Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases

Current antibiotics tend to be broad spectrum, leading to indiscriminate killing of commensal bacteria and accelerated evolution of drug resistance. Here, we use CRISPR-Cas technology to create antimicrobials whose spectrum of activity is chosen by design. RNA-guided nucleases (RGNs) targeting specific DNA sequences are delivered efficiently to microbial populations using bacteriophage or bacteria carrying plasmids transmissible by conjugation. The DNA targets of RGNs can be undesirable genes or polymorphisms, including antibiotic resistance and virulence determinants in carbapenem-resistant Enterobacteriaceae and enterohemorrhagic Escherichia coli. Delivery of RGNs significantly improves survival in a Galleria mellonella infection model. We also show that RGNs enable modulation of complex bacterial populations by selective knockdown of targeted strains based on genetic signatures. RGNs constitute a class of highly discriminatory, customizable antimicrobials that enact selective pressure at the DNA level to reduce the prevalence of undesired genes, minimize off-target effects and enable programmable remodeling of microbiota.National Institutes of Health (U.S.) (New Innovator Award 1DP2OD008435)National Centers for Systems Biology (U.S.) (Grant 1P50GM098792)United States. Defense Threat Reduction Agency (HDTRA1-14-1-0007)Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (W911NF13D0001)National Institute of General Medical Sciences (U.S.) (Interdepartmental Biotechnology Training Program 5T32 GM008334)Fonds de la recherche en sante du Quebec (Master's Training Award

Localisation nasosinusienne des tumeurs plasmocytaires

Introduction : Les tumeurs plasmocytaires représentent 3 à 4% des tumeurs des cavités naso-sinusiennes. Elles nécessitent un bilan diagnostique spécifique et une prise en charge adéquate. Nous nous proposons d’étudier les particularités diagnostiques et thérapeutiques des plasmocytomes naso-sinusiens. Matériel et méthodes : Notre étude est rétrospective comportant 5 cas de plasmocytomes naso-sinusiens confirmés histologiquement.Résultats : Il s’agit de 3 hommes et 2 femmes âgés de 32 à 77 ans. Le plasmocytome avait une localisation sphénoïdale dans un cas, nasale dans 2 cas, ethmoïdo-nasale dans un cas et naso-maxillaire dans le cas restant. Il s’agissait d’un myélome multiple dans un cas. Trois patients ont eu une radiothérapie. Celle-ci était associée à une chimiothérapie dans le cas du myélome multiple et à une exérèse chirurgicale dans les 2 autres cas La chirurgie a été seule dans un cas. La chimiothérapie exclusive a été proposée dans un cas de plasmocytome localement avancé mais le patient a été perdu de vue. Pour les patients suivis, une seule récidive a été notée à 18 mois.Conclusion : La présentation clinique des plasmocytomes nasosinusiens est aspécifique. Le diagnostic est confirmé par l’histologie. Le pronostic est dominé par la présence ou non d’un myélome multiple et par la taille tumorale. Un suivi prolongé est nécessaire.Mots clés : plasmocytome extramédullaire ; cavités naso-sinusiennes ; radiothérapie ; chirurgie.Introduction: Plasmocytomas represent 3-4% of tumors naso-sinus cavities. Their diagnosis requires a specific investigations and adequate management. We report 5 cases of naso-sinus plasmacytoma and we propose to study their diagnostic and therapeutic characteristics.Materials and methods: Our study is retrospective including 5 cases of naso-sinus plasmacytoma confirmed histologically.Results: There were 3 men and 2 women aged 32 to 77 years. The plasmacytoma had a sphenoidal location in one case, nasal in 2 cases, ethmoid-nasal in one case and naso-maxillary in the remaining case. Multiple myeloma was found in one case. Three patients underwent radiotherapy. This was associated with chemotherapy in multiple myeloma case and surgical resection in 2 cases. Surgery alone was performed in one case. Exclusive chemotherapy was proposed in a case of plasmacytoma locally advanced but the patient was lost sight of. For followed patients, only one recurrence was noted at 18 months.Conclusion: The clinical presentation of sinonasal plasmacytomas is aspecific. The diagnosis is confirmed by histology. The prognosis is dominated by the presence or absence of multiple myeloma and tumor size. Prolonged follow-up is necessary.Keywords : extramedullary plasmacytoma, naso-sinus cavities, radiotherapy ; surgery

Infection néonatale bactérienne précoce : Quand mettre sous antibiotique et quelle antibiothérapie ? Early bacterial neonatal infection: When to indicate antibiotic treatment and what antibiotic therapy ?

Objective. Propose a relevant management strategy that can identify newborns with a bacterial infectious risk and those under clinical monitoring alone or in combination with parenteral antibiotic therapy.Methods. Retrospective study carried out between SA < 42, suspected of early bacterial infection and monitored in Maternity and in the Neonatology Unit of the Hospital Group Carnelle Portes of Oise [Val France]. The clinical-biological and bacteriological data, the therapeutic strategy and the evolution are analyzed. Results. Two hundred and forty newborns were eligible and divided into three groups: 120 asymptomatic newborns with antenatal criteria for bacterial infectious risk [G1NAS], 70 symptomatic newborns with antenatal criteria for bacterial infectious risk [G2NSCARIB] and 50 symptomatic newborns without antenatal criteria of bacterial infectious risk [G3NSSCARIB]. Inflammatory biology is limited tocolonized G1NAS newborns and symptomatic groups. The identified bacteria [Peripheral samples, gastric fluid, blood and cerebrospinal fluid] were mainly the Streptococcus of the group and the E Coli. Antibiotic therapy has been shown to be useful in asymptomatic newborns with inflammatory syndrome and bacteria identified on peripheral samples and gastric fluid, but  also in all symptomatic newborns. Conclusion. In a early bacterial infection, an interventionist attitude is required, but early antibiotic therapy is only useful in the situation of symptomatic newborns. On the otherhand, in the asymptomatic newborns, antibiotic therapy will be reserved for those carrying both an identified bacteria and an inflammatory syndrome. Contexte et objectif. L‟infection néonatale bactérienne précoce est greffée d‟une forte mortalité et morbidité conduisant à une antibiothérapie probabiliste sans délai souvent à posteriori inutile. L‟objectif du présent travail était de proposer une stratégie de prise en charge pertinente susceptible de bien identifier les nouveau-nés à risque infectieux bactérien et ceux relevant d‟une surveillance clinique seule ou associée à une antibiothérapie parentérale.    Méthodes. Etude documentaire menée entre janvier 2014 et janvier 2016 sur des nouveau-nés de 36≥SA<42, suspects d‟infection bactérienne précoce et suivis en Maternité et dans l‟unité de Néonatologie du Groupe Hospitalier Carnelle Portes de l‟Oise [Val D‟Oise, France]. Les données clinico-biologiques et bactériologiques, la stratégie thérapeutique et l‟évolution sont analysées.  Résultats. Deux cent quarante nouveau-nés [NNES] ont été éligibles et repartis en trois groupes : 120 NNES asymptomatiques avec critères anténatals de risque infectieux bactérien [G1NAS], 70 NNES symptomatiques avec critères anténatals de risque infectieux bactérien [G2NSCARIB] et 50 NNES symptomatiques sans critères anténatals de risque infectieux bactérien [G3NSSCARIB]. La biologie inflammatoire est limitée aux NNES du groupe G1NAS colonisés et aux groupes symptomatiques. Les germes identifiés [Prélèvements périphériques, liquide gastrique, sang et liquide céphalorachidien] ont été principalement le Streptocoque du groupe β et l‟E Coli. L‟antibiothérapie s‟est avérée utile chez les NNES asymptomatiques avec syndrome inflam-matoire et germes identifiés sur les prélèvements périphériques et liquide gastrique, mais aussi chez tous les NNES symptomatiques.                                                                    Conclusion. Chez un NNE âgé de ≥ 36SA et suspect d‟infection bactérienne précoce, une attitude interventionniste est de rigueur, mais l‟antibiothérapie sans délai n‟est utile que dans les situations des NNES symptomatiques. En revanche, chez les NNES asymptomatiques, l‟antibiothérapie sera réservée à ceux porteurs à la fois d‟un germe et d‟un syndrome inflammatoire

Agroecology and Health: Lessons from Indigenous Populations.

Purpose of reviewThe article aims to systematize and disseminate the main contributions of indigenous ancestral wisdom in the agroecological production of food, especially in Latin America. For this purpose, it is necessary to ask whether such knowledge can be accepted by academia research groups and international forums as a valid alternative that could contribute to overcome the world's nutritional problems.Recent findingsAlthough no new findings are being made, the validity of ancestral knowledge and agroecology is recognized by scientific research, and by international forums organized by agencies of the United Nations. These recommend that governments should implement them in their policies of development, and in the allocation of funds to support these initiatives. Agroecology and ancestral knowledge are being adopted by a growing number of organizations, indigenous peoples and social groups in various parts of the world, as development alternatives that respond to local needs and worldviews. Its productive potential is progressively being recognized at an international level as a model that contributes to improve the condition of people regarding nutritional food

Challenges Predicting Ligand-Receptor Interactions of Promiscuous Proteins: The Nuclear Receptor PXR

Transcriptional regulation of some genes involved in xenobiotic detoxification and apoptosis is performed via the human pregnane X receptor (PXR) which in turn is activated by structurally diverse agonists including steroid hormones. Activation of PXR has the potential to initiate adverse effects, altering drug pharmacokinetics or perturbing physiological processes. Reliable computational prediction of PXR agonists would be valuable for pharmaceutical and toxicological research. There has been limited success with structure-based modeling approaches to predict human PXR activators. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning. In this study, we present a comprehensive analysis focused on prediction of 115 steroids for ligand binding activity towards human PXR. Six crystal structures were used as templates for docking and ligand-based modeling approaches (two-, three-, four- and five-dimensional analyses). The best success at external prediction was achieved with 5D-QSAR. Bayesian models with FCFP_6 descriptors were validated after leaving a large percentage of the dataset out and using an external test set. Docking of ligands to the PXR structure co-crystallized with hyperforin had the best statistics for this method. Sulfated steroids (which are activators) were consistently predicted as non-activators while, poorly predicted steroids were docked in a reverse mode compared to 5α-androstan-3β-ol. Modeling of human PXR represents a complex challenge by virtue of the large, flexible ligand-binding cavity. This study emphasizes this aspect, illustrating modest success using the largest quantitative data set to date and multiple modeling approaches

Critical evaluation of key evidence on the human health hazards of exposure to bisphenol A

Despite the fact that more than 5000 safety-related studies have been published on bisphenol A (BPA), there seems to be no resolution of the apparently deadlocked controversy as to whether exposure of the general population to BPA causes adverse effects due to its estrogenicity. Therefore, the Advisory Committee of the German Society of Toxicology reviewed the background and cutting-edge topics of this BPA controversy. The current tolerable daily intake value (TDI) of 0.05 mg/kg body weight [bw]/day, derived by the European Food Safety Authority (EFSA), is mainly based on body weight changes in two- and three-generation studies in mice and rats. Recently, these studies and the derivation of the TDI have been criticized. After having carefully considered all arguments, the Committee had to conclude that the criticism was scientifically not justified; moreover, recently published additional data further support the reliability of the two-and three-generation studies demonstrating a lack of estrogen-dependent effects at and below doses on which the current TDI is based. A frequently discussed topic is whether doses below 5 mg/ kg bw/day may cause adverse health effects in laboratory animals. Meanwhile, it has become clear that positive results from some explorative studies have not been confirmed in subsequent studies with higher numbers of animals or a priori defined hypotheses. Particularly relevant are some recent studies with negative outcomes that addressed effects of BPA on the brain, behavior, and the prostate in rodents for extrapolation to the human situation. The Committee came to the conclusion that rodent data can well be used as a basis for human risk evaluation. Currently published conjectures that rats are insensitive to estrogens compared to humans can be refuted. Data from toxicokinetics studies show that the half-life of BPA in adult human subjects is less than 2 hours and BPA is completely recovered in urine as BPA-conjugates. Tissue deconjugation of BPA-glucuronide and -sulfate may occur. Because of the extremely low quantities, it is only of minor relevance for BPA toxicity. Biomonitoring studies have been used to estimate human BPA exposure and show that the daily intake of BPA is far below the TDI for the general population. Further topics addressed in this article include reasons why some studies on BPA are not reproducible; the relevance of oral versus non-oral exposure routes; the degree to which newborns are at higher systemic BPA exposure; increased BPA exposure by infusions in intensive care units; mechanisms of action other than estrogen receptor activation; and the current regulatory status in Europe, as well as in the USA, Canada, Japan, New Zealand, and Australia. Overall, the Committee concluded that the current TDI for BPA is adequately justified and that the available evidence indicates that BPA exposure represents no noteworthy risk to the health of the human population, including newborns and babies