic measurements and models that have been used to understand the mechanism of qE in plants with a focus on measurements of samples that perform qE in response to light. In addition, we address the outstanding questions and challenges in the field. One of the current challenges in gaining a full understanding of qE is the difficulty in simultaneously measuring both the photophysical mechanism of quenching and the physiological state of the thylakoid membrane. We suggest that new experimental and modeling efforts that can monitor the many processes that occur on multiple timescales and length scales will be important for elucidating the quantitative details of the mechanism of qE

Primjena i kompozicija individualiziranih zaštitnih elemenata linijske grafike u projektiranju novčanica

Proces stvaranja novčanica je dugotrajan i složen, što rezultira kompleksnim rješenjima koja predstavljaju pravo remek djelo grafike. Novčanice su prožete brojnim detaljima i prenose različite informacije koje se analiziraju u teorijskom dijelu rada. Prvotno se postavljaju kriteriji po kojima se izrađuje detaljna analiza velikog broja zaštitnih i konceptualnih elemenata na primjerima novčanica. Time je prikazan okvirni povijesni pregled razvoja novčanica i utjecaji kojima je bio izložen. Analizira se međuovisnost dizajna o sigurnosnim značajkama, te se ispituje razina informiranosti javnosti o zaštitama na novčanicama. Zaključuje se koje metode zaštite su najučinkovitije, te kako šira javnost najčešće provjerava autentičnost novčanica. U eksperimentalnom dijelu rada se na temelju donesenih zaključaka iz teorijskog dijela izrađuje prototip novčanice koja je u najvećoj mjeri prožeta individualiziranim PostScript programskim rješenjima elemenata linijske grafike (rozete, mikrotekst, zaštitne linije, brojevi apoena), a od ostalih zaštita modeliran je individualizirani raster transformacijom matematičkog izraza u PostScript programski kod. Sve ostale zaštite tipične za novčanice simulirane su alatima za rastersku i vektorsku grafiku. U radu se ispituje utjecaj kompozicije zaštitnih elemenata na prepoznavanje autentičnosti novčanica, te efikasnost samih individualiziranih programskih rješenja

FDG PET/MRI in the follow-up of hepatocellular carcinoma after liver transplantation

Background There is limited evidence regarding the application of [18F] fluorodeoxyglucose (FDG)-PET/MRI in patients with a suspected clinical recurrence, who underwent liver transplantation for hepatocellular carcinoma (HCC). Therefore, we compared the accuracy of PET/MR and standard-of-care (SOC) imaging in these patients. Methods We retrospectively reviewed 26 patients, whose liver were transplanted for HCC and were suspected of disease relapse based on biochemical analysis or SOC follow-up imaging, and carried out PET/MRI with diffusion-weighted imaging sequences on them. All patients underwent SOC imaging within the 2 months prior to the PET/MRI examination and had follow-up data for at least 12 months after. Reference standards were histopathology, clinical and imaging follow-up data. Results Sensitivity, specificity, positive predictive value, negative predictive value and accuracy for PET/MRI were 100, 94, 91, 100 and 96%, whereas for SOC imaging were 80, 69, 61, 85 and 73%. The accuracy of PET/MRI was higher with respect to SOC imaging, although not significantly. Conclusions PET/MRI is useful for oncological surveillance of patients who have undergone liver transplantation for HCC, particularly in cases of allergy to contrast media, renal failure or persistently elevated alpha-fetoprotein levels, and with no identification of metastatic/relapsing foci at standard-of-care imaging