Synthesizing attractors of Hindmarsh-Rose neuronal systems

In this paper a periodic parameter switching scheme is applied to the Hindmarsh-Rose neuronal system to synthesize certain attractors. Results show numerically, via computer graphic simulations, that the obtained synthesized attractor belongs to the class of all admissible attractors for the Hindmarsh-Rose neuronal system and matches the averaged attractor obtained with the control parameter replaced with the averaged switched parameter values. This feature allows us to imagine that living beings are able to maintain vital behavior while the control parameter switches so that their dynamical behavior is suitable for the given environment.Comment: published in Nonlinear Dynamic

Understanding the decline of incident, active tuberculosis in people with HIV in Switzerland

BACKGROUND: People with human immunodeficiency virus type 1 (HIV) (PWH) are frequently coinfected with Mycobacterium tuberculosis (MTB) and at risk for progressing from asymptomatic latent TB infection (LTBI) to active tuberculosis (TB). LTBI testing and preventive treatment (TB specific prevention) are recommended, but its efficacy in low transmission settings is unclear. METHODS: We included PWH enrolled from 1988 to 2022 in the Swiss HIV Cohort study (SHCS). The outcome, incident TB, was defined as TB ≥6 months after SHCS inclusion. We assessed its risk factors using a time-updated hazard regression, modeled the potential impact of modifiable factors on TB incidence, performed mediation analysis to assess underlying causes of time trends, and evaluated preventive measures. RESULTS: In 21,528 PWH, LTBI prevalence declined from 15.1% in 2001 to 4.6% in 2021. Incident TB declined from 90.8 cases/1000 person-years in 1989 to 0.1 in 2021. A positive LTBI test showed a higher risk for incident TB (HR 9.8, 5.8-16.5) but only 10.5% of PWH with incident TB were tested positive. Preventive treatment reduced the risk in LTBI test positive PWH for active TB (relative risk reduction, 28.1%, absolute risk reduction 0.9%). On population level, the increase of CD4 T-cells and reduction of HIV viral load were the main driver of TB decrease. CONCLUSIONS: TB specific prevention is effective in selected patient groups. On a population level, control of HIV-1 remains the most important factor for incident TB reduction. Accurate identification of PWH at highest risk for TB is an unmet clinical need

A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms

Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) – a crucial transcriptional regulator serving major functions in PA virulence – can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry-driven hit-to-lead optimization and in-depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter-gene with IC50 values as low as 200 and 11 × 10−9 m, respectively. Drug metabolism and pharmacokinetics (DMPK) as well as safety pharmacology studies especially highlight the promising translational properties of the lead QSI for pulmonary applications. Moreover, target engagement of the lead QSI is shown in a PA mucoid lung infection mouse model. Beyond that, a significant synergistic effect of a QSI-tobramycin (Tob) combination against PA biofilms using a tailor-made squalene-derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32-fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker-mediated therapy against PA infections opening up avenues for preclinical development

Inactivation of VCP/ter94 Suppresses Retinal Pathology Caused by Misfolded Rhodopsin in Drosophila

The most common Rhodopsin (Rh) mutation associated with autosomal dominant retinitis pigmentosa (ADRP) in North America is the substitution of proline 23 by histidine (RhP23H). Unlike the wild-type Rh, mutant RhP23H exhibits folding defects and forms intracellular aggregates. The mechanisms responsible for the recognition and clearance of misfolded RhP23H and their relevance to photoreceptor neuron (PN) degeneration are poorly understood. Folding-deficient membrane proteins are subjected to Endoplasmic Reticulum (ER) quality control, and we have recently shown that RhP23H is a substrate of the ER–associated degradation (ERAD) effector VCP/ter94, a chaperone that extracts misfolded proteins from the ER (a process called retrotranslocation) and facilitates their proteasomal degradation. Here, we used Drosophila, in which Rh1P37H (the equivalent of mammalian RhP23H) is expressed in PNs, and found that the endogenous Rh1 is required for Rh1P37H toxicity. Genetic inactivation of VCP increased the levels of misfolded Rh1P37H and further activated the Ire1/Xbp1 ER stress pathway in the Rh1P37H retina. Despite this, Rh1P37H flies with decreased VCP function displayed a potent suppression of retinal degeneration and blindness, indicating that VCP activity promotes neurodegeneration in the Rh1P37H retina. Pharmacological treatment of Rh1P37H flies with the VCP/ERAD inhibitor Eeyarestatin I or with the proteasome inhibitor MG132 also led to a strong suppression of retinal degeneration. Collectively, our findings raise the possibility that excessive retrotranslocation and/or degradation of visual pigment is a primary cause of PN degeneration

Framework and baseline examination of the German National Cohort (NAKO)

The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19–74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2–3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4–5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10654-022-00890-5

A chromosome conformation capture ordered sequence of the barley genome

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Fachlicher Schlussbericht des BMBF Forschungsvorhabens Verbundprojekt 'PROcess of radioactive MErcury Treatment under EU Safety-standards (PROMETEUS)', Förderkennzeichen 15S9266A-B

Im Rahmen des BMBF-Verbundprojekts „PROcess of radioactive MErcury Treatment under EU Safety-standards“ (PROMETEUS), Förderkennzeichen 15S9266A-B, wurde ein Entsor-gungskonzept für radioaktiv kontaminiertes Quecksilber aus dem Rückbau kerntechnischer Einrichtungen entwickelt.Die aus dem Rückbau von kerntechnischen Einrichtungen in Jülich stammenden kontaminier-ten Quecksilberabfälle wurden gesichtet und einzelne Proben radiologisch charakterisiert. Hier-für wurde zunächst ein radiologisches Charakterisierungskonzept für radioaktiv kontaminierte Quecksilberabfälle entwickelt und verschiedene Dekontaminationsverfahren getestet. Die radi-oaktiven Verunreinigungen konnten mit verschiedenen, einfachen chemischen und mechani-schen Verfahren abgetrennt und das Quecksilber so dekontaminiert werden. Für das dekontaminierte Quecksilber wurde ein Freigabekonzept entwickelt, um es der konventionellen Entsorgung oder Weiterverwendung zuführen zu können. Hierfür wurde eine gammaspektro-metrische Messanlage konzipiert und aufgebaut. Anhand realer Quecksilberproben wurde die grundsätzliche praktische Realisierbarkeit der Dekontamination und anschließenden Freigabe von Quecksilberabfällen demonstriert. Für die quecksilberhaltigen Rückstände wurden Be-handlungsverfahren untersucht, die das Einbinden in eine stabile Matrix und Untersuchungen zur Stabilität dieser Abfallform umfassen. In Auslaugversuchen konnte die Eignung von Quecksilbersulfid als Abfallform aufgrund seiner Schwerlöslichkeit demonstriert werden.Die Förderung junger Nachwuchswissenschaftler stellte einen Schwerpunkt dieses Projekts dar und so konnten mehrere Studierende, Doktoranden und ein Postdoktorand gefördert werden. Ihre Ausbildung im Bereich der nuklearen Entsorgungsforschung stellt einen wichtigen Beitrag zum Kompetenzerhalt in Deutschland dar

Understanding and assessing uncertainty of observational climate datasets for model evaluation using ensembles

In climate science, observational gridded climate datasets that are based on in situ measurements serve as evidence for scientific claims and they are used to both calibrate and evaluate models. However, datasets only represent selected aspects of the real world, so when they are used for a specific purpose they can be a source of uncertainty. Here, we present a framework for understanding this uncertainty of observational datasets which distinguishes three general sources of uncertainty: (1) uncertainty that arises during the generation of the dataset; (2) uncertainty due to biased samples; and (3) uncertainty that arises due to the choice of abstract properties, such as resolution and metric. Based on this framework, we identify four different types of dataset ensembles—parametric, structural, resampling, and property ensembles—as tools to understand and assess uncertainties arising from the use of datasets for a specific purpose. We advocate for a more systematic generation of dataset ensembles by using these sorts of tools. Finally, we discuss the use of dataset ensembles in climate model evaluation. We argue that a more systematic understanding and assessment of dataset uncertainty is needed to allow for a more reliable uncertainty assessment in the context of model evaluation. The more systematic use of such a framework would be beneficial for both scientific reasoning and scientific policy advice based on climate datasets.ISSN:1757-7780ISSN:1757-779