PLEASE CLICK ON LINK TO VIEW PDF OF SER-8594:

PLEASE CLICK ON LINK TO VIEW PDF OF SER-8584:

PLEASE CLICK ON LINK TO VIEW PDF OF SER-8596:

Topics in this issue include:

• Support for Non-Consecutive Month CSOs - November 18 ^New
• Price Precision Extension - 2018

New - Support for Non-Consecutive Month CSOs

Effective Sunday, November 18 (trade date Monday, November 19), to simplify the submission of trade entry reports, CME ClearPort will support trade entry for Calendar Spread Options (CSOs) on products, typically Agricultural, that do not list consecutive monthly contracts.

This enhancement will be available in New Release for customer testing on Wednesday, November 7.

Back to Top

Price Precision Extension

CME Group is implementing end-to-end technology changes to support increased price granularity. Currently, CME Group systems support a maximum of 7 decimals. With this initiative, products with up to 9 decimals may be listed and traded. Effective Sunday, January 13 (trade date Monday, January 14), pending regulatory approval, the 2 Year Treasury Note futures and spreads will move from 7 decimals to 8 to support trading at 1/8 of 1/32.

Customers are encouraged to move to support 9 decimals now; but there are no plans to list a product that uses the 9th decimal at this time.

For more on impacted products and CME Globex, iLink messaging, Drop Copy and Market Data impacts, view the CME Globex Client Impact Assessment.

These enhancements are currently available for testing in New Release.

Back to Top

Please be advised that effective Sunday, August 25, 2013 (for the August 26th business date) there will be changes to CME ClearPort API Entity Reference Data that will impact Party Detail List Reports and Party Entitlement Reports for CME ClearPort API Brokers and CME ClearPort API Platforms who request Entity Reference Data on behalf of Brokers.

These changes will be available for testing in the New Release environment on August 14th.

Changes to Existing Reponses

When a Broker (or Platform on behalf of Broker) submits a request for all related accounts using the Party Details List Request message or a request for all related accounts which trade a particular product using the Party Entitlement Request message, the following information is provided for each account in Related Party Detail blocks:  The Clearing ID of the Account’s Clearing Firm (Party Role 1), the Trading Firm / Account Owner’s firm identifier (Party Role 7),  and the Broker Firm’s firm identifier (Party Role 30).

Going forward, when the same requests are submitted, an additional Related Party Detail block will appear on the response if there is an Asset Manager Firm assigned to the account:  the Asset Manager Firm’s identifier (Party Role 49).

In the following examples, ACCT1 has been assigned an Asset Manager by the Clearing Firm, while ACCT2 has not.

<FIXML v="5.0 SP2" xv="109" s="20090815" cv="CME.0001">

<PtyDetlListRpt ReqID="123437" RptID="1376864472358" ReqRslt="0" Txt="Valid request">

<Hdr SID="CME" SSub="CPAPI" TID="PLTFM" TSub="username"/>

<PtyDetl ID="ACCT1" Src="C" R="24">

<AltPty ID="A-12345" Src="H"/>

<ReltdPtyDetl ID="123" Src="C" R="1">

<Rltnshp Rltnshp="2"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="trading_firm1" Src="C" R="7">

<Rltnshp Rltnshp="36"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="broker_firm1" Src="C" R="30">

<Rltnshp Rltnshp="22"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="asset_mgr_firm1" Src="C" R="49">

<Rltnshp Rltnshp="32"/>

</ReltdPtyDetl>

</PtyDetl>

<PtyDetl ID="ACCT2" Src="C" R="24">

<AltPty ID="A-67890" Src="H"/>

<ReltdPtyDetl ID="456" Src="C" R="1">

<Rltnshp Rltnshp="2"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="trading_firm2" Src="C" R="7">

<Rltnshp Rltnshp="36"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="broker_firm1" Src="C" R="30">

<Rltnshp Rltnshp="22"/>

</ReltdPtyDetl>

</PtyDetl>

</PtyDetlListRpt>

</FIXML>

<FIXML v="5.0 SP2" xv="109" s="20090815" cv="CME.0001">

<PtyEntlmntRpt ReqID="123412" RptID="1376865078371" ReqRslt="0" Txt="Valid request">

<Hdr SID="CME" SSub="CPAPI" TID="PLTFM" TSub="username"/>

<PtyEntlmnt>

<PtyDetl ID="ACCT1" Src="C" R="24">

<AltPty ID="A-12345" Src="H"/>

<ReltdPtyDetl ID="broker_firm1" Src="C" R="30">

<Rltnshp Rltnshp="22"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="trading_firm1" Src="C" R="7">

<Rltnshp Rltnshp="36"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="asset_mgr_firm1" Src="C" R="49">

<Rltnshp Rltnshp="32"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="123" Src="C" R="1">

<Rltnshp Rltnshp="2"/>

</ReltdPtyDetl>

</PtyDetl>

<PtyDetl ID="ACCT2" Src="C" R="24">

<AltPty ID="A-67890" Src="H"/>

<ReltdPtyDetl ID="broker_firm1" Src="C" R="30">

<Rltnshp Rltnshp="22"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="trading_firm2" Src="C" R="7">

<Rltnshp Rltnshp="36"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="456" Src="C" R="1">

<Rltnshp Rltnshp="2"/>

</ReltdPtyDetl>

</PtyDetl>

<Entlmnt Typ="0" Ind="Y">

<InstrmtScope Oper="1" ID="NN" Src="H" SecTyp="FUT"

Exch="NYMEX"/>

</Entlmnt>

</PtyEntlmnt>

</PtyEntlmntRpt>

</FIXML>

NEW- Broker Requests Asset Manager Users at an Asset Manager Firm

In a previous CME ClearPort API release a change was made to allow Brokers (or Platforms on behalf of Brokers) to specify asset manager users in party role 36 (instead of a trader at the account owner firm) to satisfy the trader individual requirements for applicable market types like energy and metals.  Now Brokers can use ClearPort API reference data to obtain a list of asset manager users for their related accounts.  Once the above responses are received, the Broker or Platform can use each related Asset

Manager Firm (Party Role 49) to request a list of users at the firm:

Request

<FIXML v="5.0 SP2" xv="109" s="20090815" cv="CME.0001">

<PtyDetlListReq ReqID="123437">

<Hdr SID="PLTFM" SSub="username" TID="CME" TSub="CPAPI"/>

<ReqPty ID="broker_firm1" R="30"/>

<Pty ID="asset_mgr_firm1" R="49"/>

<ReqR R="36"/>

</PtyDetlListReq>

</FIXML>

Response

<FIXML v="5.0 SP2" xv="109" s="20090815" cv="CME.0001">

<PtyDetlListRpt ReqID="123437" RptID="1376866782295" ReqRslt="0" Txt="Valid request">

<Hdr SID="CME" SSub="CPAPI" TID="PLTFM" TSub="username"/>

<PtyDetl ID="asset_mgr_user1" Src="C" R="36">

<Sub ID="First Last" Typ="9"/>

<ReltdPtyDetl ID="asset_mgr_firm1" Src="C" R="49">

<Sub ID="Company Name" Typ="5"/>

<Rltnshp Rltnshp="6"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="CMD" Src="C" R="22">

<Rltnshp Rltnshp="12"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="CME" Src="C" R="22">

<Rltnshp Rltnshp="12"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="DME" Src="C" R="22">

<Rltnshp Rltnshp="12"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="NYMEX" Src="C" R="22">

<Rltnshp Rltnshp="12"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="COMEX" Src="C" R="22">

<Rltnshp Rltnshp="12"/>

</ReltdPtyDetl>

<ReltdPtyDetl ID="CBT" Src="C" R="22">

<Rltnshp Rltnshp="12"/>

</ReltdPtyDetl>

</PtyDetl>

</PtyDetlListRpt>

</FIXML>

For more detailed information regarding entity reference data retrieval through CME ClearPort API, please see the CME ClearPort API Reference Data Guide:

http://www.cmegroup.com/clearing/files/Clearport_Reference_Data_API_FIXML_Message_Specification_

and_Samples.pdf

If you have questions or need help facilitating your tests in the New Release environment, please contact:

Market Operations Technical Support

24 Hour 6 Days a Week Support available from Sundays at 5PM ET to Fridays at 5PM ET

Phone: 800-275-6215 / 212-301-4720

Email:  thirdpartyservices@cmegroup.com

Effective Sunday, June 2 (trade date Monday, June 3), CME STP and CME STP FIX will support values entered in the Notes field for CME ClearPort UI and API (TrdCaptRpt/RptSide/@Notes) deals.

This enhancement will be supported in CME STP and CME STP FIX in the New Release environment today, Wednesday, May 15.

Effective Friday, April 3, 2020, CME Group will implement changes to CME ClearPort Reporting functionality. CME ClearPort Reporting supports the generation of reports based on CME ClearPort trade activity, and CME Account Management information.

These changes include:

• A new look and feel of the user interface
• Improved performance
• Streamlined search features
• New downloadable report format
  • Generated reports will be exportable in Excel (csv) and Adobe (pdf) format.

These changes arecurrently available for customer testing in New Release.

Please Note: User roles and entitlements will remain unchanged.

Access ClearPort Reports from: CME Customer Center>Reports>ClearPort Reporting

Please contact the following support teams for:

• Production Environment Support:
  CME Global Command Center (GCC) in the U.S. +1 800 438 8616, in Europe at +44 20 7623 4747 or in Asia at +65 6532 5010.
• Application Access Support:
  Enterprise Application & Systems Entitlements (EASE) in the US at +1 312 456 1560, in Europe at +44 203 379 3802 or in Asia at +1 65 6593 5536.

Effective Friday, April 3, 2020, CME Group will implement enhancements to CME ClearPort Reporting functionality. CME ClearPort Reporting supports the generation of reports based on CME ClearPort trade activity, and CME Account Management information.

The enhancements will include:

• A new look and feel of the user interface
• Improved performance
• Streamlined search features
• New downloadable report format
  • Generated reports will be exportable in Excel (csv) and Adobe (pdf) format.

On Wednesday, March 18, ClearPort Reporting will be available for customer testing in New Release.

Access ClearPort Reports from: CME Customer Center>Reports>ClearPort Reporting

Please contact the following support teams for:

• Production Environment Support:
  CME Global Command Center (GCC) in the U.S. +1 800 438 8616, in Europe at +44 20 7623 4747 or in Asia at +65 6532 5010.
• Application Access Support:
  Enterprise Application & Systems Entitlements (EASE) in the US at +1 312 456 1560, in Europe at +44 203 379 3802 or in Asia at +1 65 6593 5536.

† Denotes update to the article

Effective †Friday, April 17, 2020, CME Group will implement changes to CME ClearPort Reporting functionality. CME ClearPort Reporting supports the generation of reports based on CME ClearPort trade activity, and CME Account Management information.

These changes include:

• A new look and feel of the user interface
• Improved performance
• Streamlined search features
• New downloadable report format
  • Generated reports will be exportable in Excel (csv) and Adobe (pdf) format.

These changes arecurrently available for customer testing in New Release.

Please Note: User roles and entitlements will remain unchanged.

Access ClearPort Reports from: CME Customer Center>Reports>ClearPort Reporting

Please contact the following support teams for:

• Production Environment Support:
  CME Global Command Center (GCC) in the U.S. +1 800 438 8616, in Europe at +44 20 7623 4747 or in Asia at +65 6532 5010.
• Application Access Support:
  Enterprise Application & Systems Entitlements (EASE) in the US at +1 312 456 1560, in Europe at +44 203 379 3802 or in Asia at +1 65 6593 5536.

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Source: www.reuters.com - Saturday, May 09, 2020
Little Richard, the self-proclaimed "architect of rock 'n' roll" who built his ground-breaking sound with a boiling blend of boogie-woogie, rhythm and blues and gospel, died on Saturday at the age of 87, Rolling Stone magazine reported.

Source: www.thestar.com - Saturday, May 09, 2020
Canada approved a verbal demarche to two senior WHO executives that urged them to allow Taiwan to be admitted as an observer to an upcoming meeting because its input would be “meaningful and important.”

Source: www.businessinsider.com - Saturday, May 09, 2020
Dating apps like Tinder, Bumble, and Hinge have reported increased use amid the coronavirus pandemic, while touting virtual dating alternatives for users instead of meeting up in person. Swaths of users are still encouraging matches to break quarantine to have sex and go on dates, despite social distancing guidelines and fines to comply with them. An illustrator on Instagram has been collecting screenshots of these situations, and told Business Insider that users will brand themselves as "badasses," dispute the effectiveness of isolating, and lash out in anger and hurl abusive language when they're rejected. Spokespeople for Grindr, Tinder and Bumble told Business Insider they've informed users to adhere to social-distancing guidelines, but did not respond to inquiries about actions they're taking against users in places where violating lockdown orders can be against the law. Visit Business Insider's homepage for more stories . As millions remain confined to their homes to prevent the spread of coronavirus, the desire for human contact and connection has risen dramatically and led some to search for ways to break those social distancing rules. Popular dating apps — including Tinder , Bumble , and Hinge — have reported significant increases during the outbreak of swiping activity, matches between users, and messages exchanged. It's also led to the introduction of a breed of users who are interested in shirking lockdown orders, an

Source: theweek.com - Saturday, May 09, 2020
1. The Labor Department on Friday said that 20.5 million jobs were lost in April, and the unemployment rate climbed to 14.7 percent. The staggering report showed that a decade of job gains were wiped out in just one month. The report also notes that if it included workers classified as furloughed or temporarily laid off, "the overall unemployment rate would have been almost 5 percentage points higher than reported." The Labor Department's March report showed the unemployment rate climbing to 4.4 percent, from 3.5 percent in February. Weekly data previously showed that more than 33 million Americans have filed initial jobless claims over the course of seven weeks, a number that's equivalent to about 21 percent of the labor force. The ADP National Employment Report also said earlier this week that 20.2 million private sector jobs were lost from March to April. President Trump, who was live on Fox & Friends the moment the report was released, described the unemployment numbers as "fully expected" and "no surprise." [ U.S. Bureau of Labor Statistics , The Washington Post ] 2. The Office of Special Counsel is recommending that ousted vaccine official Dr. Rick Bright be reinstated while it investigates his case, his lawyers announced Friday. Bright, while leading coronavirus vaccine development, was recently removed from his position as the director of the Department of Health and Human Services' Biomedical Advanced Research and Devel

Source: www.nbcnews.com - Saturday, May 09, 2020
The U.S. unemployment rate reached 14.7 percent for April - the worst monthly rate since the Great Depression. The White House has projected optimism, saying they expect the economy to rocket upward once coronavirus restrictions are lifted. But many experts think that is not a realistic expectation.

Source: ninetymilesfromtyranny.blogspot.com - Saturday, May 09, 2020
What is  Ancipient.com ? It Is A Pro-American (Nationalist), Pro-Trump, Pro-American Exceptionalism, And Pro-Western Values automated news aggregation website. Ancipient.com  is an automated, curated, rules based news aggregation website. If I wanted it to sound sexy, I could say it uses artificial intelligence to select news articles. It does not. It uses negative and positive keywords, data rules and curation to select news articles. When other news aggregaters have not updated any new news in hours, you can always depend on my trusty robot ancipient to work 24/7 to keep you updated. Ancipient is a new word, it means: an·cip·i·ent /anˈsipēənt/ adjective in an initial stage of understanding; beginning to understand or learn.  "he could feel ancipient knowledge growing" (of a person) learning, and improving their understanding on a topic or topics. Oh Yeah, The Links I Promised: Russia, China spinning coronavirus conspiracies to blame West Georgetown sues US for not giving money to illegal immigrant families Release the hounds! Singapore deploys ROBOT DOG to help enforce social distancing (PHOTOS, VIDEO) 'Palestinian' Authority hiding terrorist salaries from donor countries in financial reports Sens. Cotton, Cruz, Hawley & Grassley Press Trump to Suspend Most Visas Take a look at Ancipient.com and check it out!

Source: www.businessinsider.com - Saturday, May 09, 2020
Many superyacht crew members have been stuck on their vessels after lockdowns and travel bans were instated due to the coronavirus pandemic. We spoke to crew members who felt 'lucky' to be quarantined in such luxury digs — and grateful to still have jobs and secure wages. There is still plenty of work to be done, but workers also described trivia games, sundeck BBQs, and hot tub nights they're using to pass the time and bond with colleagues. Strict new hygiene and sanitation rules have also been put into place. Visit Business Insider's homepage for more stories . In late March, billionaire businessman David Geffen posted a shot on Instagram taken from his 452-foot superyacht Rising Sun. It was hastily deleted — but not before it had raised more than a few eyebrows and stirred discourse around the 1% and their self-isolation privilege. But it's not just the rare billionaire who is bunkering down on their yacht during the COVID-19 pandemic. Here is another group of people for whom this is a new reality: the yacht's crews.  Before this crisis, there were around 80,000 people employed on pleasure craft around the globe, according to Laurence Lewis, CEO of YPI Crew, a yacht recruitment agency. As countries rushed to close their borders, ports were closed — and overnight, many found themselves unable to travel to get to or leave their yachts.  For many, a superyacht sounds like the dream scenario to see out lockdown. But is it?  "Ther

This article, published ahead of print on 28 July 2008, has been withdrawn by the authors. Although moderate synergy between P2-RANTES and C peptides can be observed with high statistical significance in cell fusion assays, this synergy was not able to be verified in HIV viral assays. The authors regret the overstatement of synergy and will revise the paper for publication at a later date.

Objectives. The aim of this study was to assess the safety of early oral switch (EOS) prior to 14 days for low-risk Staphylococcus aureus bacteremia (LR-SAB), which is the primary treatment strategy employed at our institution. Usually recommended therapy is 14 days of intravenous (IV) antibiotics.

Methods. All patients with SAB at our hospital were identified between 1 January 2014 and 31 December 2018. Those meeting low-risk criteria (healthcare-associated, no evidence of deep infection or demonstrated involvement of prosthetic material, and no further positive blood cultures after 72-hours) were included in the study. The primary outcome was occurrence of a SAB-related complication within 90 days.

Results. There were 469 SAB episodes during the study period, 100 (21%) of whom met inclusion criteria. EOS was performed in 84 patients. In this group, line infection was the source in 79%, methicillin-susceptible S. aureus caused 95% of SABs and 74% of patients received IV flucloxacillin. The median duration of IV and oral antibiotics in the EOS group was 5 (IQR 4-6) and 10 days (IQR 9-14), respectively. Seventy-one percent of patients received flucloxacillin as their EOS agent. Overall, 86% of oral step-down therapy was with beta-lactams. One patient (1%) undergoing EOS had SAB relapse within 90 days. No deaths attributable to SAB occurred within 90 days.

Conclusions. In this low MRSA prevalence LR-SAB cohort, EOS was associated with a low incidence of SAB-related complications. This was achieved with oral beta-lactam therapy in most patients. Larger prospective studies are needed to confirm these findings.

Background: This study summarizes drug resistance analyses in 4 recent phase 2b trials of the respiratory syncytial virus (RSV) fusion inhibitor presatovir in naturally infected adults.

Methods: Adult hematopoietic cell transplant (HCT) recipients, lung transplant recipients, or hospitalized patients with naturally acquired, laboratory-confirmed RSV infection were enrolled in 4 randomized, double-blind, placebo-controlled studies with study-specific presatovir dosing. Full-length RSV F sequences amplified from nasal swabs obtained at baseline and postbaseline were analyzed by population sequencing. Substitutions at RSV fusion inhibitor resistance-associated positions are reported.

Results: Genotypic analyses were performed on 233 presatovir-treated and 149 placebo-treated subjects. RSV F variant V127A was present in 8 subjects at baseline. Population sequencing detected treatment-emergent substitutions in 10/89 (11.2%) HCT recipients with upper and 6/29 (20.7%) with lower respiratory tract infection, 1/35 (2.9%) lung transplant recipients, and 1/80 (1.3%) hospitalized patients treated with presatovir; placebo-treated subjects had no emergent resistance-associated substitutions. Subjects with substitutions at resistance-associated positions had smaller decreases in viral load during treatment relative to those without, but similar clinical outcomes.

Conclusions: Subject population type and dosing regimen may have influenced RSV resistance development during presatovir treatment. Subjects with vs without genotypic resistance development had decreased virologic responses but comparable clinical outcomes.

QPX7728 is a new ultra-broad-spectrum inhibitor of serine and metallo beta-lactamases from a class of cyclic boronates that gave rise to vaborbactam. The spectrum and mechanism of beta-lactamase inhibition by QPX7728 were assessed using purified enzymes from all molecular classes. QPX7728 inhibits class A ESBLs (IC₅₀ range 1-3 nM) and carbapenemases such as KPC (IC₅₀ 2.9±0.4 nM) as well as class C P99 (IC₅₀ of 22±8 nM) with a potency that is comparable or higher than recently FDA approved BLIs avibactam, relebactam and vaborbactam. Unlike those other BLIs, QPX7728 is also a potent inhibitor of class D carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from A. baumannii (OXA-23/24/58, IC₅₀ range 1-2 nM) as well as MBLs such as NDM-1 (IC₅₀ 55±25 nM), VIM-1 (IC₅₀ 14±4 nM) and IMP-1 (IC₅₀ 610±70 nM). Inhibition of serine enzymes by QPX7728 is associated with progressive inactivation with a high efficiency k₂/K ranging from of 6.3 x 10⁴ (for P99) to 9.9 x 10⁵ M^-1 s^-1 (for OXA-23). This inhibition is reversible with variable stability of the QPX7728-beta-lactamase complexes with target residence time ranging from minutes to several hours: 5-20 minutes for OXA carbapenemases from A. baumanii, ~50 minutes for OXA-48 and 2-3 hours for KPC and CTX-M-15. QPX7728 inhibited all tested serine enzymes at 1:1 molar ratio. Metallo-beta-lactamases NDM, VIM, and IMP were inhibited by a competitive mechanism with fast-on-fast-off kinetics, with K_is of 7.5±2.1 nM, 32±14 nM and 240±30 nM for VIM-1, NDM-1 and IMP-1, respectively. QPX7728 ultra-broad-spectrum of BLI inhibition combined with its high potency enables combinations with multiple different beta-lactam antibiotics.

Leishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL and current drug regimens present several drawbacks such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase-1 (MetAP1), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro antileishmanial activity of eight novel MetAP1 inhibitors (OJT001-OJT008) were investigated. Three compounds OJT006, OJT007, and OJT008 demonstrated potent anti-proliferative effect in macrophages infected with L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect was diminished by almost 10-fold in transgenic L. major promastigotes overexpressing MetAP1_LM in comparison to wild-type promastigotes. Furthermore, the in vivo activity of OJT006, OJT007, and OJT008 were investigated in L. major-infected BALB/c mice. In comparison to the control group, OJT008 significantly decreased footpad parasite load by 86%, and exhibited no toxicity against in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by L. major infection.

Malaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 (clag3) family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds and parasites can acquire resistance by silencing clag3 gene expression, thereby reducing drug uptake. We found that exposure to sub-IC50 concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in both clag3 gene expression and RBC permeability, reversing acquired resistance to the antimalarial compound blasticidin S that is transported through PSAC. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance in P. falciparum.

Continuous spread of antimalarial drug resistance is a threat to current chemotherapy efficacy. Therefore, characterizing the genetic diversity of drug resistance markers is needed to follow treatment effectiveness and further update control strategies. Here, we genotyped Plasmodium falciparum resistance gene markers associated with sulfadoxine-pyrimethamine (SP) and artemisinin-based combination therapy (ACT) in isolates from pregnant women in Ghana. The prevalence of the septuple IRNI-A/FGKGS/T pfdhfr/pfdhps haplotypes including the pfdhps A581G and A613S/T mutations was high at delivery among post-SP treatment isolates (18.2%) compared to those of first-antenatal care (before initiation of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP); 6.1%; p = 0.03). Regarding the pfk13 marker gene, two non-synonymous mutations (N458D and A481C) were detected at positions previously related to artemisinin resistance in isolates from Southeast-Asia. These mutations were predicted in silico to alter the stability of the pfk13 propeller-encoding domain. Overall, these findings highlight the need for intensified monitoring and surveillance on additional mutations associated with increased SP resistance as well as emergence of resistance against artemesinin derivatives.

Lipid II is an essential precursor of the bacterial cell wall biosynthesis and thereby an important target for various antibiotics. Several lanthionine-containing peptide antibiotics target lipid II with lanthionine-stabilized lipid II-binding motifs. Here, we used the biosynthesis system of the lantibiotic nisin to synthesize a two lipid II binding motifs-containing lantibiotic, termed TL19, which contains the N-terminal lipid II binding motif of nisin and the distinct C-terminal lipid II binding motif of one peptide of the two-component haloduracin (i.e. HalA1). Further characterization demonstrated that (i) TL19 exerts 64-fold stronger antimicrobial activity against E. faecium than nisin (1-22), which has only one lipid II binding site, and (ii) both the N- and C-terminal domains are essential for the potent antimicrobial activity of TL19, as evidenced by mutagenesis of each single and double domains. These results show the feasibility of a new approach to synthesize potent lantibiotics with two different lipid II binding motifs to treat specific antibiotic-resistant pathogens.

The quinoline MK-571 is the most commonly used inhibitor of multidrug resistance protein-1 (MRP-1) but was originally developed as a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist. While studying the modulatory effect of MRP-1 on anti-hepatitis C virus (HCV) direct acting-antivirals (DAA) efficiency, we observed an unexpected anti-HCV effect of compound MK-571 alone. This anti-HCV activity was characterized in Huh7.5 cells stably harboring a subgenomic genotype 1b replicon. A dose-dependent decrease of HCV RNA levels was observed upon MK-571 administration, with an EC₅₀ of 9±0.3 μM and a maximum HCV RNA level reduction of approximatively 1 Log₁₀. MK-571 also reduced the replication of the HCV full-length J6/JFH1 model in a dose-dependent manner. However, probenecid and apigenin homodimer (APN), two specific inhibitors of MRP-1, had no effect on HCV replication. In contrast, the CysLTR1 antagonists SR2640 increased HCV-SGR RNA levels in a dose-dependent manner, with a maximum increase of 10-fold. In addition, a combination of natural CysLTR1 agonist (LTD4) or antagonists (zafirlukast, cinalukast, and SR2640) with MK-571 completely reversed its antiviral effect, suggesting its anti-HCV activity is related to CysLTR1 rather to MRP-1 inhibition. In conclusion, we showed that MK-571 inhibits HCV replication in hepatoma cell cultures by acting as a CysLTR1 receptor antagonist, thus unraveling a new host-virus interaction in the HCV life cycle.

Since 2012, single low dose of primaquine (SLDPQ, 0.25mg/kg) has been recommended with artemisinin-based combination therapies, as first-line treatment of acute uncomplicated Plasmodium falciparum malaria, to interrupt its transmission, especially in low transmission settings of multidrug, including artemisinin, resistance. Policy makers in Cambodia have been reluctant to implement this recommendation due to primaquine safety concerns and lack of data on its efficacy.

In this randomized controlled trial, 109 Cambodians with acute uncomplicated P. falciparum malaria received dihydroartemisinin-piperaquine (DP) alone or combined with SLDPQ on the first treatment day. Transmission-blocking efficacy of SLDPQ was evaluated on Days 0, 1, 2, 3, 7, 14, 21, 28 and recrudescence by reverse transcriptase polymerase chain reaction (RT-PCR) (gametocyte prevalence) and membrane-feeding assays with Anopheles minimus mosquitoes (gametocyte infectivity). Without the influence of recrudescent infections, DP+SLDPQ reduced gametocyte carriage 3 fold compared to DP. Of 48 patients tested on Day 0, only three patients were infectious to mosquitoes (~6%). Post-treatment, three patients were infectious: on D14 (3.5%, 1/29), and on the first and seventh day of recrudescence (8.3%, 1/12 for each); this overall low infectivity precluded our ability to assess its transmission blocking efficacy.

Our study confirms effective gametocyte clearance of SLDPQ when combined with DP in multidrug resistant P. falciparum and the negative impact of recrudescent infections due to poor DP efficacy. Artesunate-mefloquine (ASMQ) has replaced DP and ASMQ-SLDPQ has been deployed to treat all P. falciparum symptomatic patients to further support the elimination of multidrug resistant P. falciparum in Cambodia.