The Korn Shell (ksh) uses temp files in an insecure manner. Demonstration included.

ENGIE Storage has announced it will supply and operate a 19 MW/38 MWh portfolio of six energy storage sites that will contribute to the Solar Massachusetts Renewable Target Program and participate in ISO-New England wholesale markets.

California, long a progressive leader on renewable energy and climate change mitigation, has neglected a key market segment for renewable energy: the “community-scale,” or “wholesale distributed generation” (DG), market. This market segment is defined as projects below 20 megawatts that connect to the distribution grid and export power to the grid for sale.

Last week, Sunrun announced that its bid to supply 20 MW of residential solar + storage capacity into the New England ISO Forward Capacity Market for 2022-2023 was approved. According to Chris Rauscher, Director of Policy and Storage Market Strategy for Sunrun, this is not a pilot project or an experiment in any way.

ENGIE Storage has announced it will supply and operate a 19 MW/38 MWh portfolio of six energy storage sites that will contribute to the Solar Massachusetts Renewable Target Program and participate in ISO-New England wholesale markets.

ENGIE Storage has announced it will supply and operate a 19 MW/38 MWh portfolio of six energy storage sites that will contribute to the Solar Massachusetts Renewable Target Program and participate in ISO-New England wholesale markets.

Last week, we announced a number of actions we are taking to support our people and community during the global COVID-19 crisis. Today, we’re pleased to provide more detail about one of those actions, which, with the help of registrars, will make it easier for domain name registrants worldwide to keep their domain names in […]

The post Verisign Will Waive Wholesale Restore Fee to Help Registrants Keep Their Domain Names During COVID-19 Crisis appeared first on Verisign Blog.

Why is getting it right important? Each year statutory undertakers are engaged in hundreds of thousands of street works activities across the country to keep our key utilities and infrastructure running. They must all comply with the New Roads and S...

WHO has warned that Africa could be become the next epicentre of the pandemic.

In the lead-up to the Truth Matters conference in October, we will be focusing our attention on the sufficiency, authority, and clarity of Scripture. Of our previous blog series, none better embodies that emphasis than Frequently Abused Verses. The following entry from that series originally appeared on October 9, 2015. -ed.

You wouldn’t tell your children, “Bathe regularly; if necessary, use water.”

Nor would you advise a friend, “Be a faithful husband; if necessary, love your wife.”

Those redundant instructions defy logic. They also beg the question about what other means you would employ to accomplish those goals. You might as well tell someone, “Stay alive; if necessary, breath oxygen.”

And yet many Christians rally around a similarly illogical statement when it comes to evangelism. “Preach the gospel; if necessary, use words,” is a mantra that is a darling of social gospel activists. That quote, wrongly attributed to Francis of Assisi, is wielded when it’s time to poke zealous evangelists in the eye, or rebrand social work as a form of evangelism. Social gospel advocates like Rick Warren ^[1] Rick Warren, 40 Days of Community: Better Together Devotional: What on Earth Are We Here For? (Grand Rapids: Zondervan, 2010) 61. and Jim Wallis ^[2] https://sojo.net/about-us/news/pope-francis-message-washington love to use it.

And let’s face it, there is a winsome ring of truth to the idea that my lifestyle can be a testimony of God’s saving work. Moreover, there is a built-in rebuke of evangelists who fail to walk their talk. Their hypocrisy—faith without works—is a reproach on God, His Word, and His people (James 2:14–17). But it’s absurd to turn that hypocrisy into an argument for the primacy of good works apart from the clear proclamation of the gospel.

The Necessity of Words

Paul never said, “How will they see without a preacher?” He said, “How will they hear without a preacher” (Romans 10:14). That is because every time the word “preach” appears in the New Testament it refers to vigorous verbal proclamation. It is verbal in its testimony of the works of a Savior who fulfilled the law that we have continually broken (Matthew 5:17–18; Romans 3:23), suffered the punishment that we could never bear (Isaiah 53:4–6; 1 Peter 2:24), and defeated the grave (2 Timothy 1:10; Hebrews 2:14).

And because Christ’s people depend entirely upon His unique work done on their behalf (2 Corinthians 5:21), there is no way to fully demonstrate it through actions alone. As Voddie Baucham points out: “For me to think that I can live the gospel is to put myself in the place of Christ.” ^[3] https://www.youtube.com/watch?v=2Rd2WiYyDxs

So where does that leave works of social justice such as feeding the hungry, clothing the poor, and caring for the oppressed? No one would argue that they are bad things to do. Indeed James defines them as integral to pure religion (James 1:27). But do those acts of mercy have any role to play in a person’s salvation?

Advocates of the social gospel argue yes, and appeal to Matthew 25 as their apex argument:

Then the King will say to those on His right, “Come, you who are blessed of My Father, inherit the kingdom prepared for you from the foundation of the world. For I was hungry, and you gave Me something to eat; I was thirsty, and you gave Me something to drink; I was a stranger, and you invited Me in; naked, and you clothed Me; I was sick, and you visited Me; I was in prison, and you came to Me.” Then the righteous will answer Him, “Lord, when did we see You hungry, and feed You, or thirsty, and give You something to drink? And when did we see You a stranger, and invite You in, or naked, and clothe You? When did we see You sick, or in prison, and come to You?” The King will answer and say to them, “Truly I say to you, to the extent that you did it to one of these brothers of Mine, even the least of them, you did it to Me.”

Then He will also say to those on His left, “Depart from Me, accursed ones, into the eternal fire which has been prepared for the devil and his angels; for I was hungry, and you gave Me nothing to eat; I was thirsty, and you gave Me nothing to drink; I was a stranger, and you did not invite Me in; naked, and you did not clothe Me; sick, and in prison, and you did not visit Me.” Then they themselves also will answer, “Lord, when did we see You hungry, or thirsty, or a stranger, or naked, or sick, or in prison, and did not take care of You?” Then He will answer them, “Truly I say to you, to the extent that you did not do it to one of the least of these, you did not do it to Me.” These will go away into eternal punishment, but the righteous into eternal life. (Matthew 25:34–46)

Was Jesus saying that our eternal destinies hinge on feeding the hungry, housing the homeless, clothing the naked, and visiting the oppressed? And how would that square with salvation by grace through faith apart from works (Ephesians 2:8-9)?

The Whole [Other] Gospel

Tony Campolo is one of the most prominent advocates for the social gospel. His handling of Matthew 25 typifies the wider movement. While not explicitly denying the gospel of grace alone, he argues that it is our treatment of the poor and oppressed that will determine our eternity:

I place my highest priority on the words of Jesus, emphasizing the 25th chapter of Matthew, where Jesus makes clear that on Judgment Day the defining question will be how each of us responded to those he calls “the least of these.” ^[4] http://tonycampolo.org/for-the-record-tony-campolo-releases-a-new-statement/#.Vg4Hbnh7DxM

The recently closed Evangelical Association for the Promotion of Education (EAPE), of which Campolo was founder and president, clearly defines who he thinks “the least of these” are:

That Jesus was homeless and taught that we may encounter Him in “the least of these”—the hungry, thirsty, naked, sick, widow, stranger and imprisoned (Matthew 25:35-40), is the basis of what Tony calls the Whole Gospel and informs EAPE’s holistic ministry.  And it raises questions for the Church and every Christian: what should be our response to the homeless and to “the least of these”? ^[5] http://eape.org/tag/matthew-2535-40-rich-mullins/

Note Campolo’s use of the term “Whole Gospel.” He is implying that proclamation of the good news is only a partial gospel and must be accompanied by social action in order to become a complete or “whole” gospel. But his imbalanced emphasis betrays his mishandling of Matthew 25:35–40.

The Bible repeatedly teaches that good works are ultimately God’s works because they are the natural fruit of salvation; never the cause (cf. Ezekiel 36:25-27; James 2:14–17). And in Matthew 25 you don’t see judgment based on works, you see works revealing who is truly saved by faith. John MacArthur is emphatic on this point:

The good deeds commended in Matthew 25:35–36 are the fruit, not the root, of salvation. It cannot be emphasized too strongly that they are not the basis of entrance into the kingdom. Christ will judge according to works only insofar as those works are or are not a manifestation of redemption, which the heavenly Father has foreordained. If a person has not trusted in Jesus Christ as Lord and Savior, no amount of seemingly good works done in His name will avail to any spiritual benefit. ^[6] John MacArthur, The MacArthur New Testament Commentary: Matthew 24–28 (Chicago: Moody Publishers, 1989) 122.

Who’s Who Among the Judged

Another critical issue in understanding Matthew 25 is to recognize that the division Christ makes is not between the church and the pagan world, but between true and false Christians. While the pagan lives in open unbelief, the false Christian is an imposter who has blended in among God’s people. False Christians are the recipients of Christ’s most terrifying judgment:

So then, you will know them by their fruits. Not everyone who says to Me, “Lord, Lord,” will enter the kingdom of heaven, but he who does the will of My Father who is in heaven will enter. Many will say to Me on that day, “Lord, Lord, did we not prophesy in Your name, and in Your name cast out demons, and in Your name perform many miracles?” And then I will declare to them, “I never knew you; depart from Me, you who practice lawlessness.” (Matthew 7:20–23)

Matthew 25:34-46 makes a similar division between those who have genuine faith and those whose faith is false, according to the evidence of their works. Note carefully that both groups of people think they are Christians because they address Jesus as “Lord” (Matthew 25:37, 44). Both groups are also surprised by the verdict. The surprise reveals humility among Christ’s people (“when did we,” Matthew 25:37–39) and self-righteousness among those who are faking it (“when did we . . . not,” Matthew 25:44).

Who’s Who Among the Lowly

Finally, the beneficiaries of these good works are not the disenfranchised people of the world, as Campolo suggests. The word “brothers” (Matthew 25:40) is vital to understanding where our benevolence is to be directed. Jesus is saying that the fruit of genuine faith is evidenced in the way we care for fellow believers who are suffering (cf. John 13:35; 1 John 3:10–11). MacArthur brings this point home:

The King’s addressing these people as brothers of Mine gives still further evidence that they are already children of God. . . . Because of their identity with Christ, they will often be hungry, thirsty, without decent shelter or clothing, sick, imprisoned, and alienated from the mainstream of society. ^[7] The MacArthur New Testament Commentary: Matthew 24–28, 124–125.

Conclusion

This is not to deny any duty we have to love the disenfranchised people of the world. But if proponents of the social gospel were serious about Scripture, they would target passages that refer to loving our neighbors—even loving our enemies (Matthew 22:39; 5:44). Christ’s words in Matthew 25 have nothing to do with the social justice they advocate. 

Matthew 25:34­–46 was never written as a blueprint for salvation through social work nor should it be employed as such. It’s not an argument for preaching the gospel through our actions alone, but rather that our actions authenticate the gospel we preach. And those actions must be prioritized towards our suffering fellow believers. So please, care for other believers because Jesus commanded us to. Realize that a lack of care may point to a lack of saving faith. And preach the gospel with words because they’re always necessary.

With the opening of its Luxury Audio Studio, HARMAN is building on the success of its Experience Store in Munich and creating a whole new dimension of experiential excellence. Dedicated to the Art of Listening, the new Luxury Studio celebrates and...

We’re only just grasping how cosmic black holes and Einstein’s theories relate – and that deepens our sense of wonder, says Chanda Prescod-Weinstein

Exotic primordial black holes born in the moments after the universe began could be the key to solving some of cosmology’s biggest problems… if only we can find them.

When a large asteroid hit the Earth 66 million years ago, it sent huge curtains of dust flying tens of kilometres up into the air that quickly covered the planet

Down is a sci-fi podcast about a crewed mission into a mysterious Antarctic hole that has opened up as a result of climate change, what will the crew find?

Some people have a visceral fear-like reaction to the holes in sponges, Swiss cheese or seed pods. Known as trypophobia, this response is increasingly common but isn’t what it seems

Our images of deep space are spectacular, but don’t reflect what our eyes would see. Here's what their stunning true colours reveal about the cosmos

Astronomers found a star that appeared to be orbiting nothing at all – but it’s actually the closest black hole ever at just 1000 light years away

Title: Watch Your Cholesterol, Your Blood Pressure ... and This Enzyme?
Category: Health News
Created: 4/29/2010 8:10:00 PM
Last Editorial Review: 4/30/2010 12:00:00 AM

Title: For Breast Cancer Care, Radiation of Whole Breast May Be Best
Category: Health News
Created: 5/1/2012 6:05:00 PM
Last Editorial Review: 5/2/2012 12:00:00 AM

Title: Secondhand Smoke Tied to Lower 'Good' Cholesterol in Teen Girls
Category: Health News
Created: 4/30/2013 2:35:00 PM
Last Editorial Review: 5/1/2013 12:00:00 AM

Title: New Drug Class Slashes 'Bad' Cholesterol, Review Finds
Category: Health News
Created: 4/27/2015 12:00:00 AM
Last Editorial Review: 4/28/2015 12:00:00 AM

Title: Whole Blood Best for Youngest Heart Surgery Patients: Study
Category: Health News
Created: 4/30/2015 12:00:00 AM
Last Editorial Review: 4/30/2015 12:00:00 AM

Title: AHA News: A Father's Death at 37 Reveals a Hidden History of Cholesterol
Category: Health News
Created: 4/30/2019 12:00:00 AM
Last Editorial Review: 5/1/2019 12:00:00 AM

Title: Americans' Cholesterol Levels Decline: Study
Category: Health News
Created: 11/12/2019 12:00:00 AM
Last Editorial Review: 11/13/2019 12:00:00 AM

Title: Especially in the Young, Cholesterol Is No Friend to the Heart
Category: Health News
Created: 12/4/2019 12:00:00 AM
Last Editorial Review: 12/4/2019 12:00:00 AM

Title: Health Tip: Should I Get a Cholesterol Test?
Category: Health News
Created: 12/10/2019 12:00:00 AM
Last Editorial Review: 12/10/2019 12:00:00 AM

Title: HDL vs. LDL Cholesterol (Good and Bad)
Category: Diseases and Conditions
Created: 7/14/2017 12:00:00 AM
Last Editorial Review: 12/11/2019 12:00:00 AM

Title: New Cholesterol Drug Approved by FDA
Category: Health News
Created: 2/24/2020 12:00:00 AM
Last Editorial Review: 2/24/2020 12:00:00 AM

Title: Fewer Americans Have High Cholesterol
Category: Health News
Created: 4/22/2020 12:00:00 AM
Last Editorial Review: 4/23/2020 12:00:00 AM

Title: What Is a Choledochojejunostomy?
Category: Procedures and Tests
Created: 5/6/2020 12:00:00 AM
Last Editorial Review: 5/6/2020 12:00:00 AM

Title: How Long Does a Cholecystostomy Tube Stay In?
Category: Procedures and Tests
Created: 5/7/2020 12:00:00 AM
Last Editorial Review: 5/7/2020 12:00:00 AM

Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα (^–/–) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women.­

Cellular membranes are not homogenous mixtures of proteins; rather, they are segregated into microdomains on the basis of preferential association between specific lipids and proteins. These microdomains, called lipid rafts, are well known for their role in receptor signaling on the plasma membrane (PM) and are essential to such cellular functions as signal transduction and spatial organization of the PM. A number of disease states, including atherosclerosis and other cardiovascular disorders, may be caused by dysfunctional maintenance of lipid rafts. Lipid rafts do not occur only in the PM but also have been found in intracellular membranes and extracellular vesicles (EVs). Here, we focus on discussing newly discovered functions of lipid rafts and microdomains in intracellular membranes, including lipid and protein trafficking from the ER, Golgi bodies, and endosomes to the PM, and we examine lipid raft involvement in the production and composition of EVs. Because lipid rafts are small and transient, visualization remains challenging. Future work with advanced techniques will continue to expand our knowledge about the roles of lipid rafts in cellular functioning.

Lipid rafts are highly ordered regions of the plasma membrane that are enriched in cholesterol and sphingolipids and play important roles in many cells. In hematopoietic stem and progenitor cells (HSPCs), lipid rafts house receptors critical for normal hematopoiesis. Lipid rafts also can bind and sequester kinases that induce negative feedback pathways to limit proliferative cytokine receptor cycling back to the cell membrane. Modulation of lipid rafts occurs through an array of mechanisms, with optimal cholesterol efflux one of the major regulators. As such, cholesterol homeostasis also regulates hematopoiesis. Increased lipid raft content, which occurs in response to changes in cholesterol efflux in the membrane, can result in prolonged receptor occupancy in the cell membrane and enhanced signaling. In addition, certain diseases, like diabetes, may contribute to lipid raft formation and affect cholesterol retention in rafts. In this review, we explore the role of lipid raft-related mechanisms in hematopoiesis and CVD (specifically, atherosclerosis) and discuss how defective cholesterol efflux pathways in HSPCs contribute to expansion of lipid rafts, thereby promoting myelopoiesis and thrombopoiesis. We also discuss the utility of cholesterol acceptors in contributing to lipid raft regulation and disruption, and highlight the potential to manipulate these pathways for therapeutic gain in CVD as well as other disorders with aberrant hematopoiesis.

North Carolina is developing a unique and innovative infrastructure to support integrated physical, behavioral, and social health care. Efforts by the North Carolina Department of Health and Human Services, the Foundation for Health Leadership & Innovation, Cone Health, Atrium Health, and the One Charlotte Health Alliance advance our understanding of how to best operationalize the design and payment of integrated services. Best practices such as the collaborative care and primary care behavioral health models reduce inefficiencies and disparities by bringing together teams of primary care and behavioral health care providers.

Antimicrobial peptides play an important role in host defense against Vibrio cholerae. Generally, the V. cholerae O1 classical biotype is polymyxin B (PB) sensitive and El Tor is relatively resistant. Detection of classical biotype traits like the production of classical cholera toxin and PB sensitivity in El Tor strains has been reported in recent years, including in the devastating Yemen cholera outbreak during 2016-2018. To investigate the factor(s) responsible for the shift in the trend of sensitivity to PB, we studied the two-component system encoded by carRS, regulating the lipid A modification of El Tor vibrios, and found that only carR contains a single nucleotide polymorphism (SNP) in recently emerged PB-sensitive strains. We designated the two alleles present in PB-resistant and -sensitive strains carR^r and carR^s alleles, respectively, and replaced the carR^s allele of a sensitive strain with the carR^r allele, using an allelic-exchange approach. The sensitive strain then became resistant. The PB-resistant strain N16961 was made susceptible to PB in a similar fashion. Our in silico CarR protein models suggested that the D89N substitution in the more stable CarR^s protein brings the two structural domains of CarR closer, constricting the DNA binding cleft. This probably reduces the expression of the carR-regulated almEFG operon, inducing PB susceptibility. Expression of almEFG in PB-sensitive strains was found to be downregulated under natural culturing conditions. In addition, the expression of carR and almEG decreased in all strains with increased concentrations of extracellular Ca²⁺ but increased with a rise in pH. The downregulation of almEFG in CarR^s strains confirmed that the G265A mutation is responsible for the emergence of PB-sensitive El Tor strains.

In mammalian cells, alphavirus replication complexes are anchored to the plasma membrane. This interaction with lipid bilayers is mediated through the viral methyl/guanylyltransferase nsP1 and reinforced by palmitoylation of cysteine residue(s) in the C-terminal region of this protein. Lipid content of membranes supporting nsP1 anchoring remains poorly studied. Here, we explore the membrane binding capacity of nsP1 with regard to cholesterol. Using the medically important chikungunya virus (CHIKV) as a model, we report that nsP1 cosegregates with cholesterol-rich detergent-resistant membrane microdomains (DRMs), also called lipid rafts. In search for the critical factor for cholesterol partitioning, we identify nsP1 palmitoylated cysteines as major players in this process. In cells infected with CHIKV or transfected with CHIKV trans-replicase plasmids, nsP1, together with the other nonstructural proteins, are detected in DRMs. While the functional importance of CHIKV nsP1 preference for cholesterol-rich membrane domains remains to be determined, we observed that U18666A- and imipramine-induced sequestration of cholesterol in late endosomes redirected nsP1 to these compartments and simultaneously dramatically decreased CHIKV genome replication. A parallel study of Sindbis virus (SINV) revealed that nsP1 from this divergent alphavirus displays a low affinity for cholesterol and only moderately segregates with DRMs. Behaviors of CHIKV and SINV with regard to cholesterol, therefore, match with the previously reported differences in the requirement for nsP1 palmitoylation, which is dispensable for SINV but strictly required for CHIKV replication. Altogether, this study highlights the functional importance of nsP1 segregation with DRMs and provides new insight into the functional role of nsP1 palmitoylated cysteines during alphavirus replication.

IMPORTANCE Functional alphavirus replication complexes are anchored to the host cell membranes through the interaction of nsP1 with the lipid bilayers. In this work, we investigate the importance of cholesterol for such an association. We show that nsP1 has affinity for cholesterol-rich membrane microdomains formed at the plasma membrane and identify conserved palmitoylated cysteine(s) in nsP1 as the key determinant for cholesterol affinity. We demonstrate that drug-induced cholesterol sequestration in late endosomes not only redirects nsP1 to this compartment but also dramatically decreases genome replication, suggesting the functional importance of nsP1 targeting to cholesterol-rich plasma membrane microdomains. Finally, we show evidence that nsP1 from chikungunya and Sindbis viruses displays different sensitivity to cholesterol sequestering agents that parallel with their difference in the requirement for nsP1 palmitoylation for replication. This research, therefore, gives new insight into the functional role of palmitoylated cysteines in nsP1 for the assembly of functional alphavirus replication complexes in their mammalian host.

Reactive immunization with a single-dose cholera vaccine that could rapidly (within days) protect immunologically naive individuals during virgin soil epidemics, when cholera reaches immunologically naive populations that have not experienced cholera for decades, would facilitate cholera control. One dose of attenuated Vibrio cholerae O1 classical Inaba vaccine CVD 103-HgR (Vaxchora) containing ≥2 x 10⁸ CFU induces vibriocidal antibody seroconversion (a correlate of protection) in >90% of U.S. adults. A previous CVD 103-HgR commercial formulation required ≥2 x 10⁹ CFU to elicit high levels of seroconversion in populations in developing countries. We compared the vibriocidal responses of Malians (individuals 18 to 45 years old) randomized to ingest a single ≥2 x 10⁸-CFU standard dose (n = 50) or a ≥2 x 10⁹-CFU high dose (n = 50) of PaxVax CVD 103-HgR with buffer or two doses (n = 50) of Shanchol inactivated cholera vaccine (the immunologic comparator). To maintain blinding, participants were dosed twice 2 weeks apart; CVD 103-HgR recipients ingested placebo 2 weeks before or after ingesting vaccine. Seroconversion (a ≥4-fold vibriocidal titer rise) between the baseline and 14 days after CVD 103-HgR ingestion and following the first and second doses of Shanchol were the main outcomes measured. By day 14 postvaccination, the rates of seroconversion after ingestion of a single standard dose and a high dose of CVD 103-HgR were 71.7% (33/46 participants) and 83.3% (40/48 participants), respectively. The rate of seroconversion following the first dose of Shanchol, 56.0% (28/50 participants), was significantly lower than that following the high dose of CVD 103-HgR (P = 0.003). The vibriocidal geometric mean titer (GMT) of the high dose of CVD 103-HgR exceeded the GMT of the standard dose at day 14 (214 versus 95, P = 0.045) and was ~2-fold higher than the GMT on day 7 and day 14 following the first Shanchol dose (P > 0.05). High-dose CVD 103-HgR is recommended for accelerated evaluation in developing countries to assess its efficacy and practicality in field situations. (This study has been registered at ClinicalTrials.gov under registration no. NCT02145377.)

We recently reported that restoring the CYP27A1–27hydroxycholesterol axis had antitumor properties. Thus, we sought to determine the mechanism by which 27HC exerts its anti–prostate cancer effects. As cholesterol is a major component of membrane microdomains known as lipid rafts, which localize receptors and facilitate cellular signaling, we hypothesized 27HC would impair lipid rafts, using the IL6–JAK–STAT3 axis as a model given its prominent role in prostate cancer. As revealed by single molecule imaging of DU145 prostate cancer cells, 27HC treatment significantly reduced detected cholesterol density on the plasma membranes. Further, 27HC treatment of constitutively active STAT3 DU145 prostate cancer cells reduced STAT3 activation and slowed tumor growth in vitro and in vivo. 27HC also blocked IL6-mediated STAT3 phosphorylation in nonconstitutively active STAT3 cells. Mechanistically, 27HC reduced STAT3 homodimerization, nuclear translocation, and decreased STAT3 DNA occupancy at target gene promoters. Combined treatment with 27HC and STAT3 targeting molecules had additive and synergistic effects on proliferation and migration, respectively. Hallmark IL6–JAK–STAT gene signatures positively correlated with CYP27A1 gene expression in a large set of human metastatic castrate-resistant prostate cancers and in an aggressive prostate cancer subtype. This suggests STAT3 activation may be a resistance mechanism for aggressive prostate cancers that retain CYP27A1 expression. In summary, our study establishes a key mechanism by which 27HC inhibits prostate cancer by disrupting lipid rafts and blocking STAT3 activation.

The Stenotrophomonas maltophilia complex (Smc) comprises opportunistic environmental Gram-negative bacilli responsible for a variety of infections in both humans and animals. Beyond its large genetic diversity, its genetic organization in genogroups was recently confirmed through the whole-genome sequencing of human and environmental strains. As they are poorly represented in these analyses, we sequenced the whole genomes of 93 animal strains to determine their genetic background and characteristics. Combining these data with 81 newly sequenced human strains and the genomes available from RefSeq, we performed a genomic analysis that included 375 nonduplicated genomes with various origins (animal, 104; human, 226; environment, 30; unknown, 15). Phylogenetic analysis and clustering based on genome-wide average nucleotide identity confirmed and specified the genetic organization of Smc in at least 20 genogroups. Two new genogroups were identified, and two previously described groups were further divided into two subgroups each. Comparing the strains isolated from different host types and their genogroup affiliation, we observed a clear disequilibrium in certain groups. Surprisingly, some antimicrobial resistance genes, integrons, and/or clusters of attC sites lacking integron-integrase (CALIN) sequences targeting antimicrobial compounds extensively used in animals were mainly identified in animal strains. We also identified genes commonly found in animal strains coding for efflux systems. The result of a large whole-genome analysis performed by us supports the hypothesis of the putative contribution of animals as a reservoir of Stenotrophomonas maltophilia complex strains and/or resistance genes for strains in humans.

IMPORTANCE Given its naturally large antimicrobial resistance profile, the Stenotrophomonas maltophilia complex (Smc) is a set of emerging pathogens of immunosuppressed and cystic fibrosis patients. As it is group of environmental microorganisms, this adaptation to humans is an opportunity to understand the genetic and metabolic selective mechanisms involved in this process. The previously reported genomic organization was incomplete, as data from animal strains were underrepresented. We added the missing piece of the puzzle with whole-genome sequencing of 93 strains of animal origin. Beyond describing the phylogenetic organization, we confirmed the genetic diversity of the Smc, which could not be estimated through routine phenotype- or matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF)-based laboratory tests. Animals strains seem to play a key role in the diversity of Smc and could act as a reservoir for mobile resistance genes. Some genogroups seem to be associated with particular hosts; the genetic support of this association and the role of the determinants/corresponding genes need to be explored.