Der Einfluss der Darmmikrobiota auf die Immunantwort der Wirtsschleimhaut und ihre Auswirkungen auf die gastrointestinale Entzündung

In healthy individuals the intestinal microbiota, a complex microbial ecosystem, and the host maintain a mutually beneficial relationship. A balanced composition of the microbiota is crucial to provide its beneficial functions to the hostÕs health. In contrast, alterations of the balanced gut microbiota have been associated to worse or recover disease outcomes. Specifically, studies have demonstrated that alteration in the composition of gut microbiota can dramatically affect host immunity and are frequently associated to common gastrointestinal diseases. Therefore it is essential to investigate and identify the key players that tip the balance between pathogenic or homeostatic host-microbiota interactions to eventually develop novel microbiome-centered therapeutics to modulate inflammatory diseases. Here we demonstrated that alterations in gut microbial communities are able to directly enhance the disease severity in a mouse model of human inflammatory bowel disease (IBD). Specifically, we unveiled that distinct microbial communities utilized opposing arms of host immunity to promote disease severity. While one community required microbiota-specific CD4+ T cell responses, another community triggered severe intestinal inflammation even in the absence of adaptive immunity. Intriguingly, an overexpansion in the Proteobacteria over the Firmicutes phylum was associated to pathogenic CD4+ T cell response. Next, we elucidated beneficial CD4+ T cell responses driven by specific commensals during intestinal inflammation. Specifcally, we explored a previously reported immunomodulatory bacteria, segmented filamentous bacteria (SFB) and its effect on Salmonella induced gastroenteritis. While this bacterium is known to induce proinflammatory cells, SFB specific CD4+ T cells served as 'innate-like' source of antibacterial cytokines rapidly after infection. Importantly, SFB colonized mice displayed reduced pathogen invasion in the cecum suggesting that modulation of CD4 T cells by SFB is associated with improved immune defense. Together our studies demonstrate that the intestinal microbiota can directly influence host immunity to exert both pathogenic and beneficial disease outcome. Further studies are needed to explore specific interactions among distinct microbial members and host factors to drive different disease pathogenicity. Elucidation of similar microbiota induced effects in human may help to develop personalized therapies.Die intestinale Mikrobiota ist ein komplexes mikrobielles Ökosystem, das mit dem Wirt in einer gegenseitigen positiven Wechselwirkung steht. Die Mikrobiota spielt eine entscheidende Rolle in der Physiologie des Wirts. Eine günstige Zusammensetzung der Mikrobiota ist wichtig, um nützlichen Funktionen für die Gesundheit des Wirts zu garantieren. Im Gegensatz dazu werden mikrobielle Veränderungen und die Zugabe oder das Fehlen spezifischer Mitglieder bzw. bestimmter Funktionen der Darmmikrobiota mit einer Verschlechterung oder Verbesserung der Krankheit assoziiert. Es ist von Bedeutung, die wichtigsten Akteure, die das Gleichgewicht zwischen pathogenen oder homöostatischen Wechselwirkungen mit der Mikrobiota beeinflussen können, zu identifizieren und zu untersuchen. In dieser Dissertation konnte gezeigt werden, dass Veränderungen in der Darmmikrobiota in Mäusen einen direkten Einfluss auf die Schwere von chronisch-entzündlichen Darmerkrankungen haben. Außerdem konnte nachgewiesen werden, dass verschiedene mikrobielle Gemeinschaften gegensätzliche Signale der Wirtsimmunität nutzten, um den Schweregrad der Krankheit zu regulieren. Während eine Gemeinschaft von Bakterien spezifische CD4+ T-Zellantworten benötigte, um eine schwerwiegende Darmentzündung auszulösen, konnten diese von einer anderen Gemeinschaft auch in Abwesenheit einer adaptiven Immunantwort geschehen. Darüber hinaus war eine Überexpansion an Proteobakterien mit einer pathogenen CD4+ T-Zellreaktion assoziiert. Zudem wurden nützliche CD4+ T-Zellantworten entdeckt, die durch spezifische kommensale Bakterien während der Darmentzündung angeregt werden. Insbesondere wurde die Wirkung eines zuvor beschriebenen immunregulierenden Bakteriums, das 'Segmentierte filamentöse Bakterium' (SFB), auf Salmonella-induzierte Gastroenteritis untersucht. SFB-spezifische CD4+-T-Zellen wurden hier als neue "angeborene" Quelle von schnell induzierten antibakteriellen Zytokinen während der Infektion identifiziert. SFB-kolonisierte Mäuse zeigten eine reduzierte Pathogeninvasion im Cecum zeigten, was daraufhin deutet, dass die Modulation von CD4-T-Zellen durch SFB mit einer verbesserten Immunabwehr verbunden ist. Zusammenfassend konnten gezeigt werden, dass die intestinale Mikrobiota die Wirtsimmunität direkt beeinflussen kann. Weitere Untersuchungen sind erforderlich, um spezifische Wechselwirkungen zwischen verschiedenen mikrobiellen Mitgliedern und Faktoren des Wirts zu erforschen

A study of the prognostic role of serum fucose and fucosyl transferase in cancer of the uterine cervix.

Serum fucose levels and fucosyl transferase activities have been designated as nonspecific markers of malignancy, and play an important role in the diagnosis of different types of malignancies. In the present study, attempts were made to determine the prognostic significance of these markers in patients with cancer of the uterine cervix after therapy. It was found that both serum fucose and fucosyl transferase, which were elevated in untreated patients declined significantly in patients responsive to therapy at different follow-up intervals, but not in patients unresponsive to therapy.</p

Host&ndash;Virus Interactions in Japanese Encephalitis Virus

Japanese encephalitis (JE) is a mosquito-borne zoonotic disease that causes severe brain inflammation. The JE virus envelope protein domain III (JEV-ED3) plays a critical role in activating receptor binding and membrane fusion. This communication briefly describes, in a computational approach, how structural changes within the JEV-ED3 mutant epitopes suppress their antibody neutralization function. The simulated results demonstrate that mutant Ser40Lys acts as an antibody neutralization escape while Asp41Arg may play the role of an escape mutant. Additionally, an examination of the double mutants on JEV-ED3 suggests that these mutants may qualify as stronger neutralizing escape agents than their single variants. The structural analysis of this work helps to identify the proper antiviral target sequences and specific monoclonal antibodies for the JEV-ED3 escape mutants

Reduction of cadmium toxicity in wheat through plasma technology.

Cadmium (Cd) contamination in plant-derived food is a big concern. This study examines whether and how Ar/O2 and Ar/Air plasma techniques lead to Cd detoxification in wheat. Treatment with Ar/O2 and Ar/Air changed the seed surface and decreased the pH of seeds as well as the cultivation media. Generally, plants subjected to Cd treatment from seeds treated with Ar/O2and Ar/Air plasma showed considerable progress in morphology and total chlorophyll synthesis compared to Cd-treated wheat, suggesting that plasma technology is effective for Cd detoxification. Furthermore, Ar/O2 and Ar/Air plasma treated plants showed a significant decrease in root and shoot Cd concentration, which is consistent with the reduced expression of Cd transporters in the root (TaLCT1 and TaHMA2) compared with the plants not treated with plasma in response to Cd stress. This Cd inhibition is possibly accomplished by the decrease of pH reducing the bioavailability of Cd in the rhizosphere. These observations are in line with maintenance of total soluble protein along with reduced electrolyte leakage and cell death (%) in root and shoot due to Ar/O2 and Ar/Air treatments. Further, Cd-induced elevated H2O2 or oxidative damage in tissues was mainly diminished through the upregulation of antioxidant enzymes (SOD and CAT) and their corresponding genes (TaSOD and TaCAT) induced by Ar/O2 and Ar/Air plasma. Grafting results suggest that root originating nitric oxide signal possibly drives the mechanisms of Cd detoxification due to plasma treatment in wheat. These findings provide a novel and eco-friendly use of plasma technology for the mitigation of Cd toxicity in wheat plants

Protein-protein interactions: switch from classical methods to proteomics and bioinformatics-based approaches

Following the sequencing of the human genome and many other organisms, research on protein-coding genes and their functions (functional genomics) has intensified. Subsequently, with the observation that proteins are indeed the molecular effectors of most cellular processes, the discipline of proteomics was born. Clearly, proteins do not function as single entities but rather as a dynamic network of team players that have to communicate. Though genetic (yeast two-hybrid Y2H) and biochemical methods (co-immunoprecipitation Co-IP, affinity purification AP) were the methods of choice at the beginning of the study of protein-protein interactions (PPI), in more recent years there has been a shift towards proteomics-based methods and bioinformatics-based approaches. In this review, we first describe in depth PPIs and we make a strong case as to why unraveling the interactome is the next challenge in the field of proteomics. Furthermore, classical methods of investigation of PPIs and structure-based bioinformatics approaches are presented. The greatest emphasis is placed on proteomic methods, especially native techniques that were recently developed and that have been shown to be reliable. Finally, we point out the limitations of these methods and the need to set up a standard for the validation of PPI experiments

Lactoferrin-tethered betulinic acid nanoparticles promote rapid delivery and cell death in triple negative breast and laryngeal cancer cells

Cancer management presents multifarious problems. Triple negative breast cancer (TNBC) is associated with inaccurate prognosis and limited chemotherapeutic options. Betulinic acid (BA) prevents angiogenesis and causes apoptosis of TNBC cells. NIH recommends BA for rapid access in cancer chemotherapy because of its cell-specific toxicity. BA however faces major challenges in therapeutic practices due to its limited solubility and cellular entree. We report lactoferrin (Lf) attached BA nanoparticles (Lf-BAnp) for rapid delivery in triple negative breast (MDA-MB-231) and laryngeal (HEp-2) cancer cell types. Lf association was confirmed by SDS-PAGE and FT-IR analysis. Average hydrodynamic size of Lf-BAnp was 147.7 ± 6.20 nm with f potential of �28.51 ± 3.52 mV. BA entrapment efficiency was 75.38 ± 2.70% and the release mechanism followed non-fickian pattern. Impact of Lf-BAnp on cell cycle and cytotoxicity of triple negative breast cancer and its metastatic site laryngeal cancer cell lines were analyzed. Lf-BAnp demonstrated strong anti-proliferative and cytotoxic effects, along with increased sub-G1 population and reduced number of cells in G1 and G2/M phases of the cell cycle, confirming reduced cell proliferation and significant cell death. Speedy intracellular entry of Lf-BAnp occurred within 30 min. Lf-BAnp design was explored for the first time as safer chemotherapeutic arsenals against complex TNBC conditions

Assessment of knowledge on Glaucoma amongst International Medical Students in Tbilisi, Georgia

Glaucoma is the second largest cause of blindness worldwide. Early diagnosis and appropriate examination are essential to prevent progressive vision loss in patients.  The goal of the study was to assess the level of awareness on glaucoma amongst medical students studying in the Republic of Georgia. A survey comprising of 16 questions was distributed among medical students in their clinical and non-clinical years on world sight day on the first week of October 2021. The survey entailed questions ranging from etiology up to prognosis of glaucoma. A total of 129 responses were recorded, 10.1% (n=13) students showed interest in pursuing ophthalmology in the future. Only 55.8% (n=72) students had adequate knowledge on glaucoma and among them, 65%(n=53) of clinical year students performed well. Medical students in their clinical years were more aware about glaucoma compared to the ones in their non-clinical years however majority of students had inadequate knowledge on genetics, diagnostics methods and treatments related to glaucoma. Organizing interactive programs, seminars, and campaigns on glaucoma amongst medical students might bridge the gap and help in early diagnosis of glaucoma in patients, which will help in preventing progressive vision loss

Distinct Microbial Communities Trigger Colitis Development upon Intestinal Barrier Damage via Innate or Adaptive Immune Cells

Summary: Inflammatory bowel disease comprises a group of heterogeneous diseases characterized by chronic and relapsing mucosal inflammation. Alterations in microbiota composition have been proposed to contribute to disease development, but no uniform signatures have yet been identified. Here, we compare the ability of a diverse set of microbial communities to exacerbate intestinal inflammation after chemical damage to the intestinal barrier. Strikingly, genetically identical wild-type mice differing only in their microbiota composition varied strongly in their colitis susceptibility. Transfer of distinct colitogenic communities in gene-deficient mice revealed that they triggered disease via opposing pathways either independent or dependent on adaptive immunity, specifically requiring antigen-specific CD4+ T cells. Our data provide evidence for the concept that microbial communities may alter disease susceptibility via different immune pathways despite eventually resulting in similar host pathology. This suggests a potential benefit for personalizing IBD therapies according to patient-specific microbiota signatures. : Alterations in the microbiota contribute to the development of intestinal inflammation. Roy et al. demonstrate that distinct intestinal microbial communities cause colitis via opposing effector mechanisms independent or dependent on adaptive immunity. Their findings suggest that personalized immunomodulatory treatment according to distinct microbial signatures may be beneficial for IBD patients. Keywords: gut microbiota, IBD, innate colitis, adaptive colitis, colitis pathogenesis, DSS coliti