Quorum sensing dynamics in the alpha-proteobacterium Sinorhizobium meliloti at the single-cell and population level

In quorum sensing, bacteria produce and release so-called autoinducers that accumulate in the environment while the cells grow. Once these molecules reach a threshold concentration, they trigger major behavioral changes in the population. Since the triggered behaviors are thought to be effective only when performed by a large enough group, autoinducers are generally taken to indicate when this sufficient cell density has been reached. However, little is known about how these components interact dynamically at the single-cell level to fulfill their task of cell-cell communication. Furthermore, quorum sensing is often studied in well-shaken liquid cultures, but little is known about autoinducer dispersal and response dynamics over larger distances in physiological niches like the rhizosphere where active mixing is negligible. The aim of this work therefore was to investigate these aspects in the model organism Sinorhizobium meliloti. In (Bettenworth et al., 2022.), quorum sensing dynamics were investigated with respect to autoinducer synthase gene expression in single cells and the timing of the response in the respective colonies. Surprisingly, in S. meliloti the autoinducer synthase gene is not expressed continuously, but in discrete stochastic pulses. Stochasticity stems from scarcity and, presumably, low binding affinity of the essential transcription activator. Physiological factors modulate abundance of this activator or its binding affinity to the autoinducer synthase gene promoter and thereby modulate gene expression pulse frequency. Higher or lower pulse frequencies in turn trigger the onset of the quorum sensing response at lower or higher cell numbers, respectively. In other words: S. meliloti quorum sensing is based on a stochastic regulatory system that encodes each cell’s physiological condition in the pulse frequency with which it expresses its autoinducer synthase gene; pulse frequencies of all members of a population are then integrated in the common pool of autoinducers. Only once this vote crosses the threshold, the response behavior is initiated. Consequently, S. meliloti quorum sensing is not so much a matter of counting cell numbers as suggested by the analogy of the quorum, but more comparable to a voting in a local community, or the collective decision-making described for social insects (Bettenworth et al., 2022). In (Bettenworth et al., 2018), the dynamics of autoinducer dispersal by diffusion in a two-dimensional environment were explored. At first sight, diffusive spreading should yield a dilution of the molecules and, with increasing distance from the source, slow down progression of the concentration level necessary to trigger a response in distantly located receiver cells. In contrast to this expectation, however, this threshold concentration did not decelerate in respective experiments, but instead travelled with constant speed, comparable to front propagation in pattern-forming systems. According to a mathematical model, this effect was due to the exponential growth of the sender cells which yielded adding-up of an exponentially growing number of autoinducer concentration profiles, thus compensating for the thinning effect of diffusion. Consequently, even a single sender colony could induce a response in receiver cells up to 7 mm away (Bettenworth et al., 2018)

Medical therapy of stricturing Crohn’s disease: what the gut can learn from other organs - a systematic review

Crohn’s disease (CD) is a chronic remitting and relapsing disease. Fibrostenosing complications such as intestinal strictures, stenosis and ultimately obstruction are some of its most common long-term complications. Despite recent advances in the pathophysiological understanding of CD and a significant improvement of anti-inflammatory therapeutics, medical therapy for stricturing CD is still inadequate. No specific anti-fibrotic therapy exists and the incidence rate of strictures has essentially remained unchanged. Therefore, the current therapy of established fibrotic strictures comprises mainly endoscopic dilation as well as surgical approaches. However, these treatment options are associated with major complications as well as high recurrence rates. Thus, a specific anti-fibrotic therapy for CD is urgently needed. Importantly, there is now a growing body of evidence for prevention as well as effective medical treatment of fibrotic diseases of other organs such as the skin, lung, kidney and liver. In face of the similarity of molecular mechanisms of fibrogenesis across these organs, translation of therapeutic approaches from other fibrotic diseases to the intestine appears to be a promising treatment strategy. In particular transforming growth factor beta (TGF-β) neutralization, selective tyrosine kinase inhibitors, blockade of components of the renin-angiotensin system, IL-13 inhibitors and mammalian target of rapamycin (mTOR) inhibitors have emerged as potential drug candidates for anti-fibrotic therapy and may retard progression or even reverse established intestinal fibrosis. However, major challenges have to be overcome in the translation of novel anti-fibrotics into intestinal fibrosis therapy, such as the development of appropriate biomarkers that predict the development and accurately monitor therapeutic responses. Future clinical studies are a prerequisite to evaluate the optimal timing for anti-fibrotic treatment approaches, to elucidate the best routes of application, and to evaluate the potential of drug candidates to reach the ultimate goal: the prevention or reversal of established fibrosis and strictures in CD patients

Giant cell arteritis exclusively detected by 18F-fluorodeoxyglucose positron emission tomography: a case report

INTRODUCTION: This case of giant cell arteritis is noteworthy because it evaded standard diagnostic criteria and only emerged as fever of unknown origin. In this regard, we present (18)F-fluorodeoxyglucose positron emission tomography as a valid diagnostic method. CASE PRESENTATION: This case report describes a 58-year-old Caucasian woman who is a cigarette smoker with a 10-week history of fever of unknown origin, night sweats and weight loss of 12kg. Initially, clinical presentation was suspicious of malignant disease. Laboratory findings detected significantly elevated inflammatory blood parameters including C-reactive protein and elevated erythrocyte sedimentation rate (110mm/hour). Extensive diagnostic workup including microbiological and rheumatological assessment, ultrasonography, endoscopy and computed tomography of abdomen and thorax did not indicate any septic or malignant focus. Eventually, (18)F-fluorodeoxyglucose positron emission tomography was able to reveal arteritis of her aortic arch and supraaortic branches. Subsequently, she commenced steroid and methotrexate therapy that led to sustained remission. CONCLUSIONS: This case of giant cell arteritis may promote discussion regarding a more specific classification for this disease entity. Furthermore, it confirms that (18)F-fluorodeoxyglucose positron emission tomography might serve as a valuable tool for diagnosis of giant cell arteritis, because it could facilitate an accurate and non-invasive detection of lesions of large vessels

Alterations in serum amino acid concentrations in dogs with protein-losing enteropathy

BackgroundCertain amino acids are decreased in humans with inflammatory bowel disease (IBD) and supplementation with the same amino acids has shown beneficial effects in animal models of IBD. Currently, the amino acid status of dogs with protein-losing enteropathy (PLE) is unknown.Hypothesis/objectiveTo determine if serum amino acid concentrations are abnormal in dogs with PLE and correlated with clinical and laboratory variables and outcome.AnimalsThirty client-owned dogs diagnosed with PLE and 12 apparently healthy dogs seen at Bristol Veterinary School.MethodsRetrospective study using stored residual serum from fasted dogs with PLE, collected at the time of diagnostic investigation and from apparently healthy dogs. Serum was analyzed for 30 amino acids using an automated high-performance liquid chromatography amino acid analyzer.ResultsSerum tryptophan concentrations were significantly decreased in dogs with PLE (median, 22 nmol/mL; range, 1-80 nmol/mL) compared with apparently healthy control dogs (median, 77.5 nmol/mL; range, 42-135 nmol/mL, P < .001). There were no significant differences in the remaining 29 serum amino acids between dogs with PLE and apparently healthy. Serum tryptophan concentrations were also significantly correlated with serum albumin concentrations in dogs with PLE (P = .001, R2 = 0.506).Conclusions and clinical importanceDecreased serum tryptophan concentration might play a role in the pathogenesis of canine PLE or be a consequence of the disease

For example : martyrdom and imitation in early Christian texts and art

This volume explores the phenomenon of Christian martyrdom and ideas of “following Christ,” in particular focusing on theological and pragmatic difficulties in the early Christian period. How can martyrs successfully follow Christ without themselves entering into a competition with Christ? What happens when the idea of following Christ so faithfully as to experience martyrdom becomes impossible because of the fundamentally different living situation of the faithful? How are model and imitation shaped in comparison to pagan exempla? Contributions from archaeology, classical philology, ancient history, theology, and art history suggest some answers to these questions, drawing equally on ancient literature and material culture

Quantitative Stain-free and Continuous Multimodal Monitoring of Wound Healing in vitro with Digital Holographic Microscopy

Impaired epithelial wound healing has significant pathophysiological implications in several conditions including gastrointestinal ulcers, anastomotic leakage and venous or diabetic skin ulcers. Promising drug candidates for accelerating wound closure are commonly evaluated in in vitro wound assays. However, staining procedures and discontinuous monitoring are major drawbacks hampering accurate assessment of wound assays. We therefore investigated digital holographic microscopy (DHM) to appropriately monitor wound healing in vitro and secondly, to provide multimodal quantitative information on morphological and functional cell alterations as well as on motility changes upon cytokine stimulation. Wound closure as reflected by proliferation and migration of Caco-2 cells in wound healing assays was studied and assessed in time-lapse series for 40 h in the presence of stimulating epidermal growth factor (EGF) and inhibiting mitomycin c. Therefore, digital holograms were recorded continuously every thirty minutes. Morphological changes including cell thickness, dry mass and tissue density were analyzed by data from quantitative digital holographic phase microscopy. Stimulation of Caco-2 cells with EGF or mitomycin c resulted in significant morphological changes during wound healing compared to control cells. In conclusion, DHM allows accurate, stain-free and continuous multimodal quantitative monitoring of wound healing in vitro and could be a promising new technique for assessment of wound healing

ECCO Topical Review on Biological Treatment Cycles in Crohn’s Disease

There are now a growing number of licensed biological therapies for patients with Crohn’s disease. However, there can be significant costs associated with long-term maintenance treatment, as well as some concerns about potential side-effects. As a result, there has been increasing interest in elective biological treatment discontinuation in selected patients, after a sustained period of remission. Following discontinuation, in cases of relapse, evidence to date has suggested that remission may often be regained by re-treatment with the same biological agent. Therefore, a concept has emerged in which cycles of biological therapy might be used. If this treatment strategy were to be applied in a subgroup of patients at low risk of relapse, cycling might allow a substantial number of patients to have a lower, overall therapeutic burden—ensuring decreased exposure to biological therapy but still enabling appropriate disease control.Currently, there remains uncertainty about the benefit–risk balance for using cycles of biological treatment for patients with Crohn’s disease. Accordingly, an expert panel was convened by the European Crohn’s and Colitis Organisation [ECCO] to review the published literature and agree a series of consensus practice points. The panel aimed to provide evidence-based guidance on multiple aspects of biological treatment discontinuation and cycling, including the risk of relapse after elective treatment discontinuation, predictors of probable relapse or remission, safety, patient preferences, and pharmacoeconomic aspects. Crucially, discussions about biological treatment discontinuation and cycling should be individualized, to enable shared decision-making by patients with their clinicians