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Παρασκευή 23 Φεβρουαρίου 2018

The evolution of methods for urinary steroid metabolomics in clinical investigations particularly in childhood

Publication date: Available online 23 February 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): John W. Honour, E. Conway, R. Hodkinson, F. Lam
The metabolites of cortisol, and the intermediates in the pathways from cholesterol to cortisol and the adrenal sex steroids can be analysed in a single separation of steroids by gas chromatography (GC) coupled to MS to give a urinary steroid profile (USP). Steroids individually and in profile are now commonly measured in plasma by liquid chromatography (LC) coupled with MS/MS. The steroid conjugates in urine can be determined after hydrolysis and derivative formation and for the first time without hydrolysis using GC–MS, GC–MS/MS and liquid chromatography with mass spectrometry (LC–MS/MS). The evolution of the technology, practicalities and clinical applications are examined in this review. The patterns and quantities of steroids changes through childhood. Information can be obtained on production rates, from which children with steroid excess and deficiency states can be recognised when presenting with obesity, adrenarche, adrenal suppression, hypertension, adrenal tumours, intersex condition and early puberty, as examples. Genetic defects in steroid production and action can be detected by abnormalities from the GC–MS of steroids in urine. New mechanisms of steroid synthesis and metabolism have been recognised through steroid profiling. GC with tandem mass spectrometry (GC–MS/MS) has been used for the tentative identification of unknown steroids in urine from newborn infants with congenital adrenal hyperplasia. Suggestions are made as to areas for future research and for future applications of steroid profiling. As routine hospital laboratories become more familiar with the problems of chromatographic and MS analysis they can consider steroid profiling in their test repertoire although with LC–MS/MS of urinary steroids this is unlikely to become a routine test because of the availability, cost and purity of the internal standards and the complexity of data interpretation. Steroid profiling with quantitative analysis by mass spectrometry (MS) after chromatography now provides the most versatile of tests of adrenal function in childhood.



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A possible principal function of corticosteroid signaling that is conserved in vertebrate evolution: lessons from receptor-knockout small fish

Publication date: Available online 23 February 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Tatsuya Sakamoto, Susumu Hyodo, Wataru Takagi
Corticosteroid receptors are critical for homeostasis maintenance, but understanding of the principal roles of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) throughout vertebrates is limited. Lines of constitutive GR-knockout zebrafish and MR-knockout medaka have recently been generated as the first adult-viable corticosteroid receptor-knockout animals, in contrast to the lethality of these receptor knockouts in mice. Here, we describe behavioral and physiological modifications following disruption of corticosteroid receptor function in these animal models. We suggest these data point toward a potentially conserved function of corticosteroid receptors in integrating brain-behavior and visual responses in vertebrates. Finally, we discuss how future work in cartilaginous fishes (Chondrichthyes) will further advance understanding of the unity and diversity of corticosteroid receptor function, since distinct orthologs of GR and MR derived from an ancestral corticoid receptor appear in these basal jawed vertebrates.



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Method for identifying outliers of soil heavy metal data

Abstract

Artificial errors in the experimental process may lead to some outliers, which reduce data quality and cause erroneous judgment in soil pollution assessment. Based on this, a method for detecting outliers of soil heavy metal data was proposed in this study. The As, Cd, and Pb concentrations of the soil in Beijing, China, were taken as samples to verify the validity of the method. Results showed that there were 8, 34, and 38 outliers for the As, Cd, and Pb concentrations in the Beijing soil, respectively. The result of re-analyzed revealed that 75.0, 76.5, and 92.1% of the As, Cd, and Pb outliers, respectively, were caused by artificial errors. After correcting, the interpolation accuracy for data was improved significantly. The mean relative error (MRE) of the As, Cd, and Pb outliers decreased by 48.0, 44.6, and 54.7%, while the mean square error of these outliers decreased by 34.2, 33.3, and 46.4%, respectively. The MRE values of the nearest neighboring points which were influenced by the outliers decreased by 5.2, 20.6, and 27.6%, while the mean square error of these points decreased by 5.3, 17.3, and 33.2%, respectively. To our knowledge, this is the first study on detecting outliers of soil heavy metal data. The method considers both spatial and numerical outliers, which avoids the limitation of single method, and can effectively improve the data quality of soil heavy metal concentrations with a finite sample size and analysis time.



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Editorial Board

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Publication date: March 2018
Source:Peptides, Volume 101





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Corrigendum to “Structure, folding and stability of a minimal homologue from Anemonia sulcata of the sea anemone potassium channel blocker ShK” [Peptides 99 (2018) 169–178]

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Publication date: March 2018
Source:Peptides, Volume 101
Author(s): Bankala Krishnarjuna, Christopher A. MacRaild, Punnepalli Sunanda, Rodrigo A.V. Morales, Steve Peigneur, Jason Macrander, Heidi H. Yu, Marymegan Daly, Srinivasarao Raghothama, Vikas Dhawan, Satendra Chauhan, Jan Tytgat, Michael W. Pennington, Raymond S. Norton




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Enhancement of nitrogen and phosphorus removal in landscape water using polymeric ferric sulfate as well as the synergistic effect of four kinds of natural rocks as promoter

Abstract

Eutrophication in lakes and rivers caused by the nitrogen (N) and phosphorus (P) is urgent since the accumulation of N and P can possibly cause the algal blooms and devastation to the water ecological system. The removal of N and P in the landscape water would be an efficient way to reduce the enrichment of nutrition before they reach the large water system. The N and P removal efficiency of PFS as well as the synergistic effect of natural rocks (four types of purple parent rock (J3p, J2s, T1f, and J3s)) as promoter was examined under laboratory conditions. The results indicated that TN and TP removal efficiency of the composite coagulant was significantly better than that of PFS or purple parent rock alone and J3p + PFS (combination of PFS and J3p purple parent rock) showed the best TN and TP removal efficiency. TN and TP removal efficiency of 53.53 and 86.48%, respectively, were achieved with coagulant dosage of 6 g L−1 J3p and 30 mg L−1 PFS, water temperature of 30 °C, and wastewater initial pH of 9. In addition, Fourier transformed infrared (FTIR) spectrophotometer, X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive analysis (EDX), and the water quality index analysis revealed that the treatment of TN and TP by using J3p + PFS was taking advantage of the flocculation function of PFS and the adsorption function of PFS and J3p. In which, the flocculation mechanism was mainly charge neutralization; adsorption mechanism was mainly physical and chemical adsorption.



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Humoral immune responses to infection: common mechanisms and unique strategies to combat pathogen immune evasion tactics

Publication date: April 2018
Source:Current Opinion in Immunology, Volume 51
Author(s): Ismail Sebina, Marion Pepper
Humoral immune responses are crucial for protection against invading pathogens and are the underlying mechanism of protection for most successful vaccines. Our understanding of how humoral immunity develops is largely based on animal models utilizing experimental immunization systems. While these studies have made enormous progress for the field and have defined many of the fundamental principles of B cell differentiation and function, we are only now beginning to appreciate the complexities of humoral immune responses induced by infection. Co-evolution of the adaptive immune system and the pathogenic world has created a diverse array of B cell responses to infections, with both shared and unique strategies. In this review, we consider the common mechanisms that regulate the development of humoral immune responses during infection and highlight recent findings demonstrating the evolution of unique strategies used by either host or pathogen for survival.



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Effects of bisphenol A on metabolism and evidences of a mode of action mediated through endocrine disruption

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Publication date: Available online 23 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Brigitte Le Magueresse-Battistoni, Luc Multigner, Claire Beausoleil, Christophe Rousselle
Based on rodent studies after prenatal and/or perinatal or adult exposure, there is now evidence that BPA may increase metabolic disturbances eventually leading to type-2 diabetes development via an ED MoA. In particular, BPA has been shown to alter insulin synthesis and/or release by pancreatic β-cells, and insulin signaling within insulin-sensitive organs (i.e., liver, muscle, adipose tissues). This resulted in variations in the expression of specific hepatic or adipose tissue markers, which are indicative of a state of insulin resistance. These effects are considered by experts to be hallmarks of adverse hormonal effects, each leading to insulin resistance within the different insulin-sensitive tissues.Although epidemiological studies are inconclusive, these effects are considered relevant for humans, because similarities exist in homeostatic regulation of insulin production and sensitivity between rodents and humans and because evidence was also shown through in vitro experimental data using human cells or tissues.



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Steroid regulation: An overlooked aspect of tolerance and chronic rejection in kidney transplantation

Publication date: Available online 7 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Sofia Christakoudi, Manohursingh Runglall, Paula Mobillo, Irene Rebollo-Mesa, Tjir-Li Tsui, Estefania Nova-Lamperti, Sonia Norris, Yogesh Kamra, Rachel Hilton, Sunil Bhandari, Richard Baker, David Berglund, Sue Carr, David Game, Sian Griffin, Philip A. Kalra, Robert Lewis, Patrick B. Mark, Stephen D. Marks, Iain Macphee, William McKane, Markus G. Mohaupt, Ravi Pararajasingam, Sui Phin Kon, Daniel Serón, Manish Sinha, Beatriz Tucker, Ondrej Viklický, Robert I. Lechler, Graham M. Lord, Daniel Stahl, Maria P. Hernandez-Fuentes
Steroid conversion (HSD11B1, HSD11B2, H6PD) and receptor genes (NR3C1, NR3C2) were examined in kidney-transplant recipients with "operational tolerance" and chronic rejection (CR), independently and within the context of 88 tolerance-associated genes. Associations with cellular types were explored. Peripheral whole-blood gene-expression levels (RT-qPCR-based) and cell counts were adjusted for immunosuppressant drug intake. Tolerant (n = 17), stable (n = 190) and CR patients (n = 37) were compared. Healthy controls (n = 14) were used as reference. The anti-inflammatory glucocorticoid receptor (NR3C1) and the cortisol-activating HSD11B1 and H6PD genes were up-regulated in CR and were lowest in tolerant patients. The pro-inflammatory mineralocorticoid gene (NR3C2) was downregulated in stable and CR patients. NR3C1 was associated with neutrophils and NR3C2 with T-cells. Steroid conversion and receptor genes, alone, enabled classification of tolerant patients and were major contributors to gene-expression signatures of both, tolerance and CR, alongside known tolerance-associated genes, revealing a key role of steroid regulation and response in kidney transplantation.



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A review on Drug-induced Sedation Endoscopy – Technique, Grading Systems and Controversies

Sleep disordered breathing (SDB) comprises a spectrum of disorders, ranging from simple snoring to severe obstructive sleep apnoea (OSA), with a significant burden to health care systems in the developed world. If left untreated, obstructive sleep apnoea has significant cumulative, long-term health consequences. In the 1990s drug induced sedation endoscopy (DISE) has been developed to become a primary tool in the diagnosis and management of obstructive sleep apnoea (OSA). It allows meticulous endoscopic evaluation of the airway and identifies areas of collapse, thereby informing both on the selection of surgical techniques, where efficacy depends entirely on success at relieving obstruction at a certain level and on the usefulness of conservative measures, such as mandibular advancement splints.

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Dampened STING-Dependent Interferon Activation in Bats

Publication date: Available online 22 February 2018
Source:Cell Host & Microbe
Author(s): Jiazheng Xie, Yang Li, Xurui Shen, Geraldine Goh, Yan Zhu, Jie Cui, Lin-Fa Wang, Zheng-Li Shi, Peng Zhou
Compared with terrestrial mammals, bats have a longer lifespan and greater capacity to co-exist with a variety of viruses. In addition to cytosolic DNA generated by these viral infections, the metabolic demands of flight cause DNA damage and the release of self-DNA into the cytoplasm. However, whether bats have an altered DNA sensing/defense system to balance high cytosolic DNA levels remains an open question. We demonstrate that bats have a dampened interferon response due to the replacement of the highly conserved serine residue (S358) in STING, an essential adaptor protein in multiple DNA sensing pathways. Reversing this mutation by introducing S358 restored STING functionality, resulting in interferon activation and virus inhibition. Combined with previous reports on bat-specific changes of other DNA sensors such as TLR9, IFI16, and AIM2, our findings shed light on bat adaptation to flight, their long lifespan, and their unique capacity to serve as a virus reservoir.

Graphical abstract

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Teaser

Bats co-exist with a large variety of viruses, and infection-derived cytosolic DNA could result in heightened DNA sensing and overactivation. Xie et al. show that STING-dependent IFN activation is dampened in bats due to the replacement of the highly conserved and functionally important serine residue S358.


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Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

Publication date: 10 January 2018
Source:Cell Host & Microbe, Volume 23, Issue 1
Author(s): Youry Kim, Jenny L. Anderson, Sharon R. Lewin
Despite the success of antiretroviral therapy (ART), there is currently no HIV cure and treatment is life long. HIV persists during ART due to long-lived and proliferating latently infected CD4+ T cells. One strategy to eliminate latency is to activate virus production using latency reversing agents (LRAs) with the goal of triggering cell death through virus-induced cytolysis or immune-mediated clearance. However, multiple studies have demonstrated that activation of viral transcription alone is insufficient to induce cell death and some LRAs may counteract cell death by promoting cell survival. Here, we review new approaches to induce death of latently infected cells through apoptosis and inhibition of pathways critical for cell survival, which are often hijacked by HIV proteins. Given advances in the commercial development of compounds that induce apoptosis in cancer chemotherapy, these agents could move rapidly into clinical trials, either alone or in combination with LRAs, to eliminate latent HIV infection.

Teaser

The major barrier to a cure for HIV is the persistence of latently infected T cells. One strategy being pursued to eliminate HIV latency involves the activation of virus transcription to induce cell death. Kim et al. review approaches that aim to enhance HIV-specific cell death following virus activation.


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Botulinum Neurotoxins: Still a Privilege of Clostridia?

Publication date: 14 February 2018
Source:Cell Host & Microbe, Volume 23, Issue 2
Author(s): Michel R. Popoff
Botulinum neurotoxins (BoNTs) are potent bacterial toxins mostly produced by genetically diverse clostridial strains. Recently, BoNT variants have been reported in non-clostridial strains. In this issue of Cell Host & Microbe, Zhang et al. (2018) describe a novel BoNT in Entecoccus faecium.

Teaser

Botulinum neurotoxins (BoNTs) are potent bacterial toxins mostly produced by genetically diverse clostridial strains. Recently, BoNT variants have been reported in non-clostridial strains. In this issue of Cell Host & Microbe, Zhang et al. (2018) describe a novel BoNT in Entecoccus faecium.


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Human-Specific Adaptations in Vpu Conferring Anti-tetherin Activity Are Critical for Efficient Early HIV-1 Replication In Vivo

Publication date: 10 January 2018
Source:Cell Host & Microbe, Volume 23, Issue 1
Author(s): Eri Yamada, Shinji Nakaoka, Lukas Klein, Elisabeth Reith, Simon Langer, Kristina Hopfensperger, Shingo Iwami, Gideon Schreiber, Frank Kirchhoff, Yoshio Koyanagi, Daniel Sauter, Kei Sato
The HIV-1-encoded accessory protein Vpu exerts several immunomodulatory functions, including counteraction of the host restriction factor tetherin, downmodulation of CD4, and inhibition of NF-κB activity to facilitate HIV-1 infection. However, the relative contribution of individual Vpu functions to HIV-1 infection in vivo remained unclear. Here, we used a humanized mouse model and HIV-1 strains with selective mutations in vpu to demonstrate that the anti-tetherin activity of Vpu is a prerequisite for efficient viral spread during the early phase of infection. Mathematical modeling and gain-of-function mutations in SIVcpz, the simian precursor of pandemic HIV-1, corroborate this finding. Blockage of interferon signaling combined with transcriptome analyses revealed that basal tetherin levels are sufficient to control viral replication. These results establish tetherin as a key effector of the intrinsic immune defense against HIV-1, and they demonstrate that Vpu-mediated tetherin antagonism is critical for efficient viral spread during the initial phase of HIV-1 replication.

Graphical abstract

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Teaser

The HIV-1-encoded accessory protein Vpu exerts several functions. Using a humanized mouse model and HIV-1 Vpu mutant viruses, Yamada et al. demonstrate that Vpu-mediated antagonism of the interferon-induced antiviral protein tetherin is critical for efficient viral spread during the initial phase of HIV-1 replication in vivo.


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In Vitro Culture, Drug Sensitivity, and Transcriptome of Plasmodium Vivax Hypnozoites

Publication date: Available online 22 February 2018
Source:Cell Host & Microbe
Author(s): Nil Gural, Liliana Mancio-Silva, Alex B. Miller, Ani Galstian, Vincent L. Butty, Stuart S. Levine, Rapatbhorn Patrapuvich, Salil P. Desai, Sebastian A. Mikolajczak, Stefan H.I. Kappe, Heather E. Fleming, Sandra March, Jetsumon Sattabongkot, Sangeeta N. Bhatia
The unique relapsing nature of Plasmodium vivax infection is a major barrier to malaria eradication. Upon infection, dormant liver-stage forms, hypnozoites, linger for weeks to months and then relapse to cause recurrent blood-stage infection. Very little is known about hypnozoite biology; definitive biomarkers are lacking and in vitro platforms that support phenotypic studies are needed. Here, we recapitulate the entire liver stage of P. vivax in vitro, using a multiwell format that incorporates micropatterned primary human hepatocyte co-cultures (MPCCs). MPCCs feature key aspects of P. vivax biology, including establishment of persistent small forms and growing schizonts, merosome release, and subsequent infection of reticulocytes. We find that the small forms exhibit previously described hallmarks of hypnozoites, and we pilot MPCCs as a tool for testing candidate anti-hypnozoite drugs. Finally, we employ a hybrid capture strategy and RNA sequencing to describe the hypnozoite transcriptome and gain insight into its biology.

Graphical abstract

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Teaser

Plasmodium vivax hypnozoites are difficult to study due to the lack of human liver platforms. Gural et al. recapitulated the entire liver stage of P. vivax in vitro, including formation and reactivation of hypnozoites and release of merosomes. Hybrid capture followed by RNA-seq revealed a first look into the hypnozoite transcriptome.


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Less Is Best in the Convergent Evolution of Typhoidal Salmonella

Publication date: 14 February 2018
Source:Cell Host & Microbe, Volume 23, Issue 2
Author(s): Andrés Vázquez-Torres
Related works in this issue of Cell Host & Microbe (Bronner et al., 2018) and in a recent issue of Cell Reports (Hiyoshi et al., 2018) demonstrate how loss-of-function mutations in butyrate utilization and lipopolysaccharide O-antigen processing contribute to evasion of innate host defenses and the convergent evolution of distinct typhoidal Salmonella lineages.

Teaser

Related works in this issue of Cell Host & Microbe (Bronner et al., 2018) and in a recent issue of Cell Reports (Hiyoshi et al., 2018) demonstrate how loss-of-function mutations in butyrate utilization and lipopolysaccharide O-antigen processing contribute to evasion of innate host defenses and the convergent evolution of distinct typhoidal Salmonella lineages.


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Infectious Scarring: Setting the Trigger for Intestinal Inflammation

Publication date: 14 February 2018
Source:Cell Host & Microbe, Volume 23, Issue 2
Author(s): Andrew M.F. Johnson, R. William DePaolo
The initiating factors that trigger inflammatory bowel disease (IBD) are poorly understood. In a recent paper, Yang et al. (2017) demonstrate that IBD-like syndrome in mice can develop as a consequence of recurrent pathogen infection. Pathogenic triggering of inflammatory disease is a re-emerging concept that has significant therapeutic implications.

Teaser

The initiating factors that trigger inflammatory bowel disease (IBD) are poorly understood. In a recent paper, Yang et al. (2017) demonstrate that IBD-like syndrome in mice can develop as a consequence of recurrent pathogen infection. Pathogenic triggering of inflammatory disease is a re-emerging concept that has significant therapeutic implications.


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BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity

Publication date: 10 January 2018
Source:Cell Host & Microbe, Volume 23, Issue 1
Author(s): Rob J.W. Arts, Simone J.C.F.M. Moorlag, Boris Novakovic, Yang Li, Shuang-Yin Wang, Marije Oosting, Vinod Kumar, Ramnik J. Xavier, Cisca Wijmenga, Leo A.B. Joosten, Chantal B.E.M. Reusken, Christine S. Benn, Peter Aaby, Marion P. Koopmans, Hendrik G. Stunnenberg, Reinout van Crevel, Mihai G. Netea
The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response. The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-related viral infections, with a key role for IL-1β as a mediator of trained immunity responses.

Graphical abstract

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Teaser

In this paper, Arts et al. describe that BCG vaccination induces genome-wide epigenetic reprogramming of human monocytes that correlates with protection against experimental viral infection. Reduction of viremia correlated with upregulation of non-specific IL-1β production, and genetic polymorphisms in the IL-1 pathway affect the induction of trained immunity by BCG.


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An Additive Sugar Helps the C. diff Go Round

Publication date: 14 February 2018
Source:Cell Host & Microbe, Volume 23, Issue 2
Author(s): Michael C. Abt
Outbreaks of hypervirulent strains of Clostridium difficile began to be reported in healthcare facilities worldwide around 20 years ago. Concurrently, trehalose became a common additive used by the global food industry. A new study provides evidence that these two observations are a linked phenomenon (Collins et al., 2018).

Teaser

Outbreaks of hypervirulent strains of Clostridium difficile began to be reported in healthcare facilities worldwide around 20 years ago. Concurrently, trehalose became a common additive used by the global food industry. A new study provides evidence that these two observations are a linked phenomenon (Collins et al., 2018).


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Identification of a Botulinum Neurotoxin-like Toxin in a Commensal Strain of Enterococcus faecium

Publication date: 14 February 2018
Source:Cell Host & Microbe, Volume 23, Issue 2
Author(s): Sicai Zhang, Francois Lebreton, Michael J. Mansfield, Shin-Ichiro Miyashita, Jie Zhang, Julia A. Schwartzman, Liang Tao, Geoffrey Masuyer, Markel Martínez-Carranza, Pål Stenmark, Michael S. Gilmore, Andrew C. Doxey, Min Dong
Botulinum neurotoxins (BoNTs), produced by various Clostridium strains, are a family of potent bacterial toxins and potential bioterrorism agents. Here we report that an Enterococcus faecium strain isolated from cow feces carries a BoNT-like toxin, designated BoNT/En. It cleaves both VAMP2 and SNAP-25, proteins that mediate synaptic vesicle exocytosis in neurons, at sites distinct from known BoNT cleavage sites on these two proteins. Comparative genomic analysis determines that the E. faecium strain carrying BoNT/En is a commensal type and that the BoNT/En gene is located within a typical BoNT gene cluster on a 206 kb putatively conjugative plasmid. Although the host species targeted by BoNT/En remains to be determined, these findings establish an extended member of BoNTs and demonstrate the capability of E. faecium, a commensal organism ubiquitous in humans and animals and a leading cause of hospital-acquired multi-drug-resistant (MDR) infections, to horizontally acquire, and possibly disseminate, a unique BoNT gene cluster.

Graphical abstract

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Teaser

Botulinum neurotoxins (BoNTs) are potent toxins produced by diverse bacteria in the Clostridium genus. Zhang et al. report that a commensal strain of Enterococcus faecium carries a conjugative plasmid encoding a BoNT-like toxin gene. Thus, a commensal organism can acquire and possibly disseminate BoNT genes.


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