All eligible Delaware voters will receive absentee ballot applications by mail WILMINGTON, Del. – Governor John Carney on Thursday signed the fifteenth modification to his State of Emergency declaration, rescheduling Delaware’s presidential primary for July 7. The Delaware Department of Elections will mail absentee ballot applications to all registered Democrats and Republicans in the State of […]

Todos los votantes elegibles de Delaware recibirán solicitudes de voto ausente por correo WILMINGTON, Del. – El gobernador John Carney firmó el jueves la decimoquinta modificación a su declaración de Estado de Emergencia, la cual prevé una reprogramación de las elecciones primarias presidenciales en Delaware para el 7 de julio. El Departamento de Elecciones de […]

Tout votè ki kalifye nan Delaware pral resevwa aplikasyon bilten vòt an absans yo pa lapòs WILMINGTON, Del. – Gouvènè John Carney  te siyen nan Jedi a kenzyèm modifikasyon nan Deklarasyon Dijans nan Eta a, li te repwograme Primè Prezidansyèl  pou 7 Jiye a.  Depatman Eleksyon ki nan Delaware an pral voye aplikasyon  pou bilten […]

The Bucs have never had more than four prime-time games in a year, but in 2020 they'll face the Bears, Raiders, Giants, Saints and Rams in prime time.

This is the 19th installment of The Rationalist, my column for the Times of India.

A friend of mine was very impressed by the interview Narendra Modi granted last week to Akshay Kumar. ‘Such a charming man, such great work ethic,’ he gushed. ‘He is the kind of uncle I would want my kids to have.’ And then, in the same breath, he asked, ‘How can such a good man be such a bad prime minister?”

I don’t want to be uncharitable and suggest that Modi’s image is entirely manufactured, so let’s take the interview at face value. Let’s also grant Modi his claims about the purity of his neeyat (intentions), and reframe the question this way: when it comes to public policy, why do good intentions often lead to bad outcomes? To attempt an answer, I’ll refer to a story a friend of mine, who knows Modi well, once told me about him. 

Modi was chilling with his friends at home more than a decade ago, and told them an incident from his childhood. His mother was ill once, and the young Narendra was tending to her. The heat was enervating, so the boy went to the switchboard to switch on the fan. But there was no electricity. My friend said that as he told this story, Modi’s eyes filled with tears. Even after all these years, he was moved by the memory.

My friend used this story to make the point that Modi’s vision of the world is experiential. If he experiences something, he understands it. When he became chief minister of Gujarat, he made it his stated mission to get reliable electricity to every part of Gujarat. No doubt this was shaped by the time he flicked a switch as a young boy and the fan did not budge. Similarly, he has given importance to things like roads and cleanliness, since he would have experienced the impact of those as a young man.

My term for him, inspired by Rajat Kapoor’s 2014 film, is ‘the ankhon dekhi prime minister’. At one level, this is a good thing. He sees a problem and works for the rest of his life to solve it. But what of things he cannot experience?

The economy is a complex beast, as is society itself, and beyond a certain level, you need to grasp abstract concepts to understand how the world works. You cannot experience them. For example, spontaneous order, or the idea that society and markets, like language, cannot be centrally directed or planned. Or the positive-sum nature of things, which is the engine of our prosperity: the idea that every transaction is a win-win game, and that for one person to win, another does not have to lose. Or, indeed, respect for individual rights and free speech.

One understands abstract concepts by reading about them, understanding them, applying them to the real world. Modi is not known to be a reader, and this is not his fault. Given his background, it is a near-miracle that he has made it this far. He wasn’t born into a home with a reading culture, and did not have either the resources or the time when he was young to devote to reading. The only way he could learn about the world, thus, was by experiencing it.

There are two lessons here, one for Modi himself and others in his position, and another for everyone.

The lesson in this for Modi is a lesson for anyone who rises to such an important position, even if he is the smartest person in the world. That lesson is to have humility about the bounds of your knowledge, and to surround yourself with experts who can advise you well. Be driven by values and not confidence in your own knowledge. Gather intellectual giants around you, and stand on their shoulders.

Modi did not do this in the case of demonetisation, which he carried out against the advice of every expert he consulted. We all know the damage it caused to the economy.

The other learning from this is for all of us. How do we make sense of the world? By connecting dots. An ankhon-dekhi approach will get us very few dots, and our view of the world will be blurred and incomplete. The best way to gather more dots is reading. The more we read, the better we understand the world, and the better the decisions we take. When we can experience a thousand lives through books, why restrict ourselves to one?

A good man with noble intentions can make bad decisions with horrible consequences. The only way to hedge against this is by staying humble and reading more. So when you finish reading this piece, think of an unread book that you’d like to read today – and read it!

© 2007 IndiaUncut.com. All rights reserved.
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This is the 19th installment of The Rationalist, my column for the Times of India.

A friend of mine was very impressed by the interview Narendra Modi granted last week to Akshay Kumar. ‘Such a charming man, such great work ethic,’ he gushed. ‘He is the kind of uncle I would want my kids to have.’ And then, in the same breath, he asked, ‘How can such a good man be such a bad prime minister?”

I don’t want to be uncharitable and suggest that Modi’s image is entirely manufactured, so let’s take the interview at face value. Let’s also grant Modi his claims about the purity of his neeyat (intentions), and reframe the question this way: when it comes to public policy, why do good intentions often lead to bad outcomes? To attempt an answer, I’ll refer to a story a friend of mine, who knows Modi well, once told me about him. 

Modi was chilling with his friends at home more than a decade ago, and told them an incident from his childhood. His mother was ill once, and the young Narendra was tending to her. The heat was enervating, so the boy went to the switchboard to switch on the fan. But there was no electricity. My friend said that as he told this story, Modi’s eyes filled with tears. Even after all these years, he was moved by the memory.

My friend used this story to make the point that Modi’s vision of the world is experiential. If he experiences something, he understands it. When he became chief minister of Gujarat, he made it his stated mission to get reliable electricity to every part of Gujarat. No doubt this was shaped by the time he flicked a switch as a young boy and the fan did not budge. Similarly, he has given importance to things like roads and cleanliness, since he would have experienced the impact of those as a young man.

My term for him, inspired by Rajat Kapoor’s 2014 film, is ‘the ankhon dekhi prime minister’. At one level, this is a good thing. He sees a problem and works for the rest of his life to solve it. But what of things he cannot experience?

The economy is a complex beast, as is society itself, and beyond a certain level, you need to grasp abstract concepts to understand how the world works. You cannot experience them. For example, spontaneous order, or the idea that society and markets, like language, cannot be centrally directed or planned. Or the positive-sum nature of things, which is the engine of our prosperity: the idea that every transaction is a win-win game, and that for one person to win, another does not have to lose. Or, indeed, respect for individual rights and free speech.

One understands abstract concepts by reading about them, understanding them, applying them to the real world. Modi is not known to be a reader, and this is not his fault. Given his background, it is a near-miracle that he has made it this far. He wasn’t born into a home with a reading culture, and did not have either the resources or the time when he was young to devote to reading. The only way he could learn about the world, thus, was by experiencing it.

There are two lessons here, one for Modi himself and others in his position, and another for everyone.

The lesson in this for Modi is a lesson for anyone who rises to such an important position, even if he is the smartest person in the world. That lesson is to have humility about the bounds of your knowledge, and to surround yourself with experts who can advise you well. Be driven by values and not confidence in your own knowledge. Gather intellectual giants around you, and stand on their shoulders.

Modi did not do this in the case of demonetisation, which he carried out against the advice of every expert he consulted. We all know the damage it caused to the economy.

The other learning from this is for all of us. How do we make sense of the world? By connecting dots. An ankhon-dekhi approach will get us very few dots, and our view of the world will be blurred and incomplete. The best way to gather more dots is reading. The more we read, the better we understand the world, and the better the decisions we take. When we can experience a thousand lives through books, why restrict ourselves to one?

A good man with noble intentions can make bad decisions with horrible consequences. The only way to hedge against this is by staying humble and reading more. So when you finish reading this piece, think of an unread book that you’d like to read today – and read it!

The India Uncut Blog © 2010 Amit Varma. All rights reserved.
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This Metasploit module exploits an expression language remote code execution flaw in the Primefaces JSF framework. Primefaces versions prior to 5.2.21, 5.3.8 or 6.0 are vulnerable to a padding oracle attack, due to the use of weak crypto and default encryption password and salt.

Shinzo Abe’s re-election as prime minister risks undercutting Japan’s commitment to clean energy at a time when incentives are under review and the nation’s utilities say they can’t accommodate capacity already planned.

In New York, Raymond James released its Clean Tech Primer 2017, arguably the most cogent and concise summary of activity and prospects across the gamut from solar power through to water technology, including all biofuels, biopower and bioindustrials.

In a portion of her statement delivered yesterday to the European Union, United Kingdom Prime Minister Theresa May said, “I hereby notify the European Council in accordance with Article 50 of the Treaty on European Union of the United Kingdom's intention to withdraw from the European Union.”
 

Shinzo Abe’s re-election as prime minister risks undercutting Japan’s commitment to clean energy at a time when incentives are under review and the nation’s utilities say they can’t accommodate capacity already planned.

Shinzo Abe’s re-election as prime minister risks undercutting Japan’s commitment to clean energy at a time when incentives are under review and the nation’s utilities say they can’t accommodate capacity already planned.

In New York, Raymond James released its Clean Tech Primer 2017, arguably the most cogent and concise summary of activity and prospects across the gamut from solar power through to water technology, including all biofuels, biopower and bioindustrials.

Check here each week to keep up with the latest from John MacArthur's pulpit at Grace Community Church.

The founder of Inri Evangelical Spiritual Church, Primate Elijah Ayodele, has said that the COVID-19 broke out because “the rich abandoned the poor”. According to the Daily Sun, the cleric said “the sickness is not for the poor”. As of Saturday morning, Nigeria had 3,912 confirmed cases of Coronavirus. Of that number, 679 patients have […]

COVID-19: Primate Ayodele reveals why pandemic broke out, warns govt about churches

The founder of Inri Evangelical Spiritual Church, Primate Elijah Ayodele, has predicted that the vaccine for COVID-19 will be discovered in July this year. Scientists around the world are yet to make a breakthrough with regards to a cure for the virus, since it broke out earlier this year in Wuhan, China. In the last […]

COVID-19: Primate Ayodele predicts when vaccine will be discovered

Iceland has the coronavirus pandemic better under control than most other countries. In an interview, Prime Minister Katrín Jakobsdóttir explains the next important steps for her country.

Following close consultation with IFI's including the IFC, World Bank and EBRD, Tunisia has launched a review process to aid with the structuring and implementation of new PPP projects. Eversheds Sutherland was privileged to have been spec...

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 7, 2015. -ed.

Just as a single cell of cancer can metastasize until it spreads throughout the physical body, a single false doctrine can multiply itself and spread throughout a body of believers. A great forest fire can be started by one spark.^[1] John MacArthur, The MacArthur New Testament Commentary: Galatians (Chicago: Moody Press, 1987), 140.

Throughout this series on Scripture’s “Frequently Abused Verses,” we’ve seen how God’s Word has been misunderstood and misapplied, as well as instances when it is intentionally twisted to accommodate blasphemous lies and spurious doctrines. Today we’re going to consider how the misappropriation of one verse—3 John 2—triggered a heretical movement that has been a scourge for God’s people and blight on the testimony of the church for more than half of a century.

The Roots of the Prosperity Gospel

Not long after Oral Roberts’s death—and amidst a tidal wave of glowing praise for the pioneering televangelist—John MacArthur wrote this summation of the preacher’s life and ministry:

Oral Roberts’s influence is not something Bible-believing Christians should celebrate. Virtually every aberrant idea the Pentecostal and charismatic movements spawned after 1950 can be traced in one way or another to Oral Roberts’s influence.

One of his primary legacies is the prosperity gospel. As John explains in the article quoted above, the prosperity gospel “is the notion that God's favor is expressed mainly through physical health and material prosperity, and that these blessings are available for the claiming by anyone who has sufficient faith.”

Roberts might not have been the first person to teach that false doctrine, but through his television ministry he served as its chief herald and the primary catalyst for its rapid growth and widespread acceptance.

And according to Roberts’s biographer, David Edwin Harrell, Jr., the televangelist’s commitment to the prosperity gospel was born out of a crisis of faith and a new perspective on an overlooked verse.

Out of this period of spiritual trauma came a sequence of instantaneous insights, revelations as Oral viewed them. The first occurred one morning as he read III John 2: “I wish above all things that thou mayest prosper and be in health, even as they soul prospereth.” Oral had rushed out of his house one morning to catch the bus to class when he realized he had not read his Bible as was his custom. He returned, hastily grabbed his Bible, opened it “at random,” and read III John 2. He had read his New Testament, he reported, at least a hundred times, but this verse seemed brand-new. He called Evelyn and read it to her. “That is not in the Bible,” she challenged. “It is,” Oral replied, “I just read it.” “Evelyn,” he said, “we have been wrong. I haven’t been preaching that God is good. And Evelyn, if this verse is right, God is a good God.” The idea seemed revolutionary, liberating. They had been nurtured in a belief system that insisted “you had to be poor to be a Christian.” Perhaps it was not so. They talked excitedly about the verse’s implications. Did it mean they could have a “new car,” a “new house,” a “brand-new ministry?” In later years, Evelyn looked back on that morning as the point of embarkation: “I really believe that that very morning was the beginning of this worldwide ministry that he has had, because it opened up his thinking.”

Oral’s new-found insight was soon put to a practical test. The agent was a Mr. Gustavus, a neighbor who owned the Buick automobile dealership in Enid. Mr. Gus liked Oral, and, although he was a “nonreligious” man, he listened to his neighbor’s preaching occasionally and liked his emphasis on the “here and now.” One morning Mr. Gus noted that Oral’s car looked “pretty bad” and suggested that he buy a new one. It seemed a preposterous idea. Cars were still “practically unobtainable” in these postwar months, and there was no slack in the Robertses’ tight budget. But Mr. Gus showed them a way; he sold their old car for the “highest ceiling” price and acquired a new Buick for Oral at “dealer’s cost.” Mr. Gus, Oral, and Evelyn drove together to Detroit to pick up the car. As they drove back to Enid in their “brand new . . . long, green slick Buick,” Oral and Evelyn pondered the significance of this seemingly impossible turn. Evelyn asked Oral to stop: “We have just got to hold hands and praise the Lord for this car.” For Oral, the “new car became a symbol to me of what a man could do if he would believe God.” Nor was Mr. Gus through. He kept egging Oral on. “Son, the message you are preaching is too big for one town,” he told Oral, “the country is waiting for it. . . . Preach it, son. And you will stir this generation.” ^[2] David Edwin Harrell, Jr., Oral Roberts: An American Life (Bloomington, IN: Indiana University Press, 1985) 65-66.

Of course there are plenty of other Bible verses that have been contorted by prosperity preachers to support their false teaching—we looked at one of them earlier in this series. But 3 John 2 is the textual soil that sprouted Roberts’s prosperity gospel, and the massive family tree of prosperity preachers who have carried on his heretical legacy.

And when you consider how the lies of the prosperity gospel have permeated and poisoned the church, you understand why the details matter, and the damage that can be done when we play fast and loose with God’s Word. The careless reading and application of this one verse has spawned multiple generations of false prophets and fraudulent healers who have feasted on the spiritually naïve and theologically shallow. And by continuing to perpetuate Roberts’s false teaching, they further tarnish the testimony of God’s Word and His people. In many parts of the world, the face of Christianity is a sneering charlatan with his hand out, preaching the get-rich gospel of health and wealth to people who have neither.

When it comes to biblical interpretation, the details are vitally important.

True Prosperity

And in the case of 3 John 2, the details make the true meaning of the verse abundantly clear. In his short letter to a man named Gaius, the apostle John wrote, “Beloved, I pray that in all respects you may prosper and be in good health, just as your soul prospers.”

The reality is that the apostle’s words are not a prophecy of blessing. As John MacArthur explains in his commentary on 3 John, “The phrase ‘I pray that in all respects you may prosper and be in good health’ was a standard greeting in ancient letters.” ^[3] John MacArthur, The MacArthur New Testament Commentary: 1-3 John (Chicago: Moody Press, 2007) 245.

The salutations of the epistles are rich with doctrinal truth (cf. Romans 1:1-7; Galatians 1:1-5; 1 Peter 1:1-2). But it’s not theologically safe or hermeneutically sound to turn a greeting to a specific audience into a promise for all believers.

Moreover, the apostle’s words here don’t support an emphasis on physical blessings like health and wealth, since that’s the opposite of the point John was making. He was praising God for the good report on the quality of Gaius’s character. As John MacArthur explains, the apostle’s focus was spiritual prosperity.

“Prosper” translates a form of the verb euodoō. The term, used only here, Romans 1:10, and 1 Corinthians 16:2, means “to succeed,” “to have things go well,” or “to enjoy favorable circumstances.” The first use of prosper in verse 2 refers to Gaius’s physical health, as the contrast with the last part of the verse makes clear. The apostle’s wish was that Gaius’s physical health would be as good as that of his spiritual.

John’s concern for Gaius is a pastoral desire that he be free from the turmoil, pain, and debilitation of illness so as to be unrestricted in his service to the Lord and His church. . . .

But [in contrast to his physical condition] Gaius’s healthy soul brought far more delight to John. He knew he had a vibrant spiritual life. To borrow from some other apostles, Gaius was among those who are “sound in the faith” (Titus 1:13); constantly “grow[ing] in the grace and knowledge of our Lord and Savior Jesus Christ” (2 Peter 3:18); “walk[ing] in a manner worthy of the Lord, to please him in all respects, bearing fruit in every good work and increasing in the knowledge of God” (Colossians 1:10). ^[4] The MacArthur New Testament Commentary: 1-3 John, 245-246.

When considering how the Lord might bless us, we need to keep in mind that His blessings are not merely for our benefit. As long as He grants us breath, He has use of us for the work of His kingdom. It stands to reason then that even the physical blessings we enjoy have eternal purposes—and for the sake of His glory and His church, we need to pursue those purposes.

God is in the business of building His church, not handing out Buicks.

Army General Raúl Castro Ruz, President of the Councils of State and Ministers, held official talks, on Sunday December 7, with the Honorable Freundel Stuart, Prime Minister of Barbados, who is visiting the country as the head of the Barbados delegation to the 5th CARICOM-Cuba Summit.

HYDERABAD: The Hyderabad district administration on Wednesday resumed 3.31 acres of prime government land in Jubilee Hills allotted to Anand Cine Services, an outdoor film unit, as the management failed to utilise it for the purpose it was assigned. The resumed land could be worth nearly Rs 100 crore. According to revenue records, the Hyderabad district administration had allotted five-acre government land (survey No. 403) on Road No.76, Jubilee Hills in Shaikpet mandal in 2001 for putting up cinema settings and parking area. The state government had set up the Andhra Pradesh Land Management Authority (APLMA) last year and asked all district collectors to identify parcels of government land allotted […]

A relatively small quantum computer has broken a number-factoring record, which may one day threaten data encryption methods that rely on factoring large numbers

The Tully Monster is a famously odd 300-million-year-old fossil that looks like an alien, but a new analysis suggests it was a backboned animal like a hagfish or lamprey

Boris Johnson has become the new prime minister of the UK after winning the Conservative party leadership campaign. Here's what Johnson has said and done about climate change

Mykhailo Pinchuk takes a short walk around his empty zoo, greeting some animals with a stroke and a morsel of food.

The Tully Monster is a famously odd 300-million-year-old fossil that looks like an alien, but a new analysis suggests it was a backboned animal like a hagfish or lamprey

Title: U.S. Primary Care Docs Unprepared for Surge in Alzheimer's Cases
Category: Health News
Created: 3/11/2020 12:00:00 AM
Last Editorial Review: 3/11/2020 12:00:00 AM

Title: The Doctor Gap: In Areas of Greatest Need, Primary Care Is a Team Effort
Category: Health News
Created: 3/19/2020 12:00:00 AM
Last Editorial Review: 3/20/2020 12:00:00 AM

Despite advances in oral health care, inequalities in oral health outcomes persist due to problems in access. With proper training, primary care providers can mitigate this inequality by providing oral health education, screening, and referral to advanced dental treatment. Diverging sets of oral health competencies and guidelines have been released or endorsed by multiple primary care disciplines. The aim of this study was to transform multiple sets of competencies into Entrustable Professional Activities (EPAs) for oral health integration into primary care training. A scoping review of the literature between January 2000 and December 2016 was conducted according to PRISMA methodology to identify all existing sets of competencies. The following primary care disciplines were included in the search: allopathic/osteopathic medical schools and residency programs in family medicine, internal medicine, and pediatrics; physician assistant programs; and nurse practitioner programs. Competencies were compared using the Health Resources and Services Administration Integration of Oral Health and Primary Care Practice competencies as the foundational set and translated into EPAs. The resulting EPAs were tested with a reactor panel. The scoping review produced 1,466 references, of which 114 were selected for full text review. Fourteen competencies were identified as being central to the integration of oral health into primary care. These were converted to seven EPAs for oral health integration into primary care and were mapped onto Accreditation Council for Graduate Medical Education residency competency domains as well to the Association of American Medical Colleges EPAs for graduating medical students. The resulting EPAs delineate the essential, observable work required of primary care providers to ensure that oral health is treated as a critical determinant of overall health.

ABSTRACT

In the absence of a vaccine, multidrug-resistant Neisseria gonorrhoeae has emerged as a major human health threat, and new approaches to treat gonorrhea are urgently needed. N. gonorrhoeae pili are posttranslationally modified by a glycan that terminates in a galactose. The terminal galactose is critical for initial contact with the human cervical mucosa via an interaction with the I-domain of complement receptor 3 (CR3). We have now identified the I-domain galactose-binding epitope and characterized its galactose-specific lectin activity. Using surface plasmon resonance and cellular infection assays, we found that a peptide mimic of this galactose-binding region competitively inhibited the N. gonorrhoeae-CR3 interaction. A compound library was screened for potential drugs that could similarly prohibit the N. gonorrhoeae-CR3 interaction and be repurposed as novel host-targeted therapeutics for multidrug-resistant gonococcal infections in women. Two drugs, methyldopa and carbamazepine, prevented and cured cervical cell infection by multidrug-resistant gonococci by blocking the gonococcal-CR3 I-domain interaction.

IMPORTANCE Novel therapies that avert the problem of Neisseria gonorrhoeae with acquired antibiotic resistance are urgently needed. Gonococcal infection of the human cervix is initiated by an interaction between a galactose modification made to its surface appendages, pili, and the I-domain region of (host) complement receptor 3 (CR3). By targeting this crucial gonococcal–I-domain interaction, it may be possible to prevent cervical infection in females. To this end, we identified the I-domain galactose-binding epitope of CR3 and characterized its galactose lectin activity. Moreover, we identified two drugs, carbamazepine and methyldopa, as effective host-targeted therapies for gonorrhea treatment. At doses below those currently used for their respective existing indications, both carbamazepine and methyldopa were more effective than ceftriaxone in curing cervical infection ex vivo. This host-targeted approach would not be subject to N. gonorrhoeae drug resistance mechanisms. Thus, our data suggest a long-term solution to the growing problem of multidrug-resistant N. gonorrhoeae infections.

ABSTRACT

Over the last decade, innate immune priming has been evidenced in many invertebrate phyla. If mechanistic models have been proposed, molecular studies aiming to substantiate these models have remained scarce. We reveal here the transcriptional signature associated with immune priming in the oyster Crassostrea gigas. Oysters were fully protected against Ostreid herpesvirus 1 (OsHV-1), a major oyster pathogen, after priming with poly(I·C), which mimics viral double-stranded RNA. Global analysis through RNA sequencing of oyster and viral genes after immune priming and viral infection revealed that poly(I·C) induces a strong antiviral response that impairs OsHV-1 replication. Protection is based on a sustained upregulation of immune genes, notably genes involved in the interferon pathway and apoptosis, which control subsequent viral infection. This persistent antiviral alert state remains active over 4 months and supports antiviral protection in the long term. This acquired resistance mechanism reinforces the molecular foundations of the sustained response model of immune priming. It further opens the way to applications (pseudovaccination) to cope with a recurrent disease that causes dramatic economic losses in the shellfish farming industry worldwide.

IMPORTANCE In the last decade, important discoveries have shown that resistance to reinfection can be achieved without a functional adaptive immune system, introducing the concept of innate immune memory in invertebrates. However, this field has been constrained by the limited number of molecular mechanisms evidenced to support these phenomena. Taking advantage of an invertebrate species, the Pacific oyster (Crassostrea gigas), in which we evidenced one of the longest and most effective periods of protection against viral infection observed in an invertebrate, we provide the first comprehensive transcriptomic analysis of antiviral innate immune priming. We show that priming with poly(I·C) induced a massive upregulation of immune-related genes, which control subsequent viral infection, and it was maintained for over 4 months after priming. This acquired resistant mechanism reinforces the molecular foundations of the sustained response model of immune priming. It opens the way to pseudovaccination to prevent the recurrent diseases that currently afflict economically or ecologically important invertebrates.

ABSTRACT

Adjuvants can be used to potentiate the function of antibiotics whose efficacy has been reduced by acquired or intrinsic resistance. In the present study, we discovered that human milk oligosaccharides (HMOs) sensitize strains of group B Streptococcus (GBS) to trimethoprim (TMP), an antibiotic to which GBS is intrinsically resistant. Reductions in the MIC of TMP reached as high as 512-fold across a diverse panel of isolates. To better understand HMOs’ mechanism of action, we characterized the metabolic response of GBS to HMO treatment using ultrahigh-performance liquid chromatography–high-resolution tandem mass spectrometry (UPLC-HRMS/MS) analysis. These data showed that when challenged by HMOs, GBS undergoes significant perturbations in metabolic pathways related to the biosynthesis and incorporation of macromolecules involved in membrane construction. This study represents reports the metabolic characterization of a cell that is perturbed by HMOs.

IMPORTANCE Group B Streptococcus is an important human pathogen that causes serious infections during pregnancy which can lead to chorioamnionitis, funisitis, premature rupture of gestational membranes, preterm birth, neonatal sepsis, and death. GBS is evolving antimicrobial resistance mechanisms, and the work presented in this paper provides evidence that prebiotics such as human milk oligosaccharides can act as adjuvants to restore the utility of antibiotics.

ABSTRACT

Viral diseases cause significant losses in aquaculture. Prophylactic measures, such as immune priming, are promising control strategies. Treatment of the Pacific oyster (Crassostrea gigas) with the double-stranded RNA analog poly(I·C) confers long-term protection against infection with ostreid herpesvirus 1, the causative agent of Pacific oyster mortality syndrome. In a recent article in mBio, Lafont and coauthors (M. Lafont, A. Vergnes, J. Vidal-Dupiol, J. de Lorgeril, et al., mBio 11:e02777-19, 2020, https://doi.org/10.1128/mBio.02777-19) characterized the transcriptome of oysters treated with poly(I·C). This immune stimulator induced genes related to the interferon and apoptosis pathways. This response overlaps the response to viral infection, and high expression levels of potential effector genes are maintained for up to 4 months. This work opens the door to characterization of the phenomena of immune priming in a poorly studied invertebrate model. It also highlights the importance of interferon-like responses for invertebrate antiviral immunity.

N-terminal (Nt) acetylation (NTA) is an ample and irreversible cotranslational protein modification catalyzed by ribosome-associated Nt-acetyltransferases. NTA on specific proteins can act as a degradation signal (called an Ac/N-degron) for proteolysis in yeast and mammals. However, in plants, the biological relevance of NTA remains largely unexplored. In this study, we reveal that Arabidopsis (Arabidopsis thaliana) SIGMA FACTOR-BINDING PROTEIN1 (SIB1), a transcription coregulator and a positive regulator of salicylic acid-primed cell death, undergoes an absolute NTA on the initiator Met; Nt-acetyltransferase B (NatB) partly contributes to this modification. While NTA results in destabilization of certain target proteins, our genetic and biochemical analyses revealed that plant NatB-involved NTA instead renders SIB1 more stable. Given that the ubiquitin/proteasome system stimulates SIB1 degradation, it seems that the NTA-conferred stability ensures the timely expression of SIB1-dependent genes, mostly related to immune responses. Taking our findings together, here we report a noncanonical NTA-driven protein stabilization in land plants.

The way genes contribute to behavior is complicated. Although there are some single genes with large contributions, most behavioral differences are due to small effects from many interacting genes. This makes it hard to identify the genes that cause behavioral differences. Mutagenesis screens in model organisms, selective breeding experiments in animals, comparisons between related populations with different behaviors, and genome-wide association studies in humans are promising and complementary approaches to understanding the heritable aspects of complex behaviors. To connect genes to behaviors requires measuring behavioral differences, locating correlated genetic changes, determining when, where, and how these candidate genes act, and designing causative confirmatory experiments. This area of research has implications from basic discovery science to human mental health.

Kaposi sarcoma-associated herpesvirus (KSHV) is necessary but not sufficient for primary effusion lymphoma (PEL) development. Alterations in cellular signaling pathways are also a characteristic of PEL. Other B cell lymphomas have acquired an oncogenic mutation in the myeloid differentiation primary response 88 (MYD88) gene. The MYD88 L265P mutant results in the activation of interleukin-1 receptor associated kinase (IRAK). To probe IRAK/MYD88 signaling in PEL, we employed CRISPR/Cas9 technology to generate stable deletion clones in BCBL-1Cas9 and BC-1Cas9 cells. To look for off-target effects, we determined the complete exome of the BCBL-1Cas9 and BC-1Cas9 cells. Deletion of either MYD88, IRAK4, or IRAK1 abolished interleukin-1 beta (IL-1β) signaling; however, we were able to grow stable subclones from each population. Transcriptome sequencing (RNA-seq) analysis of IRAK4 knockout cell lines (IRAK4 KOs) showed that the IRAK pathway induced cellular signals constitutively, independent of IL-1β stimulation, which was abrogated by deletion of IRAK4. Transient complementation with IRAK1 increased NF-B activity in MYD88 KO, IRAK1 KO, and IRAK4 KO cells even in the absence of IL-1β. IL-10, a hallmark of PEL, was dependent on the IRAK pathway, as IRAK4 KOs showed reduced IL-10 levels. We surmise that, unlike B cell receptor (BCR) signaling, MYD88/IRAK signaling is constitutively active in PEL, but that under cell culture conditions, PEL rapidly became independent of this pathway.

IMPORTANCE One hundred percent of primary effusion lymphoma (PEL) cases are associated with Kaposi sarcoma-associated herpesvirus (KSHV). PEL cell lines, such as BCBL-1, are the workhorse for understanding this human oncovirus and the host pathways that KSHV dysregulates. Understanding their function is important for developing new therapies as well as identifying high-risk patient groups. The myeloid differentiation primary response 88 (MYD88)/interleukin-1 receptor associated kinase (IRAK) pathway, which has progrowth functions in other B cell lymphomas, has not been fully explored in PEL. By performing CRISPR/Cas9 knockout (KO) studies targeting the IRAK pathway in PEL, we were able to determine that established PEL cell lines can circumvent the loss of IRAK1, IRAK4, and MYD88; however, the deletion clones are deficient in interleukin-10 (IL-10) production. Since IL-10 suppresses T cell function, this suggests that the IRAK pathway may serve a function in vivo and during early-stage development of PEL.

The Epstein-Barr virus (EBV) causes human cancers, and epidemiological studies have shown that lytic replication is a risk factor for some of these tumors. This fits with the observation that EBV M81, which was isolated from a Chinese patient with nasopharyngeal carcinoma, induces potent virus production and increases the risk of genetic instability in infected B cells. To find out whether this property extends to viruses found in other parts of the world, we investigated 22 viruses isolated from Western patients. While one-third of the viruses hardly replicated, the remaining viruses showed variable levels of replication, with three isolates replicating at levels close to that of M81 in B cells. We cloned one strongly replicating virus into a bacterial artificial chromosome (BAC); the resulting recombinant virus (MSHJ) retained the properties of its nonrecombinant counterpart and showed similarities to M81, undergoing lytic replication in vitro and in vivo after 3 weeks of latency. In contrast, B cells infected with the nonreplicating Western B95-8 virus showed early but abortive replication accompanied by cytoplasmic BZLF1 expression. Sequencing confirmed that rMSHJ is a Western virus, being genetically much closer to B95-8 than to M81. Spontaneous replication in rM81- and rMSHJ-infected B cells was dependent on phosphorylated Btk and was inhibited by exposure to ibrutinib, opening the way to clinical intervention in patients with abnormal EBV replication. As rMSHJ contains the complete EBV genome and induces lytic replication in infected B cells, it is ideal to perform genetic analyses of all viral functions in Western strains and their associated diseases.

IMPORTANCE The Epstein-Barr virus (EBV) infects the majority of the world population but causes different diseases in different countries. Evidence that lytic replication, the process that leads to new virus progeny, is linked to cancer development is accumulating. Indeed, viruses such as M81 that were isolated from Far Eastern nasopharyngeal carcinomas replicate strongly in B cells. We show here that some viruses isolated from Western patients, including the MSHJ strain, share this property. Moreover, replication of both M81 and of MSHJ was sensitive to ibrutinib, a commonly used drug, thereby opening an opportunity for therapeutic intervention. Sequencing of MSHJ showed that this virus is quite distant from M81 and is much closer to nonreplicating Western viruses. We conclude that Western EBV strains are heterogeneous, with some viruses being able to replicate more strongly and therefore being potentially more pathogenic than others, and that the virus sequence information alone cannot predict this property.

Immune-competent animal models for the hepatitis C virus (HCV) are nonexistent, impeding studies of host-virus interactions and vaccine development. Experimental infection of laboratory rats with a rodent hepacivirus isolated from Rattus norvegicus (RHV) is a promising surrogate model due to its recapitulation of HCV-like chronicity. However, several aspects of rat RHV infection remain unclear, for instance, how RHV evades host adaptive immunity to establish persistent infection. Here, we analyzed the induction, differentiation, and functionality of RHV-specific CD8 T cell responses that are essential for protection against viral persistence. Virus-specific CD8 T cells targeting dominant and subdominant major histocompatibility complex class I epitopes proliferated considerably in liver after RHV infection. These populations endured long term yet never acquired antiviral effector functions or selected for viral escape mutations. This was accompanied by the persistent upregulation of programmed cell death-1 and absent memory cell formation, consistent with a dysfunctional phenotype. Remarkably, transient suppression of RHV viremia with a direct-acting antiviral led to the priming of CD8 T cells with partial effector function, driving the selection of a viral escape variant. These data demonstrate an intrinsic abnormality within CD8 T cells primed by rat RHV infection, an effect that is governed at least partially by the magnitude of early virus replication. Thus, this model could be useful in investigating mechanisms of CD8 T cell subversion, leading to the persistence of hepatotropic pathogens such as HCV.

IMPORTANCE Development of vaccines against hepatitis C virus (HCV), a major cause of cirrhosis and cancer, has been stymied by a lack of animal models. The recent discovery of an HCV-like rodent hepacivirus (RHV) enabled the development of such a model in rats. This platform recapitulates HCV hepatotropism and viral chronicity necessary for vaccine testing. Currently, there are few descriptions of RHV-specific responses and why they fail to prevent persistent infection in this model. Here, we show that RHV-specific CD8 T cells, while induced early at high magnitude, do not develop into functional effectors capable of controlling virus. This defect was partially alleviated by short-term treatment with an HCV antiviral. Thus, like HCV, RHV triggers dysfunction of virus-specific CD8 T cells that are vital for infection resolution. Additional study of this evasion strategy and how to mitigate it could enhance our understanding of hepatotropic viral infections and lead to improved vaccines and therapeutics.

Our study in PNAS (1) applies a mathematically based framework to the study of reported emotional experience evoked by music in the United States and China. Germane to theoretical debate, our methods reveal how specific emotions such as “triumph” are more primary across cultures than valence and arousal, a finding...

Cowen et al. (1) leverage modern gains in data science to describe impressive cross-cultural similarities in the perception of musical affect and do so in unprecedented detail. Their approach is innovative and fundamentally empirical. As such, it should have important applications for prediction in the field of affective computing, which...

Background:

Patient identification is an important step for advance care planning (ACP) discussions.

Purpose:

Clinical evidence shows minimal benefit to vitamin D screening and subsequent treatment in the general population. This study aims to assess the effectiveness of 2 light-touch interventions on reducing vitamin D test orders.

Background

Arteriovenous fistulas placed surgically for dialysis vascular access have a high primary failure rate resulting from excessive inward remodeling, medial fibrosis, and thrombosis. No clinically established pharmacologic or perisurgical therapies currently address this unmet need. Statins’ induction of multiple anti-inflammatory and antithrombotic effects suggests that these drugs might reduce arteriovenous fistula failure. Yet, the in vivo physiologic and molecular effects of statins on fistula patency and maturation remain poorly understood.

¹⁸F-rhPSMA-7 (radiohybrid prostate-specific membrane antigen [PSMA]) is a novel ligand for PET imaging. Here, we present data from a retrospective analysis using PET/CT and PET/MRI examinations to investigate the efficacy of ¹⁸F-rhPSMA-7 PET for primary N-staging of patients with prostate cancer (PC) compared with morphologic imaging (CT or MRI) and validated by histopathology. Methods: Data from 58 patients with high-risk PC (according to the D’Amico criteria) who were staged with ¹⁸F-rhPSMA-7 PET/CT or PET/MRI at our institution between July 2017 and June 2018 were reviewed. The patients had a median prescan prostate-specific antigen value of 12.2 ng/mL (range, 1.2–81.6 ng/mL). The median injected activity of ¹⁸F-rhPSMA-7 was 327 MBq (range, 132–410 MBq), with a median uptake time of 79.5 min (range, 60–153 min). All patients underwent subsequent radical prostatectomy and extended pelvic lymph node dissection. The presence of lymph node metastases was determined by an experienced reader independently for both the PET and the morphologic datasets using a template-based analysis on a 5-point scale. Patient-level and template-based results were both compared with histopathologic findings. Results: Lymph node metastases were present in 18 patients (31.0%) and were located in 52 of 375 templates (13.9%). Receiver-operating-characteristic analyses showed ¹⁸F-rhPSMA-7 PET to perform significantly better than morphologic imaging on both patient-based and template-based analyses (areas under curve, 0.858 vs. 0.649 [P = 0.012] and 0.765 vs. 0.589 [P < 0.001], respectively). On patient-based analyses, the sensitivity, specificity, and accuracy of ¹⁸F-rhPSMA-7 PET were 72.2%, 92.5%, and 86.2%, respectively, and those of morphologic imaging were 50.0%, 72.5%, and 65.5%, respectively. On template-based analyses, the sensitivity, specificity, and accuracy of ¹⁸F-rhPSMA-7 PET were 53.8%, 96.9%, and 90.9%, respectively, and those of morphologic imaging were 9.6%, 95.0%, and 83.2%, respectively. Conclusion: ¹⁸F-rhPSMA-7 PET is superior to morphologic imaging for N-staging of high-risk primary PC. The efficacy of ¹⁸F-rhPSMA-7 is similar to published data for ⁶⁸Ga-PSMA-11.