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Dose-response relationships are a general concept for quantitatively describing biological systems across multiple scales, from the molecular to the whole-cell level. A clinically relevant example is the bacterial growth response to antibiotics, which is routinely characterized by dose-response curves. The shape of the dose-response curve varies drastically between antibiotics and plays a key role in treatment, drug interactions, and resistance evolution. However, the mechanisms shaping the dose-response curve remain largely unclear. Here, we show in Escherichia coli that the distinctively shallow dose-response curve of the antibiotic trimethoprim is caused by a negative growth-mediated feedback loop: Trimethoprim slows growth, which in turn weakens the effect of this antibiotic. At the molecular level, this feedback is caused by the upregulation of the drug target dihydrofolate reductase (FolA/DHFR). We show that this upregulation is not a specific response to trimethoprim but follows a universal trend line that depends primarily on the growth rate, irrespective of its cause. Rewiring the feedback loop alters the dose-response curve in a predictable manner, which we corroborate using a mathematical model of cellular resource allocation and growth. Our results indicate that growth-mediated feedback loops may shape drug responses more generally and could be exploited to design evolutionary traps that enable selection against drug resistance.

The abscopal effect describes the ability of locally administered radiotherapy to induce systemic antitumor effects. Over the past 40 years, reports on the abscopal effect following conventional radiation have been relatively rare, especially in less immunogenic tumors such as lung cancer. However, with the continued development and use of immunotherapy, reports on the abscopal effect have become increasingly frequent during the last decade. Here, we present three illustrative case reports from our own institution and previous published cases of the abscopal effect in patients with non-small cell lung cancer, treated with immune checkpoint inhibitors and radiotherapy. We also present a concise review of the clinical and experimental literature on the abscopal effect in non-small cell lung cancer.

After 53 years of quiescence, Mount Agung awoke in August 2017, with intense seismicity, measurable ground deformation, and thermal anomalies in the summit crater. Although the seismic unrest peaked in late September and early October, the volcano did not start erupting until 21 November. The most intense explosive eruptions with accompanying rapid lava effusion occurred between 25 and 29 November. Smaller infrequent explosions and extrusions continue through the present (June 2019). The delay between intense unrest and eruption caused considerable challenges to emergency responders, local and national governmental agencies, and the population of Bali near the volcano, including over 140,000 evacuees. This paper provides an overview of the volcanic activity at Mount Agung from the viewpoint of the volcano observatory and other scientists responding to the volcanic crisis. We discuss the volcanic activity as well as key data streams used to track it. We provide evidence that magma intruded into the mid-crust in early 2017, and again in August of that year, prior to intrusion of an inferred dike between Mount Agung and Batur Caldera that initiated an earthquake swarm in late September. We summarize efforts to forecast the behavior of the volcano, to quantify exclusion zones for evacuations, and to work with emergency responders and other government agencies to make decisions during a complex and tense volcanic crisis.

Slow growth and persistence are common strategies bacteria use to survive antibiotic treatment. Bacterial growth responses to antibiotics are quantitatively characterized by dose-response curves. The shape of the dose-response curve varies drastically between antibiotics and plays a key role in drug treatments, interactions, and resistance evolution. Understanding the mechanisms that shape the dose-response curve is a major challenge. Here we show in Escherichia coli that the distinctly shallow dose-response curve of the antibiotic trimethoprim is caused by a negative growth-mediated feedback loop: Trimethoprim slows growth, which in turn weakens the effect of this antibiotic. At the molecular level, this feedback is caused by the upregulation of the drug target dihydrofolate reductase (FolA/DHFR). We show that target upregulation is not a specific response to trimethoprim but a general response to slower growth, regardless of cause. Quantitatively, folA expression follows a universal trend line that only depends on growth rate and converges to a fixed maximum value at zero growth. Synthetically breaking the negative feedback loop or reversing it to positive feedback drastically steepens the dose-response curve; a similar steepening occurs under conditions of slower growth. A general mathematical model that captures growth-mediated feedback explains these phenomena. Our results indicate that growth-mediated feedback loops shape drug responses and could be exploited to design evolutionary traps that enable selection against drug resistance.

Long-term oxygen therapy is of great importance both for reducing mortality and for improving performance in patients with chronic lung diseases. The prerequisites for Long-term oxygen therapy are adequate diagnostics and clearly defined indication. A causal distinction into chronic hypoxaemic and hypercapnic respiratory failure is reasonable, from which the differential indication for non-invasive ventilation results.The revised guideline covers the diagnostics and indication of chronic lung and heart diseases, the role of oxygen in terminal illness and gives a detailed description of available oxygen devices. The guideline is intended to help avoid undersupply, oversupply and false prescriptions. Furthermore, the chapter "Postacute Oxygen Therapy" discusses the procedure, relevant in everyday life, but not yet clearly defined, for prescribing oxygen therapy for the home at the end of an inpatient stay. Another important point, the correct prescription of mobile oxygen systems, is also presented in the guideline. This document is a revised version of the guideline for longterm oxygen therapy and replaces the version of 2008.Die Langzeit-Sauerstofftherapie hat einen hohen Stellenwert sowohl zur Verminderung der Letalität als auch zur Verbesserung der Leistungsfähigkeit bei Patienten mit chronischen Lungenerkrankungen.Die Grundvoraussetzung für die Langzeit-Sauerstofftherapie ist die adäquate Diagnostik und Indikationsstellung. Sinnvoll ist eine kausale Unterscheidung in eine chronische hypoxämische oder hyperkapnische respiratorische Insuffizienz, aus der sich die Differentialindikation zur nichtinvasiven Beatmung ergibt.Die revidierte Leitlinie behandelt u. a. die Diagnostik und die Indikation bei chronischen Lungen- und Herzerkrankungen sowie den Einsatz in der Palliativmedizin und gibt eine detaillierte Beschreibung der verfügbaren Sauerstoffsysteme. Die Leitlinie soll dazu beitragen, die teilweise bestehende Unter-, Fehl- und Überversorgung zu vermeiden. Zudem wird im Kapitel „Postakute Sauerstofftherapie“ die im Alltag relevante, bisher nicht definierte Vorgehensweise für die Verschreibung einer Sauerstofftherapie am Ende eines stationären Aufenthaltes für den häuslichen Bereich diskutiert. Ein weiterer wichtiger Punkt, die korrekte Verordnung mobiler Sauerstoffsysteme, wird auch in der Leitlinie dargestellt. Die vorliegende aktualisierte Leitlinie zur Langzeit-Sauerstofftherapie löst die alte im Jahr 2008 publizierte Version ab.

The German Respiratory Society (DGP) turns against the e-cigarette as a means for harm reduction because of potential health risk and dangers to young people. The aerosol of e-cigarettes contains toxic ingredients that have been shown to be damaging to the lungs, the cardiovascular system and the immune system and are potentially carcinogenic. Studies on e-cigarettes as a means of smoking cessation are not very convincing, in order to favor e-cigarettes over nicotine replacement therapy, which have been tried and tested for many years, or other drugs that reduce the desire to smoke.Die Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin (DGP) wendet sich gegen die E-Zigarette als Mittel zur harm-reduction wegen potenzieller Gesundheitsgefahren und Gefährdungen Jugendlicher. Das Aerosol von E-Zigaretten enthält toxische Inhaltsstoffe, die nachweislich schädigend auf die Lunge, das Herz-Kreislauf-System und Immunsystem wirken und potenziell karzinogen sind. Untersuchungen zu E-Zigaretten als Mittel in der Tabakentwöhnung sind wenig überzeugend, um E-Zigaretten gegenüber den langjährig erprobten und etablierten Nikotinersatzpräparaten (NRT) oder anderen Medikamenten, die das Rauchverlangen reduzieren, zu bevorzugen.

Cyanobacteria are mostly engineered to be sustainable cell-factories by genetic manipulations alone. Here, by modulating the concentration of allosteric effectors, we focus on increasing product formation without further burdening the cells with increased expression of enzymes. Resorting to a novel 96-well microplate cultivation system for cyanobacteria, and using lactate-producing strains of Synechocystis PCC6803 expressing different l-lactate dehydrogenases (LDH), we titrated the effect of 2,5-anhydro-mannitol supplementation. The latter acts in cells as a nonmetabolizable analogue of fructose 1,6-bisphosphate, a known allosteric regulator of one of the tested LDHs. In this strain (SAA023), we achieved over 2-fold increase of lactate productivity. Furthermore, we observed that as carbon is increasingly deviated during growth toward product formation, there is an increased fixation rate in the population of spontaneous mutants harboring an impaired production pathway. This is a challenge in the development of green cell factories, which may be countered by the incorporation in biotechnological processes of strategies such as the one pioneered here.

In Escherichia coli, the expression of heterologous genes for the production of recombinant proteins can be challenging due to the codon bias of different organisms. The rare codons AGG and AGA are among the rarest in E. coli. In this work, by using the human gene RioK2 as case study, we found that the presence of consecutive AGG-AGA led to a premature stop, which may be caused by an event of -1 frameshift. We found that translational problems caused by consecutive AGG-AGA are sequence dependent, in particular, in sequences that contain multiple rare AGG or AGA codons elsewhere. Translational problems can be alleviated by different strategies, including codon harmonization, codon optimization, or by substituting the consecutive AGG-AGA codons by more frequent arginine codons. Overall, our results furthered our understanding about the relationship between consecutive rare codons and translational problems. Such information will aid the design of DNA sequence for the production of recombinant proteins.

Gouramy (Osphronemus gouramy) is the one type of fish consumption that are quite popular in Indonesia. Modern market provides a wide range of needs such as fresh fish. Sales of fresh fish in modern markets in Surabaya could reach 80% annually. Required more careful handling against high transaction fresh fish in modern market including whether there is disease in fresh fish like fungus. This research aims to learn about identification and the prevalence of fungal infecting gouramy at modern market Surabaya. Results of the study showed that of the 10 samples taken fron 5 location, 7 fish showed positive fish infacted by the fugus. The fugus are Trichoderma, Rhizopus oryzae, Saprolegnea, Aspergillus flavus, and Fusarium. The value of the prevalence of fungus which infects fish gouramy is 70%.

OBJECTIVE Acute maternal hyperoxygenation (AMH) results in increased fetal left heart blood flow. Our aim was to perform a pilot study to determine the safety, feasibility and direction and magnitude of effect of chronic maternal hyperoxygenation (CMH) on mitral and aortic valve annular dimensions in fetuses with left heart hypoplasia (LHH) after CMH. METHODS Gravidae with fetal LHH were eligible for inclusion in a prospective evaluation of CMH. LHH was defined as: sum of aortic and mitral valve annuli Z-scores

The coincidence of tobacco smoking and psychiatric disorders is of great epidemiological and therapeutic importance. Tobacco smoking by people with mental disorders leads to disproportionately high somatic health risks, an adverse clinical course, poorer clinical outcomes and reduced quality of life (QoL). The etiological causes of the high comorbidity between smoking and mental disorders are still unclear: currently, tobacco smoking is discussed as being either the consequence or contributory cause of psychological disorders or both disorders share common antecedents and interactions. Psychiatric patients are motivated to quit and smoking cessation is not generally less effective with smokers with mental disorders than with mentally healthy individuals. Specific smoking cessation programs in the inpatient and outpatient settings are time-consuming and complex but effective. Within the framework of the current S3 guidelines the international evidence has been updated and transformed into treatment guidelines following an elaborate consensus process. Basically the same interventional measures should be used as with mentally healthy individuals; however, smokers with a psychological comorbidity often need more intensive adjuvant psychotherapeutic interventions and often need pharmaceutical support, (bupropion, varenicline and nicotine replacement therapy). Due to the overall unsatisfactory findings the treatment guidelines are partially based on clinical consensus decisions. In this field, a considerable need for research has been determined.

Motivated by recent failures of polling to estimate populist party support, we propose and analyse two methods for asking sensitive multiple choice questions where the respondent retains some privacy and therefore might answer more truthfully. The first method consists of asking for the true choice along with a choice picked at random. The other method presents a list of choices and asks whether the preferred one is on the list or not. Different respondents are shown different lists. The methods are easy to explain, which makes it likely that the respondent understands how her privacy is protected and may thus entice her to participate in the survey and answer truthfully. The methods are also easy to implement and scale up.

Nosocomial pneumonia (HAP) is a frequent complication of hospital care. Most data are available on ventilator-associated pneumonia. However, infections on general wards are increasing. A central issue are infections with multidrug resistant (MDR) pathogens which are difficult to treat in the empirical setting potentially leading to inappropriate use of antimicrobial therapy.This guideline update was compiled by an interdisciplinary group on the basis of a systematic literature review. Recommendations are made according to GRADE giving guidance for the diagnosis and treatment of HAP on the basis of quality of evidence and benefit/risk ratio.This guideline has two parts. First an update on epidemiology, spectrum of pathogens and antimicrobials is provided. In the second part recommendations for the management of diagnosis and treatment are given. New recommendations with respect to imaging, diagnosis of nosocomial viral pneumonia and prolonged infusion of antibacterial drugs have been added. The statements to risk factors for infections with MDR pathogens and recommendations for monotherapy vs combination therapy have been actualised. The importance of structured deescalation concepts and limitation of treatment duration is emphasized.Die nosokomiale Pneumonie bleibt eine häufige Komplikation von Krankenhausaufenthalten. Die meisten Daten liegen zur beatmungsassoziierten Pneumonie vor, aber auch auf Normalstationen ist vermehrt mit dieser Erkrankung zu rechnen. Problematisch ist die Zunahme von Infektionen mit multiresistenten Erregern (MRE). Diese erschwert die adäquate Initialtherapie und kann zu unkritischem Einsatz von Breitspektrumantibiotika führen.Das vorliegende Update der S3-Leitlinie von 2012 wurde von einer interdisziplinären Arbeitsgruppe auf der Basis einer systematischen Literaturrecherche erarbeitet. Die Empfehlungen zu Diagnostik und Therapie wurden nach dem GRADE-System abgefasst. Graduierung und Empfehlungsstärke entsprechen der Methodik der Nationalen Versorgungsleitlinien.Die Leitlinie besteht aus zwei Teilen. Der allgemeine Teil vermittelt einen aktuellen Überblick zu Epidemiologie, Erregerspektrum und Therapieoptionen der nosokomialen Pneumonie. Handlungsorientierte Empfehlungen zu Diagnostik und Therapie werden im zweiten Teil abgegeben. Neu in diesem Update sind detailliertere Empfehlungen zur bildgebenden Diagnostik, zur Diagnostik nosokomialer Virusinfektionen sowie zur prolongierten Applikation von Antiinfektiva. Die Angaben zur Bedeutung von Risikofaktoren für Infektionen mit MRE und die Empfehlungen zum Einsatz einer antibakteriellen Kombinationstherapie bei derartigen Infektionen wurden angepasst. Strukturierte Deeskalationskonzepte und eine konsequente Begrenzung der Therapiedauer zur Verminderung des Selektionsdrucks werden besonders betont.

Both enantiomers of lactic acid, l -lactic acid and d -lactic acid, can be produced in a sustainable way by a photosynthetic microbial cell factory and thus from CO 2 , sunlight, and water. Several properties of polylactic acid (a polyester of polymerized lactic acid) depend on the controlled blend of these two enantiomers. Recently, cyanobacterium Synechocystis sp. strain PCC6803 was genetically modified to allow formation of either of these two enantiomers. This report elaborates on the d -lactic acid production achieved by the introduction of a d -specific lactate dehydrogenase from the lactic acid bacterium Leuconostoc mesenteroides into Synechocystis . A typical batch culture of this recombinant strain initially shows lactic acid production, followed by a phase of lactic acid consumption, until production “outcompetes” consumption at later growth stages. We show that Synechocystis is able to use d -lactic acid, but not l -lactic acid, as a carbon source for growth. Deletion of the organism's putative d -lactate dehydrogenase (encoded by slr1556 ), however, does not eliminate this ability with respect to d -lactic acid consumption. In contrast, d -lactic acid consumption does depend on the presence of glycolate dehydrogenase GlcD1 (encoded by sll0404 ). Accordingly, this report highlights the need to match a product of interest of a cyanobacterial cell factory with the metabolic network present in the host used for its synthesis and emphasizes the need to understand the physiology of the production host in detail.

Background: Metabolic engineering and synthetic biology of cyanobacteria offer a promising sustainable alternative approach for fossil-based ethylene production, by using sunlight via oxygenic photosynthesis, to convert carbon dioxide directly into ethylene. Towards this, both well-studied cyanobacteria, i.e., Synechocystis sp PCC 6803 and Synechococcus elongatus PCC 7942, have been engineered to produce ethylene by introducing the ethylene-forming enzyme (Efe) from Pseudomonas syringae pv. phaseolicola PK2 (the Kudzu strain), which catalyzes the conversion of the ubiquitous tricarboxylic acid cycle intermediate 2-oxoglutarate into ethylene. Results: This study focuses on Synechocystis sp PCC 6803 and shows stable ethylene production through the integration of a codon-optimized version of the efe gene under control of the Ptrc promoter and the core Shine–Dalgarno sequence (5′-AGGAGG-3′) as the ribosome-binding site (RBS), at the slr0168 neutral site. We have increased ethylene production twofold by RBS screening and further investigated improving ethylene production from a single gene copy of efe, using multiple tandem promoters and by putting our best construct on an RSF1010-based broad-host-self-replicating plasmid, which has a higher copy number than the genome. Moreover, to raise the intracellular amounts of the key Efe substrate, 2-oxoglutarate, from which ethylene is formed, we constructed a glycogen-synthesis knockout mutant (ΔglgC) and introduced the ethylene biosynthetic pathway in it. Under nitrogen limiting conditions, the glycogen knockout strain has increased intracellular 2-oxoglutarate levels; however, surprisingly, ethylene production was lower in this strain than in the wild-type background. Conclusion: Making use of different RBS sequences, production of ethylene ranging over a 20-fold difference has been achieved. However, a further increase of production through multiple tandem promoters and a broad-host plasmid was not achieved speculating that the transcription strength and the gene copy number are not the limiting factors in our system.