San Diego-based biotechnology company, Organovo Holdings (Organovo), has announced a tie up with a Melbourne research institute to help develop regenerative medicine in Australia.

New York-based artificial intelligence (AI) specialist, Dataiku, is expanding in the Asia-Pacific region with a major new office in Sydney. The company will be hiring dozens of local employees, from customer-facing staff to data scientists.

Clarion Energy’s Teresa Hansen, vice president of global content, for a webcast Wednesday  will be making some important announcements regarding this year’s event in New Orleans. Hansen also will offer key details on content, the exhibit floor and resources available to attendees.

Energy advisory and certification body DNV GL has launched a new digital platform for renewable energy power purchase agreements.

Clarion Energy’s Teresa Hansen, vice president of global content, for a webcast Wednesday  will be making some important announcements regarding this year’s event in New Orleans. Hansen also will offer key details on content, the exhibit floor and resources available to attendees.

A year ago, under the leadership of the Internet Corporation for Assigned Names and Numbers (ICANN), the internet naming community completed the first-ever rollover of the cryptographic key that plays a critical role in securing internet traffic worldwide. The ultimate success of that endeavor was due in large part to outreach efforts by ICANN and […]

The post Recognizing Lessons Learned From the First DNSSEC Key Rollover, a Year Later appeared first on Verisign Blog.

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

Eversheds Sutherland has advised Baladna Food Industries W.L.L (“Baladna”), the largest dairy producer in Qatar and one of the largest fully integrated producers in the MENA region, on all legal and regulatory issues in connection with i...

The 2020 DNC in Milwaukee is scheduled for the week of August 17 as planning continues to stage event in the middle of a pandemic. ......

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Turkey has been the host to many ancient civilizations and empires for ages. Its heritage can be seen in its preserved sites, inscribed on the UNESCO World Heritage List. Some of them remain largely undiscovered, though. Click through for our list, prepared by İnci Hazal Özcan, including the 16 UNESCO sites in Turkey that you should --but probably did not-- see. (Photos: Alamy)

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 September 30, 2015. -ed.

We live in an age that demands short bursts of rapid-fire information. The day is fast approaching—perhaps it’s already here—when the number of Twitter followers will hold the preeminent place on a pastor’s resume. Sermon lengths are going the way of our shrinking attention spans. Modern pastors are tempted to replace exegesis and exposition with sound bite sermons and slogan theology.

But Bible verses are not slogans or sound bites. They are eternal truths that find their meaning within the overall story God is telling. Uprooting a verse, or even a biblical phrase, from its native habitat can lead to all kinds of mayhem. That is especially the case when, independent of their proper context, verses are enlisted as the supporting cast for someone’s opinion or agenda. Romans 2:4 is one verse that is regularly misused that way—carelessly sprinkled into sermons, interviews, and social media.

For example, in January 2013, Rick Warren explained to his legions of Facebook followers how the verse factored in his evangelistic methods:

In that particular case, Warren was quoting Romans 2:4 (actually only about half of it) as justification for downplaying sin and soft-peddling the threat of judgment. But is that what Romans 2:4 is really all about? Was Paul telling his Roman readers to jettison the parts of gospel preaching that lack curb appeal?

Joel Osteen is even more explicit in his use of Romans 2:4 to defend his feel-good messages:

Listen, don’t dangle people over the fires of hell. . . . Listen, that doesn’t draw people to God. They know what kind of life they live. They know how bad they’ve lived. What you’ve got to do is talk about the goodness of God. Listen, it's the goodness of God that brings people to repentance. ^[1] Joel Osteen, "What the Resurrection Means to Us as Believers" (Sermon) cited in Philip Sinitiere, Salvation with a Smile: Joel Osteen, Lakewood Church, and American Christianity (New York: New York University Press, 2015) 223.

Joel Osteen may think that people know they are sinners and that we therefore don’t need to warn them or preach about it, but does Romans 2:4 really back up his point?

Moreover, is his point biblical at all? Just as prisons are full of convicts who will proclaim their innocence, Scripture is clear that sinners reject the guilt of their sin. As Solomon explained, “Every man’s way is right in his own eyes” (Proverbs 21:2). And even those who do acknowledge their sin have little grasp of the depth of their wretchedness, or the eternal cost of their transgressions.

In fact, it’s ironic that Osteen and Warren would use Romans 2:4 to excuse themselves from discussing sin and the need for repentance, since that verse is plucked from Scripture’s most profound discourse on man’s depravity.

Romans 1–3 is undeniable proof that Paul began his exposition of the gospel by first addressing the universality of sin and the justness of God’s wrath against sin. John MacArthur points this out:

The biblical order in any gospel presentation is always first the warning of danger and then the way of escape, first the judgment on sin and then the means of pardon, first the message of condemnation and then the offer of forgiveness, first the bad news of guilt and then the good news of grace. The whole message and purpose of the loving, redeeming grace of God offering eternal life through Jesus Christ rests upon the reality of man’s universal guilt of abandoning God and thereby being under His sentence of eternal condemnation and death. Consistent with that approach, the main body of Romans begins with 1:18, a clear affirmation of God’s wrath “against all ungodliness and unrighteousness of men.” ^[2] John MacArthur, The MacArthur New Testament Commentary: Romans 1-8 (Chicago: Moody Press, 1991) 74.

It is actually our guilt and the justness of God’s wrath that provide the all-important context for Romans 2:4:

And we know that the judgment of God rightly falls upon those who practice such things. But do you suppose this, O man, when you pass judgment on those who practice such things and do the same yourself, that you will escape the judgment of God? Or do you think lightly of the riches of His kindness and tolerance and patience, not knowing that the kindness of God leads you to repentance? But because of your stubbornness and unrepentant heart you are storing up wrath for yourself in the day of wrath and revelation of the righteous judgment of God. (Romans 2:2-5)

Now you can see why Romans 2:4 is so frequently divorced from its context, and why it’s usually paraphrased instead of quoted. In the full context of Paul’s writing we see clearly what he means by God’s goodness—it is “the riches of His kindness and tolerance and patience.” And Romans 2:2-3 explains how God demonstrates that tolerance and patience—by withholding the wrath we deserve. God’s goodness is the reality that we have not yet experienced His judgment. MacArthur adds:

Forbearance [tolerance] comes from anochē, which means “to hold back,” as of judgment. It was sometimes used to designate a truce, which involves cessation of hostilities between warring parties. God’s forbearance with mankind is a kind of temporary divine truce He has graciously proclaimed. Patience translates makrothumia, which was sometimes used of a powerful ruler who voluntarily withheld vengeance on an enemy or punishment of a criminal. Until the inevitable moment of judgment, God’s kindness and forbearance and patience are extended to all mankind. ^[3] The MacArthur New Testament Commentary: Romans 1-8, 119.

It is impossible to preach the goodness of God without talking about sin and judgment because its very meaning is bound up in those terms. When we see our sinfulness and rebellion against God, and when we see our hypocrisy in condemning others for committing the same wrath-deserving sins, then we can also marvel at God’s goodness in patiently and tolerantly withholding the wrath that we deserve.

That is what leads us to repentance. And it is entirely consistent with what Paul taught elsewhere in Scripture:

I now rejoice, not that you were made sorrowful, but that you were made sorrowful to the point of repentance; for you were made sorrowful according to the will of God, so that you might not suffer loss in anything through us. For the sorrow that is according to the will of God produces a repentance without regret, leading to salvation, but the sorrow of the world produces death. (2 Corinthians 7:9-10)

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Title: Some Diet Sodas May Ward Off Kidney Stones
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Title: Cancer Risk After Kidney Transplant Unaffected by Type of Drug Treatment
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Gastrointestinal stromal tumor (GIST), the most common sarcoma, is characterized by KIT protein overexpression, and tumors are frequently driven by oncogenic KIT mutations. Targeted inhibition of KIT revolutionized GIST therapy and ushered in the era of precision medicine for the treatment of solid malignancies. Here, we present the first use of a KIT-specific DNA aptamer for targeted labeling of GIST. We found that an anti-KIT DNA aptamer bound cells in a KIT-dependent manner and was highly specific for GIST cell labeling in vitro. Functionally, the KIT aptamer bound extracellular KIT in a manner similar to KIT mAb staining, and was trafficked intracellularly in vitro. The KIT aptamer bound dissociated primary human GIST cells in a mutation agnostic manner such that tumors with KIT and PDGFRA mutations were labeled. In addition, the KIT aptamer specifically labeled intact human GIST tissue ex vivo, as well as peritoneal xenografts in mice with high sensitivity. These results represent the first use of an aptamer-based method for targeted detection of GIST in vitro and in vivo.

Physical and chemical DNA-damaging agents are used widely in the treatment of cancer. Double-strand break (DSB) lesions in DNA are the most deleterious form of damage and, if left unrepaired, can effectively kill cancer cells. DNA-dependent protein kinase (DNA-PK) is a critical component of nonhomologous end joining (NHEJ), one of the two major pathways for DSB repair. Although DNA-PK has been considered an attractive target for cancer therapy, the development of pharmacologic DNA-PK inhibitors for clinical use has been lagging. Here, we report the discovery and characterization of a potent, selective, and orally bioavailable DNA-PK inhibitor, M3814 (peposertib), and provide in vivo proof of principle for DNA-PK inhibition as a novel approach to combination radiotherapy. M3814 potently inhibits DNA-PK catalytic activity and sensitizes multiple cancer cell lines to ionizing radiation (IR) and DSB-inducing agents. Inhibition of DNA-PK autophosphorylation in cancer cells or xenograft tumors led to an increased number of persistent DSBs. Oral administration of M3814 to two xenograft models of human cancer, using a clinically established 6-week fractionated radiation schedule, strongly potentiated the antitumor activity of IR and led to complete tumor regression at nontoxic doses. Our results strongly support DNA-PK inhibition as a novel approach for the combination radiotherapy of cancer. M3814 is currently under investigation in combination with radiotherapy in clinical trials.

ABSTRACT

Merkel cell polyomavirus (MCPyV) is the only polyomavirus known to be associated with tumorigenesis in humans. Similarly to other polyomaviruses, MCPyV expresses a large tumor antigen (LT-Ag) that, together with a small tumor antigen (sT-Ag), contributes to cellular transformation and that is of critical importance for the initiation of the viral DNA replication. Understanding the cellular protein network regulated by MCPyV early proteins will significantly contribute to our understanding of the natural MCPyV life cycle as well as of the mechanisms by which the virus contributes to cellular transformation. We here describe KRAB-associated protein 1 (Kap1), a chromatin remodeling factor involved in cotranscriptional regulation, as a novel protein interaction partner of MCPyV T antigens sT and LT. Kap1 knockout results in a significant increase in the level of viral DNA replication that is highly suggestive of Kap1 being an important host restriction factor during MCPyV infection. Differently from other DNA viruses, MCPyV gene expression is unaffected in the absence of Kap1 and Kap1 does not associate with the viral genome. Instead, we show that in primary normal human dermal fibroblast (nHDF) cells, MCPyV DNA replication, but not T antigen expression alone, induces ataxia telangiectasia mutated (ATM) kinase-dependent Kap1 S824 phosphorylation, a mechanism that typically facilitates repair of double-strand breaks in heterochromatin by arresting the cells in G₂. We show that MCPyV-induced inhibition of cell proliferation is mainly conferred by residues within the origin binding domain and thereby by viral DNA replication. Our data suggest that phosphorylation of Kap1 and subsequent Kap1-dependent G₂ arrest/senescence represent host defense mechanisms against MCPyV replication in nHDF cells.

IMPORTANCE We here describe Kap1 as a restriction factor in MCPyV infection. We report a novel, indirect mechanism by which Kap1 affects MCPyV replication. In contrast with from other DNA viruses, Kap1 does not associate with the viral genome in MCPyV infection and has no impact on viral gene expression. In MCPyV-infected nHDF cells, Kap1 phosphorylation (pKap1 S824) accumulates because of genomic stress mainly induced by viral DNA replication. In contrast, ectopic expression of LT or LT MCPyV mutants, previously shown to be important for induction of genotoxic stress, does not result in a similar extent of pKap1 accumulation. We show that cells actively replicating MCPyV accumulate pKap1 (in a manner dependent on the presence of ATM) and display a senescence phenotype reflected by G₂ arrest. These results are supported by transcriptome analyses showing that LT antigen, in a manner dependent on the presence of Kap1, induces expression of secreted factors, which is known as the senescence-associated secretory phenotype (SASP).

ABSTRACT

The initiation of Escherichia coli chromosomal DNA replication starts with the oligomerization of the DnaA protein at repeat sequences within the origin (ori) region. The amount of ori DNA per cell directly correlates with the growth rate. During fast growth, the cell generation time is shorter than the time required for complete DNA replication; therefore, overlapping rounds of chromosome replication are required. Under these circumstances, the ori region DNA abundance exceeds the DNA abundance in the termination (ter) region. Here, high ori/ter ratios are found to persist in (p)ppGpp-deficient [(p)ppGpp⁰] cells over a wide range of balanced exponential growth rates determined by medium composition. Evidently, (p)ppGpp is necessary to maintain the usual correlation of slow DNA replication initiation with a low growth rate. Conversely, ori/ter ratios are lowered when cell growth is slowed by incrementally increasing even low constitutive basal levels of (p)ppGpp without stress, as if (p)ppGpp alone is sufficient for this response. There are several previous reports of (p)ppGpp inhibition of chromosomal DNA synthesis initiation that occurs with very high levels of (p)ppGpp that stop growth, as during the stringent starvation response or during serine hydroxamate treatment. This work suggests that low physiological levels of (p)ppGpp have significant functions in growing cells without stress through a mechanism involving negative supercoiling, which is likely mediated by (p)ppGpp regulation of DNA gyrase.

IMPORTANCE Bacterial cells regulate their own chromosomal DNA synthesis and cell division depending on the growth conditions, producing more DNA when growing in nutritionally rich media than in poor media (i.e., human gut versus water reservoir). The accumulation of the nucleotide analog (p)ppGpp is usually viewed as serving to warn cells of impending peril due to otherwise lethal sources of stress, which stops growth and inhibits DNA, RNA, and protein synthesis. This work importantly finds that small physiological changes in (p)ppGpp basal levels associated with slow balanced exponential growth incrementally inhibit the intricate process of initiation of chromosomal DNA synthesis. Without (p)ppGpp, initiations mimic the high rates present during fast growth. Here, we report that the effect of (p)ppGpp may be due to the regulation of the expression of gyrase, an important enzyme for the replication of DNA that is a current target of several antibiotics.