Optineurin downregulation induces endoplasmic reticulum stress, chaperone-mediated autophagy, and apoptosis in pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) shows a high level of basal autophagy. Here we investigated the role of optineurin (OPTN) in PDAC cell lines, which is a prominent member of the autophagy system. To that purpose, mining of publically available databases showed that OPTN is highly expressed in PDAC and that high levels of expression are related to reduced survival. Therefore, the role of OPTN on proliferation, migration, and colony formation was investigated by transient knockdown in Miapaca, BXPC3, and Suit2-007 human PDAC cells. Furthermore, gene expression modulation in response to OPTN knockdown was assessed by microarray. The influence on cell cycle distribution and cell death signaling cascades was followed by FACS, assays for apoptosis, RT-PCR, and western blot. Finally, autophagy and ROS induction were screened by acridine orange and DCFH-DA fluorescent staining respectively. OPTN knockdown caused significant inhibition of colony formation, increased migration and no significant effect on proliferation in Miapaca, BXPC3 and Suit2-007 cells. The microarray showed modulation of 293 genes in Miapaca versus 302 in Suit2-007 cells, of which 52 genes overlapped. Activated common pathways included the ER stress response and chaperone-mediated autophagy, which was confirmed at mRNA and protein levels. Apoptosis was activated as shown by increased levels of cleaved PARP, Annexin V binding and nuclear fragmentation. OPTN knockdown caused no increased vacuole formation as assessed by acridine orange. Also, there was only marginally increased ROS production. Combination of OPTN knockdown with the autophagy inducer erufosine or LY294002, an inhibitor of autophagy, showed additive effects, which led us to hypothesize that they address different pathways. In conclusion, OPTN knockdown was related to activation of ER stress response and chaperone-mediated autophagy, which tend to confine the damage caused by OPTN knockdown and thus question its value for PDAC therapy

Die flächenhafte Ausweisung von Bodenfeuchteregimes: Eine Methode im Rahmen des pre-processing für die Modellierung des Landschaftswasserhaushaltes

In dem Einzugsgebiet „Obere Brachtpe“ (2,6 km², Sauerland, Deutschland) wurden mit einer konventionellen Bohrstock-Kartierung (319 Bodenprofile) die verschiedenen Böden mit ihren spezifischen pedohydrologischen Eigenschaften erfasst und darauf aufbauend das Klassifikationskonzept zur Ableitung von Bodenfeuchteregime-Typen nach Zepp (1995) angewendet. Anhand dieser Informationen konnte die vorherrschende Wasserbewegungsrichtung und folglich verschiedene Abflussprozessflächen ausgewiesen werden. Um dieses Raumgliederungskonzept hinsichtlich der Frage, ob es zum pre-processing für die Modellierung des Landschaftswasserhaushalts beitragen kann, zu verfizieren, wurden zwei Niederschlags-Abfluss-Ereignisse tracerhydrologisch untersucht. Die Resultate zeigen, dass sich das Klassifikationskonzept nach Zepp (1995) zur hydrologischen Raumgliederung eines Einzugsgebietes gut eignet, es wird aber auch deutlich, dass neben den Bodeneigenschaften insbesondere die Lage der schnell reagierenden Flächen (Sättigungsflächen) innerhalb des Einzugsgebietes und deren Konnektivität mit dem Vorfluter entscheidend für den Beitrag schneller Abflusskomponenten sind. Besteht eine direkte Verbindung zwischen Sättigungsflächen und Vorfluter, so ist eine schnelle Abflussreaktion und ein hoher Anteil an Ereigniswasser zu erwarten.In the catchment “Obere Brachtpe” (2,6 km², Sauerland, Germany) the soils and their specific pedohydrological characteristics were investigated using a conventional drilling rig (319 drills). Based on the results the classification concept for deducing the soil moisture types by Zepp (1995) was applied so that the dominant flow directions and dominant runoff process areas could be detected. The question if this classification concept could be used as tool for the pre-processing within the runoff modelling was verified by the tracer hydrological investigation of two rainfall runoff-events. The results confirm that the classification concept by Zepp (1995) is an applicable tool for the spatial delineation of a catchment in hydrological response units. On the other hand it became apparent that in addition to the soil properties, the location of saturated areas within the catchment and their connectivity to the channel are especially important for the contribution of accelerated runoff components. If there exists a direct connection between the saturated areas and the channel a fast runoff reaction and a high portion of event water can be estimated

Sunlight-mediated inactivation of health-relevant microorganisms in water: a review of mechanisms and modeling approaches.

Health-relevant microorganisms present in natural surface waters and engineered treatment systems that are exposed to sunlight can be inactivated by a complex set of interacting mechanisms. The net impact of sunlight depends on the solar spectral irradiance, the susceptibility of the specific microorganism to each mechanism, and the water quality; inactivation rates can vary by orders of magnitude depending on the organism and environmental conditions. Natural organic matter (NOM) has a large influence, as it can attenuate radiation and thus decrease inactivation by endogenous mechanisms. Simultaneously NOM sensitizes the formation of reactive intermediates that can damage microorganisms via exogenous mechanisms. To accurately predict inactivation and design engineered systems that enhance solar inactivation, it is necessary to model these processes, although some details are not yet sufficiently well understood. In this critical review, we summarize the photo-physics, -chemistry, and -biology that underpin sunlight-mediated inactivation, as well as the targets of damage and cellular responses to sunlight exposure. Viruses that are not susceptible to exogenous inactivation are only inactivated if UVB wavelengths (280-320 nm) are present, such as in very clear, open waters or in containers that are transparent to UVB. Bacteria are susceptible to slightly longer wavelengths. Some viruses and bacteria (especially Gram-positive) are susceptible to exogenous inactivation, which can be initiated by visible as well as UV wavelengths. We review approaches to model sunlight-mediated inactivation and illustrate how the environmental conditions can dramatically shift the inactivation rate of organisms. The implications of this mechanistic understanding of solar inactivation are discussed for a range of applications, including recreational water quality, natural treatment systems, solar disinfection of drinking water (SODIS), and enhanced inactivation via the use of sensitizers and photocatalysts. Finally, priorities for future research are identified that will further our understanding of the key role that sunlight disinfection plays in natural systems and the potential to enhance this process in engineered systems

Early Risk Detection of Burnout: Development of the Burnout Prevention Questionnaire for Coaches

Introduction: Previous research has shown that burnout develops as the result of a continuous imbalance between chronic stress and appropriate coping resources. Hence, the essential factors to measure burnout encompassed the factors stress and recovery within our studies. However, the Burnout Prevention Questionnaire for Coaches (BPQ-C) does not represent a new questionnaire from scratch, but rather a re-evaluated, condensed, and subsequently combined instrument with scales derived from validated psychometric instruments.Methods: The objective of study 1 (N = 233) was to create and evaluate the psychometric structure of the BPQ-C. The aim of study 2 (N = 473) consisted in the validation of the BPQ-C via a Confirmatory Factor Analysis.Results: The Exploratory Factor Analysis resulted in a model with three dimensions (Pre-Burnout, Resources, and Burnout). Via the subsequent Confirmatory Factor Analysis, the model could be confirmed with good fit indices (χ2 = 96.898, df = 19, p < 0.001, CFI = 0.973, SRMR = 0.044, RMSEA = 0.093, LO90 = 0.075, HI90 = 0.112).Conclusion: The BPQ-C includes a number of previously established risk and protective factors within a single psychometric instrument. The systematic application of the BPQ-C can help to detect critical conditions at an early stage in order to derive individualized and beneficial interventions for the respective coaches

Dry Eye Parameters and Lid Geometry in Adults Born Extremely, Very, and Moderately Preterm with and without ROP: Results from the Gutenberg Prematurity Eye Study

Background/Aims: This study aimed to analyze the effects of perinatal history on tear film properties and lid geometry in adults born preterm. Methods: The Gutenberg Prematurity Eye Study (GPES) is a German prospective examination of adults born preterm and term aged 18 to 52 years with Keratograph® 5M and Schirmer test I. Main outcome measures were first non-invasive tear film break-up time (F-NITBUT), bulbar redness (BR), Schirmer test, and nasal palpebral angle measurement. The associations with gestational age (GA), birth weight (BW), and BW percentile, retinopathy of prematurity (ROP), ROP treatment, and other perinatal factors were evaluated using regression analyses. Results: 489 eyes of 255 preterm and 277 eyes of 139 full-term individuals (aged 28.6 +/− 8.8 years, 220 females) were included. Of these, 33 participants (56 eyes) had a history of spontaneously regressed ROP and 9 participants (16 eyes) had a history of ROP treatment. After adjustment for age and sex, lower F-NITBUT (<20 s) was associated with ROP treatment (OR = 4.42; p = 0.025). Lower GA correlated with increased bulbar redness (B = −0.02; p = 0.011) and increased length of wetting in the Schirmer test (B = −0.69; p = 0.003). Furthermore, low GA was associated with narrowing of the nasal palpebral angle (B = 0.22; p = 0.011) adjusted for age and sex, but not when considering ROP in the multivariable model. Conclusion: Our analyses indicate that perinatal history affects ocular surface properties, tear production and lid geometry in adults born term and preterm. This might indicate that affected persons have a predisposition to diseases of the corneal surface such as the dry eye disease

Design of a Protective Single-Dose Intranasal Nanoparticle-Based Vaccine Platform for Respiratory Infectious Diseases

Despite the successes provided by vaccination, many challenges still exist with respect to controlling new and re-emerging infectious diseases. Innovative vaccine platforms composed of adaptable adjuvants able to appropriately modulate immune responses, induce long-lived immunity in a single dose, and deliver immunogens in a safe and stable manner via multiple routes of administration are needed. This work describes the development of a novel biodegradable polyanhydride nanoparticle-based vaccine platform administered as a single intranasal dose that induced long-lived protective immunity against respiratory disease caused by Yesinia pestis, the causative agent of pneumonic plague. Relative to the responses induced by the recombinant protein F1-V alone and MPLA-adjuvanted F1-V, the nanoparticle-based vaccination regimen induced an immune response that was characterized by high titer and high avidity IgG1 anti-F1-V antibody that persisted for at least 23 weeks post-vaccination. After challenge, no Y. pestis were recovered from the lungs, livers, or spleens of mice vaccinated with the nanoparticle-based formulation and histopathological appearance of lung, liver, and splenic tissues from these mice post-vaccination was remarkably similar to uninfected control mice

Latent class analysis reveals clinically relevant atopy phenotypes in 2 birth cohorts

Background: Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. Objective: We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Methods: Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. Results: The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-gamma ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. Conclusions: LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function.Peer reviewe

Empfehlungen der Ständigen Impfkommission (STIKO) und der Deutschen Gesellschaft für Tropenmedizin, Reisemedizin und Globale Gesundheit e.V. (DTG) zu Reiseimpfungen

Die STIKO empfiehlt Reiseimpfungen zum individuellen Schutz Reisender mit einem Expositionsrisiko gegenüber bestimmten impfpräventablen Erkrankungen und um den Import von Infektionserregern in das bereiste Land oder bei Rückreise nach Deutschland zu verhindern. Die im Epidemiologischen Bulletin 14/2023 veröffentlichten Empfehlungen zu Reiseimpfungen wurden von der STIKO-AG Reiseimpfungen in Zusammenarbeit mit externen Expertinnen und Experten erarbeitet. Neuerungen sind dabei u. a. die aktualisierte Epidemiologie bei Cholera, Hepatitis A, Hepatitis B, Meningokokken und Typhus sowie eine umfassende Literatur-Aktualisierung.Peer Reviewe