Deforestation in Brazil's Amazon rainforest rose sharply in April, government data showed on Friday, as the coronavirus outbreak keeps many environmental enforcers out of the field and the country prepares to deploy troops to fight illegal logging.

As truckers move vital supplies such as food, hand sanitizer and ventilators during the COVID-19 pandemic, they're pleading with governments to allow more truck stops to reopen so they can get meals, showers and rest. Social media groups and individual businesses are doing their part to thank truckers.

While Apple has not revealed any viewing figures for Apple TV+, industry sources say the new "Defending Jacob" drama is a hit with higher viewing figures, and audience engagement, than most shows on the service.

Amazon has reissued its popular Apple Watch deal, dropping the Series 5 Watches with Cellular to $399 after a $100 price cut. Multiple styles are on sale and in stock.

Jonathan Mahler’s piece on the Osama bin Laden raid is as much about the nature of journalism as it is about the facts surrounding the event.

Starting a Christian micro-finance programme has been a long-time dream for OM Madagascar. In partnership with OM Hong Kong, this will soon become a reality.

Project Namana is OM Madagascar's microfinance project designed to empower the marginalised people in the city.

10 challenges, 3 people, 0 phones and 1 awesome God.

A local church gets excited about bringing the gospel of Christ to their small community.

OM's International Intensive School of Missions in Panama is getting ready to start in January 2012 to equip Latinos for missions.

OM Panama team members share on a live radio talk show about the upcoming International Intensive School of Missions.

A former student of OM Panama brings the world to her small church in western Panama.

OM Panama launches the new International Intensive School of Missions and hosts a new session of Mission Extreme.

OM Panama team members struggle to continue ministry as the Gnöbe Buglé people protest and bring the country to a halt.

After a week of tensions between government and the indigenous inhabitants, Panamá is on the road to recovery.

Following the recent protests and riots, OM Panama's Mission Extreme group helps clean the Volcán police station.

A group of 80 teenagers from Chicago, US, bless the local community in Volcán, Panama.

Berlin’s airports are recording a drastic slump in passenger numbers. In March, a decline in passengers of 64.7 percent was recorded at Tegel and Schönefeld for the whole month. However, the number of passengers has continued to fall significantly over ...

MOST people's memories of Millie Small in 1964 are of her climbing international charts with the massive hit song, My Boy Lollipop. But for Dennis Smith, it was her return to Jamaica that year that made the greatest impression.

A group of Costa Ricans visit a local church in an indigenous region of the country and bring encouragement by serving.

People in Talamanca, an indigenous reserve of Costa Rica with a history of witchcraft, share their problems with OM workers and receive hope in Christ.

Puntarenas, Costa Rica :: A group of indigenous people from the Talamanca region have a horizon-expanding visit to Logos Hope.

An amazing God-given tool to mobilise and inspire people to make a difference: Global Village.

Amazon still has some nice deals right now on Kindle e-readers and Fire tablets — up to $30 off, plus $5 in ebook credits on select purchases, and 3 months of Kindle Unlimited for $0.99.

The 2019 iPad mini with Wi-Fi and 256GB of storage normally sells for $549, but is available on Amazon right now for just $519. That's the lowest it's ever been on the site.

For a limited time, the 7-inch Fire 7 Kids Edition is $40 off while the 8- and 10-inch models are both $50 off. These tablets make a great gift for 3-to-12-year olds.

The 10.2-inch Apple iPad with 128GB of storage is $100 off, a 65-inch Vizio 4K TV is $500 off and includes a $250 Dell gift card, and you can score the first discount on Echo Buds.

The appeals court put the brakes on a predominantly white community's racially tinged efforts to secede from a larger school system.

Hamish Wilson, radio producer and actor

Eoin Hayes's first-half strike earned the Group B points for Irish side Region 2 as Russia's South Region failed to convert their possession into a single shot on goal.

The growing popularity of voice-activated technologies is forcing educators to think about the role such tools play in preparing students for the jobs of the future.

IT’S all too easy to lose track of many of the quirky, moving, interesting films that have been shot in Scotland over the years. Some of the sparkling gems on these pages attracted decent reviews upon release before fading from view; others slipped under most people’s radar. The 10 films here are funny, or dark, or insightful. All have something to say; all are worth tracking down, and watching, whether it’s for the first time, or the first time since they were released.

Rick talks with the CEO of Panorama Education, an ed-tech company whose college- and career-readiness tools are currently used each year in 11,500 schools.

Sen. Bingaman will be the No. 2 Democrat in the Senate on ESEA reauthorization.

Few students become more engaged in clubs, academics and student life activities than Raquele Amato. A prominent figure on Penn State Schuylkill’s campus, Amato has served as an officer in more than half a dozen student organizations, swept spring awards ceremonies, worked as a resident assistant, and helped her family run their pizza shop in Frackville, Pennsylvania, all while maintaining a full-time course load. Before she closes the book on her time at Penn State Schuylkill, Amato reflected on her time at the campus and considered what’s next.

Source: Public News Service - Economists warn that the costs of climate change in the U.S. – including from the health impacts of air pollution and natural disasters such as hurricanes and wildfires – could top $350 billion annually in the next 10 years.

Smoking during pregnancy has been related to thicker carotid intima media thickness in young adults, and this was also shown in neonates.

This study is the first to show that the effect of smoking during pregnancy on the vasculature of children is (still) visible at the age of 5 years. Pregnancy appears to be the critical period for this damage to occur. (Read the full article)

Moisture damage and mold increase the risk of asthma and asthmatic symptoms. However, the location of the damage, or the specific group of children who are at greater risk of asthma, is rarely taken into account.

Inspector-observed moisture damage or mold in the child’s bedroom, living room, or kitchen increased the risk of asthma and persistent asthma during a 6-year follow-up. Atopic children may be more susceptible to the effects of moisture damage and mold. (Read the full article)

On Thursday, the company sent an email to third-party dealers, saying they would need approval to sell used Nintendo Games. Turns out the email was actually sent out in error, Amazon claims.

The growing popularity of voice-activated technologies is forcing educators to think about the role such tools play in preparing students for the jobs of the future.

With Box Zones, Box customers can use Amazon Web Services and IBM Cloud to store data overseas.

Finance ministers meeting in Brussels will try to push forward a legislative proposal for a levy on the European sales of companies with a global annual revenue of $853m or more, such as Facebook, Alphabet and Amazon.

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.

Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo β-lactamase (MBL) families. The recent introduction of SBL carbapenemase-inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n=234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ~30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modelling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor, capable of operating in a functional space not presently filled by any clinically approved compound.

Multi-drug resistance among Gram-negative bacteria is a major global public health threat. Metallo-β-lactamases (MBLs) target the most widely-used antibiotic class, the β-lactams, including the most recent-generation carbapenems. Interspecies spread renders these enzymes a serious clinical threat and there are no clinically-available inhibitors. We present crystal structures of IMP-13, a structurally-uncharacterized MBL from Gram-negative Pseudomonas aerugionasa found in clinical outbreaks globally, and characterize the binding using solution NMR-spectroscopy and molecular-dynamics simulations. Crystal structures of apo IMP-13 and bound to four clinically-relevant carbapenem antibiotics (doripenem, ertapenem, imipenem and meropenem) are presented. Active site plasticity and the active-site loop, where a tryptophan residue stabilizes the antibiotic core scaffold, are essential to the substrate-binding mechanism. The conserved carbapenem scaffold plays the most significant role in IMP-13 binding, explaining the broad substrate specificity. The observed plasticity and substrate-locking mechanism provide opportunities for rational drug design of novel metallo-β-lactamase inhibitors, essential in the fight against antibiotic resistance.

QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of beta-lactamase inhibition by QPX7728. The MIC of multiple IV only (ceftazidime, piperacillin, cefepime, ceftolozane and meropenem) and orally bioavailable (ceftibuten, cefpodoxime, tebipenem) antibiotics alone and in combination with QPX7728 (4 μg/ml), as well as comparator agents, were determined against the panels of laboratory strains of P. aeruginosa and K. pneumoniae expressing over 55 diverse serine and metallo beta-lactamases. QPX7728 significantly enhanced the potency of antibiotics against the strains expressing Class A extended spectrum beta-lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with beta-lactamase inhibition demonstrated in biochemical assays. It also inhibits both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) Class C beta-lactamases and Class D enzymes including carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/72/58). QPX7728 is also a potent inhibitor of many class B metallo beta-lactamases (NDM, VIM, CcrA1, IMP, GIM but not SPM or L1). Addition of QPX7728 (4 μg/ml) reduced the MICs in a majority of strains to the level observed for the vector alone control, indicative of complete beta-lactamase inhibition. The ultra-broad-spectrum beta-lactamase inhibition profile makes QPX7728 a viable candidate for further development.

QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo beta-lactamases at a nano molar range in biochemical assays with purified enzymes. The broad-spectrum inhibitory activity of QPX7728 observed in biochemical experiments translates into enhancement of the potency of many beta-lactams against strains of target pathogens producing beta-lactamases. The impact of bacterial efflux and permeability on inhibitory potency were determined using isogenic panels of KPC-3 producing isogenic strains of K. pneumoniae and P. aeruginosa and OXA-23-producing strains of A. baumannii with various combinations of efflux and porin mutations. QPX7728 was minimally affected by multi-drug resistance efflux pumps in either Enterobacteriaceae, or in non-fermenters such as P. aeruginosa or A. baumannii. In P. aeruginosa, the potency of QPX7728 was further enhanced when the outer membrane is permeabilized. The potency of QPX7728 in P. aeruginosa is not affected by inactivation of the carbapenem porin OprD. While changes in OmpK36 (but not OmpK35) reduced the potency of QPX7728 (8-16-fold), QPX7728 (4 μg/ml) nevertheless completely reversed KPC-mediated meropenem resistance in strains with porin mutations, consistent with a lesser effect of these mutations on the potency of QPX7728 compared to other agents. The ultra-broad-spectrum beta-lactamase inhibition profile combined with enhancement of the activity of multiple beta-lactam antibiotics with varying sensitivity to the intrinsic resistance mechanisms of efflux and permeability indicate QPX7728 is a useful inhibitor for use with multiple beta-lactam antibiotics.

Recent studies highlight the abundance of commensal coagulase-negative staphylococci (CoNS) on healthy skin. Evidence suggests that CoNS actively shape the skin immunological and microbial milieu to resist colonization or infection by opportunistic pathogens, including methicillin resistant Staphylococcus aureus (MRSA), in a variety of mechanisms collectively termed colonization resistance. One potential colonization resistance mechanism is the application of quorum sensing, also called the Accessory Gene Regulator (agr) system, which is ubiquitous among staphylococci. Common and rare CoNS make autoinducing peptides (AIPs) that function as MRSA agr inhibitors, protecting the host from invasive infection. In a screen of CoNS spent media we found that Staphylococcus simulans, a rare human skin colonizer and frequent livestock colonizer, released potent inhibitors of all classes of MRSA agr signaling. We identified three S. simulans agr classes, and have shown intraspecies cross-talk between non-cognate S. simulans agr types for the first time. The S. simulans AIP-I structure was confirmed, and the novel AIP-II and AIP-III structures were solved via mass spectrometry. Synthetic S. simulans AIPs inhibited MRSA agr signaling with nanomolar potency. S. simulans in competition with MRSA reduced dermonecrotic and epicutaneous skin injury in murine models. Addition of synthetic AIP-I also effectively reduced MRSA dermonecrosis and epicutaneous skin injury in murine models. These results demonstrate potent anti-MRSA quorum sensing inhibition by a rare human skin commensal, and suggest that cross-talk between CoNS and MRSA may be important in maintaining healthy skin homeostasis and preventing MRSA skin damage during colonization or acute infection.

Klebsiella pneumoniae that produce extended spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being developed for treatment of serious infections caused by ESBL-producing organisms. The pharmacokinetics-pharmacodynamics (PK-PD) of cefepime-enmetazobactam against ESBL-producing K. pneumoniae was studied in a neutropenic murine pneumonia model. Dose ranging studies were performed. Dose fractionation studies were performed to define the relevant PD index for the inhibitor. The partitioning of cefepime and enmetazobactam into the lung was determined by comparing area under the concentration time curve (AUC) in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains. Cefepime 100 mg/kg q8h i.v. had minimal antimicrobial effect. When this background regimen of cefepime was combined with enmetazobactam half-maximal effect was induced with enmetazobactam 4.71 mg/kg q8h i.v. The dose fractionation study suggest both fT>threshold and fAUC:MIC are potentially relevant PD indices. The AUC_ELF:AUC_plasma for cefepime and enmetazobactam was 73.4% and 61.5%, respectively. A ≥2-log kill in the lung was achieved with a plasma and ELF cefepime fT>MIC of ≥20% and enmetazobactam fT>2 mg/L of ≥20% of the dosing interval. These data and analyses provide the underpinning evidence for the combined use of cefepime and enmetazobactam for nosocomial pneumonia.

Chromosomal and plasmid-borne AmpC cephalosporinases are a major resistance mechanism to β-lactams in Enterobacteriaceae and Pseudomonas aeruginosa. The new β-lactamase inhibitor avibactam effectively inhibits class C enzymes and can fully restore ceftazidime susceptibility. The conserved amino acid residue Asn³⁴⁶ of AmpC cephalosporinases directly interacts with the avibactam sulfonate. Disruption of this interaction caused by the N³⁴⁶Y amino acid substitution in Citrobacter freundii AmpC was previously shown to confer resistance to the ceftazidime-avibactam combination (CAZ-AVI). The aim of this study was to phenotypically and biochemically characterize the consequences of the N³⁴⁶Y substitution in various AmpC backgrounds. Introduction of N³⁴⁶Y into Enterobacter cloacae AmpC (AmpC_cloacae), plasmid-mediated DHA-1, and P. aeruginosa PDC-5, led to 270-, 12,000-, and 79-fold decreases in the inhibitory efficacy (k₂/K_i) of avibactam, respectively. The kinetic parameters of AmpC_cloacaeand DHA-1 for ceftazidime hydrolysis were moderately affected by the substitution. Accordingly, AmpC_cloacaeand DHA-1 harboring N³⁴⁶Y conferred CAZ-AVI resistance (MIC of ceftazidime of 16 µg/ml in the presence of 4 µg/ml of avibactam). In contrast, production of PDC-5 N³⁴⁶Y was associated with a lower MIC (4 µg/ml) since this β-lactamase retained a higher inactivation efficacy by avibactam in comparison to AmpC_cloacaeN³⁴⁶Y. For FOX-3, the I³⁴⁶Y substitution did not reduce the inactivation efficacy of avibactam and the substitution was highly deleterious for β-lactam hydrolysis, including ceftazidime, preventing CAZ-AVI resistance. Since AmpC_cloacaeand DHA-1 display substantial sequence diversity, our results suggest that loss of hydrogen interaction between Asn³⁴⁶ and avibactam could be a common mechanism of acquisition of CAZ-AVI resistance.