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In late 2015, the first example of a transferrable polymyxin resistance mechanism in Gram-negative pathogens, MCR-1, was reported. Since that report, MCR-1 has been described to occur in many Gram-negative pathogens, and the mechanism of MCR-1-mediated resistance was rapidly determined: an ethanolamine is attached to lipid A phosphate groups, rendering the membrane more electropositive and repelling positively charged polymyxins. Acquisition of MCR-1 is clinically significant because polymyxins are frequently last-line antibiotics used to treat extensively resistant organisms, so acquisition of this mechanism might lead to pan-resistant strains. Therefore, the ability to inhibit MCR-1 and restore polymyxin sensitivity would be an important scientific advancement. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are antisense molecules that were designed to target mRNA, preventing translation. Peptide conjugation enhances cellular entry, but they are positively charged, so we tested our lead antibacterial PPMOs by targeting an essential Escherichia coli gene, acpP , and demonstrated that they were still effective in mcr - 1 -positive E.coli strains. We then designed and synthesized two PPMOs targeted to mcr-1 mRNA. Five clinical mcr-1 -positive E.coli strains were resensitized to polymyxins by MCR-1 inhibition, reducing MICs 2- to 16-fold. Finally, therapeutic dosing of BALB/c mice with MCR-1 PPMO combined with colistin in a sepsis model reduced morbidity and bacterial burden in the spleen at 24h and offered a survival advantage out to 5days. This is the first example of a way to modulate colistin resistance with an antisense approach and may be a viable strategy to combat this globally emerging antibiotic resistance threat.

IMPORTANCE Polymyxin use has been increasing as a last line of defense against Gram-negative pathogens with high-level resistance mechanisms, such as carbapenemases. The recently described MCR-1 is a plasmid-mediated mechanism of resistance to polymyxins. MCR-1 is currently found in Gram-negative organisms already possessing high-level resistance mechanisms, leaving clinicians few or no antibacterial options for infections caused by these strains. This study utilizes antisense molecules that target mRNA, preventing protein translation. Herein we describe antisense molecules that can be directly antibacterial because they target genes essential to bacterial growth or blockade of MCR-1, restoring polymyxin sensitivity. We also demonstrate that MCR-1 antisense molecules restore the efficacies of polymyxins in mouse models of E.coli septicemia. Considering all things together, we demonstrate that antisense molecules may be effective therapeutics either alone when they target an essential gene or combined with antibiotics when they target specific resistance mechanisms, such as those seen with MCR-1.

EU Immigration and Asylum Law and Policy

23 Friday Mar 2018

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By Nula Frei , PhD, Senior Researcher, Institute of European Law, University of Fribourg nike free run 5 black uk movies
, Max Planck Institute for Social Law and Social Policy, Munich

As a reaction to the “unprecedented migratory flows”, the EU Commission issued a new womens nike air max 2017 orange
on 7 June 2016. The EU Partnership Framework essentially unites all actions of the EU Member States (individually and collectively) to combat smuggling and trafficking, to address “the fate of migrants and refugees” as well as to manage migration “in a sustainable way” and to fight against deaths at sea.

As part of the actions under the new Partnership Framework, measures to prevent irregular migration and irregular entries play a primary role ( alongside with “fast and operational returns” and “specific and measurable increases in the number and rate of return and readmission” ). These measures always take place in a legal grey zone, threatening to conflict with the obligations arising from international and European law and especially the prohibition of refoulement. While the European Court of Human Rights (ECtHR) has already provided a legal compass for measures at the borders and under the control of European states (see following paragraph), such guidance lacks for cooperation with third countries. The following article aims to provide such legal orientation, using the example of the central Mediterranean route.

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09 Friday Mar 2018

By nike id roshe run yeezy colors v1 MGCgYL4xR6
Universität Konstanz

Daniel Thym,

Last year‘s general election was a game changer in German politics. The ‘grand coalition’ of Christian and Social Democrats, which had governed the federal republic from 2005-09 and 2013-17, lost considerably and won no less than nike air max 90 womens authentic original 2 eye boat shoe with ties sperry
(33 % for the CDU/CSU; 20.5% for the SPD). Moreover, a populist right-wing party entered the German Bundestag for the first time: the Alternative für Deutschland AfD which gained 12.6 % last September and continues to do well in opinion polls.

Pots are somewhere to save, not spend. Money you put into pots will be set aside from your main Monzo account, secure from any spending.

But remember, if you don’t have enough money in your main account, payments that exceed the available amount in your account will be declined, unless you have an overdraft. This applies to Standing Orders and Direct Debits, as well as transactions you make in person or online. You can always move money out of your pots to cover any upcoming payments.

As well as being a helpful tool for saving, pots will form the basis of some exciting new features we have in the works.

Imagine having a pot set aside for bills, and paying your direct debits straight from the pot. You’d always know you had enough cash to cover the essentials, leaving you free to use your Monzo card for everyday expenses, without worrying you’ll overspend.

We also plan to introduce rules, so you can automatically move money in or out of pots. You’d be able to tie your savings to your spending, or automate regular tasks. For example, you could set a rule to round up transactions and put small change into a holiday fund. Or every time you order a takeaway, you could add the same amount into a savings pot.

If you live with housemates or a partner, you could set up shared pots and use them to pay the bills, the rent or other shared expenses. Each of you can pay into the pot each month, then see and manage all the outgoings from within your own Monzo apps.

If you want to see your pot grow, we could help you turn a savings pot into an ISA, or invest the money through an online investment manager. You’d be able to monitor the performance or manage your portfolio, all within Monzo.

You could even ‘lock’ your pots with a pattern or a puzzle, if you need the chance to think twice about moving money out of your saving pot and into your spending account.

We think Pots have a lot of potential, and plenty of you have already shared your suggestions for amazing things we can use them to do.

In fact, the idea for Pots first came about back in January 2016, when one of our early users posted to our community forum with an idea for “folders” or “buckets” where you could set aside money. It was early days at Monzo, but the idea struck a chord, and we’re pleased to be at the point where we’re putting it into practice!

If you have any bright ideas of your own, share them with us on our community forum 💡

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. You can see more of our upcoming plans in our transparent product roadmap .

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