Naikon Hacking Group Targeted Asia-Pacific Countries With New RAT
Over the last five years, a hacking group that's apparently tied to China has been targeting government ministries in the Asia-Pacific region as part of a cyber-espionage campaign, according to Check Point Research.

Naikon Hacking Group Targeted Asia-Pacific Countries With New RAT
Over the last five years, a hacking group that's apparently tied to China has been targeting government ministries in the Asia-Pacific region as part of a cyber-espionage campaign, according to Check Point Research.

Naikon Hacking Group Targeted Asia-Pacific Countries With New RAT
Over the last five years, a hacking group that's apparently tied to China has been targeting government ministries in the Asia-Pacific region as part of a cyber-espionage campaign, according to Check Point Research.

Naikon Hacking Group Targeted Asia-Pacific Countries With New RAT
Over the last five years, a hacking group that's apparently tied to China has been targeting government ministries in the Asia-Pacific region as part of a cyber-espionage campaign, according to Check Point Research.

Naikon Hacking Group Targeted Asia-Pacific Countries With New RAT
Over the last five years, a hacking group that's apparently tied to China has been targeting government ministries in the Asia-Pacific region as part of a cyber-espionage campaign, according to Check Point Research.

Naikon Hacking Group Targeted Asia-Pacific Countries With New RAT
Over the last five years, a hacking group that's apparently tied to China has been targeting government ministries in the Asia-Pacific region as part of a cyber-espionage campaign, according to Check Point Research.

Naikon Hacking Group Targeted Asia-Pacific Countries With New RAT
Over the last five years, a hacking group that's apparently tied to China has been targeting government ministries in the Asia-Pacific region as part of a cyber-espionage campaign, according to Check Point Research.

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

Venezuela will try two Americans captured during a failed bid by mercenaries to invade the country, President Nicolas Maduro said on Wednesday, as the United States vowed to “use every tool available”

The number of coronavirus cases is slowly sinking in Italy, but the country is now facing the next phase of a serious crisis: how to kickstart an economy that has been at a standstill for weeks.

A 97-year-old Russian World War II veteran has been inspired by the fund-raising efforts of Captain Tom Moore. She says she can't walk around a garden to gather donations like the 100-year-old British veteran did, but she is posting war stories online every day to raise money for the families of Russian medics who have died fighting COVID-19.

THE Philippines has “adapted well” as its health care capacity was “not overwhelmed” by the coronavirus disease 2019 (covid-19)due to the enhanced community quarantine (ECQ) the government had enforced , an expert and consultant for the Interagency Taskforce on Emerging Infectious Diseases (IATF-EID) said on Friday. Edcel Salvana, director of the Institute of Molecular Biology […]

[Nation] Captain Mabruk Islam Sherman spoke to his wife and three children around noon, informing them of his trip to Somalia.

Set in 1954, “Liberty Heights” is the fourth and final installment of Levinson’s “Baltimore movies,” which began with “Diner” in 1982 and includes both “Tin Men” (1987) and “Avalon” (1990).

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 August 15, 2016. -ed.

Faith and repentance are not easy. Submission contradicts the natural disposition of the human heart. And the transforming and sanctifying work of the Holy Spirit is often uncomfortable and difficult.

Salvation would be so much more inviting and enticing to our human understanding if it didn’t require humility, repentance, and the transformation of your entire being. Why can’t it simply be the product of a one-time activity?

For those looking to bypass the difficulty and discomfort of salvation, 1 Peter 3:21 seemingly provides a shortcut in the form of this simple declaration: “Baptism now saves you.” This and a select few other verses are often used to promote “baptismal regeneration”–the view that teaches that one is saved (regenerated) though water baptism.

However, not all proponents of baptismal regeneration see baptism as a shortcut to salvation or a quick fix to the problem of sin. Many view it as a necessary element—in addition to repentance and faith—that completes the work of salvation. And as a proof text, they point to Peter’s words in Acts 2:38, “Peter said to them, ‘Repent, and each of you be baptized in the name of Jesus Christ for the forgiveness of your sins; and you will receive the gift of the Holy Spirit’” (emphasis added).

So what should we make of that—was Peter the first proponent of baptismal regeneration? And moreover, does that mean that no one is truly saved until they’ve been baptized?

To find the answers to those questions, we need to consider what it meant to become a Christian and make a public declaration of your faith in the earliest days of the church. In his commentary on Acts, John MacArthur sheds some light on the issue:

It is difficult for modern readers to grasp the magnitude of the change facing Peter’s Jewish hearers. They were part of a unique community, with a rich cultural and religious history. Despite long years of subjugation to Rome, they were fiercely nationalistic. The nation had rejected Jesus as a blasphemer and executed Him. Now Peter calls on them to turn their back on all that and embrace Jesus as their Messiah.

By calling on each of them to “be baptized in the name of Jesus Christ” Peter does not allow for any “secret disciples” (cf. Matthew 10:32-33). Baptism would mark a public break with Judaism and identification with Jesus Christ. Such a drastic public act would help weed out any conversions which were not genuine. In sharp contrast to many modern gospel presentations, Peter made accepting Christ difficult, not easy. By so doing, he followed the example of our Lord Himself (Luke 14:26-33; 18:18-27). Baptism was always “in the name of Jesus Christ.” That was the crucial identification, and the cost was high for such a confession. ^[1] John MacArthur, The MacArthur New Testament Commentary: Acts 1-12 (Chicago: Moody Press, 1994), 73.

Baptism doesn’t accomplish or seal your salvation; it’s a public declaration of the work the Lord has already accomplished within. So the whole premise of baptismal regeneration defies the meaning and purpose of baptism. Not only that, the immediate context of Peter’s exhortation eliminates the possibility of anyone successfully using Acts 2:38 as an argument for baptismal regeneration. As John MacArthur explains,

[Baptismal regeneration] ignores the immediate context of the passage. As already noted, baptism would be a dramatic step for Peter’s hearers. By publicly identifying themselves as followers of Jesus of Nazareth, they risked becoming outcasts in their society (cf. John 9:22). Peter calls upon them to prove the genuineness of their repentance by submitting to public baptism. In much the same way, our Lord called upon the rich young ruler to prove the genuineness of his repentance by parting with his wealth (Luke 18:18-27). Surely, however, no one would argue from the latter passage that giving away one’s possessions is necessary for salvation. Salvation is not a matter of either water or economics. True repentance, however, will inevitably manifest itself in total submission to the Lord’s will. ^[2] The MacArthur New Testament Commentary: Acts 1-12, 73-74.

Moreover, the idea of baptismal regeneration represents a significant contradiction to other passages of Scripture that clearly teach salvation by faith alone. In Acts 16:31, Paul and Silas tell their jailor how he can be saved, “Believe in the Lord Jesus, and you will be saved.” In Galatians 2:16, Paul unmistakably denies salvation by works with these words:

Nevertheless knowing that a man is not justified by the works of the Law but through faith in Christ Jesus, even we have believed in Christ Jesus, so that we may be justified by faith in Christ and not by the works of the Law; since by the works of the Law no flesh will be justified. (cf. Romans 3:28)

Even Christ Himself—in perhaps His most famous quote—denied the need for works to accomplish salvation: “For God so loved the world that He gave His only begotten Son, that whosoever believes in Him shall not perish, but have eternal life” (John 3:16). In fact, the need for baptism would contradict the entirety of Christ’s ministry. As John MacArthur puts it, “After condemning the ritualistic religion of the scribes and Pharisees, our Lord would hardly have instituted one of His own.” ^[3] The MacArthur New Testament Commentary: Acts 1-12, 74.

John MacArthur describes another reason Peter’s words cannot be read as an endorsement of baptismal regeneration:

This interpretation is not true to the facts of Scripture. Throughout the book of Acts, forgiveness is linked to repentance, not baptism (cf. Acts 3:19; 5:31; 26:20). In addition, the Bible records that some who were baptized were not saved (Acts 8:13, 21-23), while some were saved with no mention of their being baptized (Luke 7:37-50; Matthew 9:2; Luke 18:13-14). The story of the conversion of Cornelius and his friends very clearly shows the relationship of baptism to salvation. It was only after they were saved, as shown by their receiving the Holy Spirit (Acts 10:44-46), that they were baptized (Acts 10:47-48). Indeed, it was because they had received the Spirit (and hence were saved) that Peter ordered them to be baptized (v. 47). That passage clearly shows that baptism follows salvation; it does not cause it. ^[4] The MacArthur New Testament Commentary: Acts 1-12, 74.

So why do Peter’s words in Acts 2:38 read as an endorsement of baptismal regeneration? The confusion likely stems from the way the Greek preposition eis is translated. While it is often translated “for the purpose of,” it can also mean “because of”—that’s clearly the sense it conveys in Matthew 12:41, as Jesus described how the people of Ninevah repented after hearing Jonah’s preaching. That’s the sense we ought to see in Acts 2:38—Peter exhorted the people to be baptized because of the forgiveness of their sins.

As John MacArthur explains, that understanding is in keeping with the pattern presented throughout Scripture.

The order is clear. Repentance is for forgiveness. Baptism follows that forgiveness; it does not cause it (cf. Acts 8:12, 34-39; 10:34-48; 16:31-33). It is the public sign or symbol of what has taken place on the inside. It is an important step of obedience for all believers, and should closely follow conversion. In fact, in the early church it was inseparable from salvation, so that Paul referred to salvation as being related to “one Lord, one faith, one baptism” (Ephesians 4:5). ^[5] The MacArthur New Testament Commentary: Acts 1-12, 75.

With that in mind, how do we make sense of the simple declaration we began with: “Baptism now saves you” (1 Peter 3:21)?

As so often is the case in this series on Frequently Abused Verses, context is key. While those four words might seem to say one thing, a look at Peter’s complete statement makes his point abundantly clear.

When the patience of God kept waiting in the days of Noah, during the construction of the ark, in which a few, that is, eight persons, were brought safely through the water. Corresponding to that, baptism now saves you—not the removal of dirt from the flesh, but an appeal to God for a good conscience—through the resurrection of Jesus Christ. (1 Peter 3:20-21)

As John MacArthur explains in his commentary on 1 Peter, it’s illegitimate to use Peter’s words to make a case for salvation through water baptism, because that’s not even the kind of baptism Peter has in mind here.

“Baptism” (from baptizō) simply means “to immerse,” and not just in water. Peter here uses baptism to refer to a figurative immersion into Christ as the ark of safety that will sail over the holocaust of judgment on the wicked. Noah and his family were immersed not just in water, but in the world under divine judgment. All the while they were protected by being in the ark. God preserved them in the midst of His judgment, which is what he also does for all those who trust in Christ. God’s final judgment will bring fire and fury on the world, destroying the entire universe (cf. 2 Peter 3:10-12); but the people of God will be protected and taken into the eternal new heavens and new earth (2 Peter 3:13).

Peter made clear that he did not want readers to think he was referring to water baptism when he specifically said “not the removal of dirt from the flesh” (1 Peter 3:21). That he was actually referring to a spiritual reality when he wrote “baptism now saves” is also clear from the phrase, “an appeal to God for a good conscience—through the resurrection of Jesus Christ” (v. 21). The only baptism that saves people is dry—the spiritual one into the death as well as the resurrection of Christ—of those who appeal to God to place them into the spiritual ark of salvation safety (cf. Romans 10:9-10).

Just as the Flood immersed all people in the judgment of God, yet some passed through safely, so also his final judgment will involve everyone, but those who are in Christ will pass through securely. The experience of Noah’s family in the Flood is also analogous to the experience of everyone who receives salvation. Just as they died to their previous world when they entered the ark and subsequently experienced a resurrection of sorts when they exited the ark to a new post-Flood world, so all Christians die to their old world when they enter the body of Christ (Romans 7:4-6; Galatians 2:19-20; Ephesians 4:20-24). They subsequently enjoy newness of life that culminates one day with the resurrection to eternal life. . . .

Therefore, God provides salvation because a sinner, by faith, is immersed into Christ’s death and resurrection and becomes His own through that spiritual union. Salvation does not occur by means of any rite, including water baptism. ^[6] John MacArthur, The MacArthur New Testament Commentary: 1 Peter (Chicago: Moody Publishers, 2004) 217-218.

There are no shortcuts or religious rituals that can achieve salvation—in fact, it’s not a product of human works at all. As Paul writes in his letter to the Ephesians, “For by grace you have been saved through faith; and that not of yourselves, it is the gift of God; not as a result of works, so that no one may boast” (Ephesians 2:8-9).

1

PARIS: On May 11, 1960, Nazi war criminal Adolf Eichmann was nabbed by a team of Israeli spies after years on the run in Argentina, ending a long manhunt. Ten days later, drugged and dressed as a crew member of Israeli flag carrier El Al, he was smuggled to Israel by Mossad agents and put on...

By some estimates, the digital economy now accounts for trillions of dollars. But policymakers and companies still lack the data needed to fully understand it.

Microchip Smart Storage Adapters Now Interoperate Seamlessly with MegaRAC® SP-X Management Firmware from AMI for At-Scale Secure Storage Management

ADB is proposing a project to deliver climate adaptive solutions for water resources management and modernize outdated irrigation and drainage systems within the Amu Darya and selected reaches of the Zarafshan irrigation system.

This publication presents an overview of the Water Efficiency Improvement in Drought-Affected Provinces (WEIDAP) Project that aims to apply cost-effective technology for irrigation modernization and agricultural development in Viet Nam.

GENEVA MOTOR SHOW 2015 – HARMAN, the premium global audio, visual, infotainment and enterprise automation group (NYSE:HAR), will demo its expanded scalable embedded infotainment platform at the Geneva International Motor Show. The offering addresses the full spectrum of vehicle segments, including entry- to mid-level cars, with a feature-rich, automotive-grade platform that leverages the latest smartphone integration technologies such as Apple CarPlay, Android Auto™ and MirrorLink for best-in-class connectivity for the world’s automakers.

A king kobra is spotted near a train station in Singapore, animal rescuers were alerted to catch it.

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A new dinosaur species related to velociraptors has been found in New Mexico, and its claws were larger and stronger than average

A king kobra is spotted near a train station in Singapore, animal rescuers were alerted to catch it.

Armed with drones, helicopters and military-grade software, a British photographer has developed a new way to remember glaciers

To find subjects to photograph, Kacper Kowalski takes to the air in a paramotor or gyrocopter, barely steering to allow the wind to dictate the direction

Kate, Britain's Duchess of Cambridge, launched a project on Thursday to encourage Britons to submit pictures of their daily lives during lockdown. Edward Baran reports.

Kate, Britain's Duchess of Cambridge, launched a project on Thursday to encourage Britons to submit pictures of their current daily lives and the work of "Helpers and Heroes" to capture a snapshot of the nation in coronavirus lockdown.

For more than two years, the Global Research and Analysis Team (GReAT) at Kaspersky has been publishing quarterly summaries of advanced persistent threat (APT) activity. This is our latest installment, focusing on activities that we observed during Q1 2020.

Title: Black Kids Less Apt to Get Meds for Stomach Pain in ER: Study
Category: Health News
Created: 4/28/2012 10:05:00 AM
Last Editorial Review: 4/30/2012 12:00:00 AM

Title: Rydapt Approved for Adults With Acute Myeloid Leukemia
Category: Health News
Created: 4/28/2017 12:00:00 AM
Last Editorial Review: 5/1/2017 12:00:00 AM

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.

ABSTRACT

Interactions between microorganisms in mixed communities are highly complex, being either syntrophic, neutral, predatory, or competitive. Evolutionary changes can occur in the interaction dynamics between community members as they adapt to coexistence. Here, we report that the syntrophic interaction between Geobacter sulfurreducens and Pseudomonas aeruginosa coculture change in their dynamics over evolutionary time. Specifically, Geobacter sp. dominance increases with adaptation within the cocultures, as determined through quantitative PCR and fluorescence in situ hybridization. This suggests a transition from syntrophy to competition and demonstrates the rapid adaptive capacity of Geobacter spp. to dominate in cocultures with P. aeruginosa. Early in coculture establishment, two single-nucleotide variants in the G. sulfurreducens fabI and tetR genes emerged that were strongly selected for throughout coculture evolution with P. aeruginosa phenazine wild-type and phenazine-deficient mutants. Sequential window acquisition of all theoretical spectra-mass spectrometry (SWATH-MS) proteomics revealed that the tetR variant cooccurred with the upregulation of an adenylate cyclase transporter, CyaE, and a resistance-nodulation-division (RND) efflux pump notably known for antibiotic efflux. To determine whether antibiotic production was driving the increased expression of the multidrug efflux pump, we tested Pseudomonas-derived phenazine-1-carboxylic acid (PHZ-1-CA) for its potential to inhibit Geobacter growth and drive selection of the tetR and fabI genetic variants. Despite its inhibitory properties, PHZ-1-CA did not drive variant selection, indicating that other antibiotics may drive overexpression of the efflux pump and CyaE or that a novel role exists for these proteins in the context of this interaction.

IMPORTANCE Geobacter and Pseudomonas spp. cohabit many of the same environments, where Geobacter spp. often dominate. Both bacteria are capable of extracellular electron transfer (EET) and play important roles in biogeochemical cycling. Although they recently in 2017 were demonstrated to undergo direct interspecies electron transfer (DIET) with one another, the genetic evolution of this syntrophic interaction has not been examined. Here, we use whole-genome sequencing of the cocultures before and after adaptive evolution to determine whether genetic selection is occurring. We also probe their interaction on a temporal level and determine whether their interaction dynamics change over the course of adaptive evolution. This study brings to light the multifaceted nature of interactions between just two microorganisms within a controlled environment and will aid in improving metabolic models of microbial communities comprising these two bacteria.

For cell entry, vaccinia virus requires fusion with the host membrane via a viral fusion complex of 11 proteins, but the mechanism remains unclear. It was shown previously that the viral proteins A56 and K2 are expressed on infected cells to prevent superinfection by extracellular vaccinia virus through binding to two components of the viral fusion complex (G9 and A16), thereby inhibiting membrane fusion. To investigate how the A56/K2 complex inhibits membrane fusion, we performed experimental evolutionary analyses by repeatedly passaging vaccinia virus in HeLa cells overexpressing the A56 and K2 proteins to isolate adaptive mutant viruses. Genome sequencing of adaptive mutants revealed that they had accumulated a unique G9R open reading frame (ORF) mutation, resulting in a single His44Tyr amino acid change. We engineered a recombinant vaccinia virus to express the G9^H44Y mutant protein, and it readily infected HeLa-A56/K2 cells. Moreover, similar to the A56 virus, the G9^H44Y mutant virus on HeLa cells had a cell fusion phenotype, indicating that G9^H44Y-mediated membrane fusion was less prone to inhibition by A56/K2. Coimmunoprecipitation experiments demonstrated that the G9^H44Y protein bound to A56/K2 at neutral pH, suggesting that the H44Y mutation did not eliminate the binding of G9 to A56/K2. Interestingly, upon acid treatment to inactivate A56/K2-mediated fusion inhibition, the G9^H44Y mutant virus induced robust cell-cell fusion at pH 6, unlike the pH 4.7 required for control and revertant vaccinia viruses. Thus, A56/K2 fusion suppression mainly targets the G9 protein. Moreover, the G9^H44Y mutant protein escapes A56/K2-mediated membrane fusion inhibition most likely because it mimics an acid-induced intermediate conformation more prone to membrane fusion.

IMPORTANCE It remains unclear how the multiprotein entry fusion complex of vaccinia virus mediates membrane fusion. Moreover, vaccinia virus contains fusion suppressor proteins to prevent the aberrant activation of this multiprotein complex. Here, we used experimental evolution to identify adaptive mutant viruses that overcome membrane fusion inhibition mediated by the A56/K2 protein complex. We show that the H44Y mutation of the G9 protein is sufficient to overcome A56/K2-mediated membrane fusion inhibition. Treatment of virus-infected cells at different pHs indicated that the H44Y mutation lowers the threshold of fusion inhibition by A56/K2. Our study provides evidence that A56/K2 inhibits the viral fusion complex via the latter’s G9 subcomponent. Although the G9^H44Y mutant protein still binds to A56/K2 at neutral pH, it is less dependent on low pH for fusion activation, implying that it may adopt a subtle conformational change that mimics a structural intermediate induced by low pH.

The most fundamental genetic program of an annual plant defines when to grow and reproduce and when to remain dormant in the soil as a seed. With the right timing, plants can even live in hostile regions with only a few months of growth-favorable abundant rains and mild temperatures. To...

Lucy A. Winder, Stewart A. White, Andreas Nord, Barbara Helm, and Dominic J. McCafferty

During winter at temperate and high latitudes, the low ambient temperatures, limited food supplies and short foraging periods mean small passerines show behavioural, morphological and physiological adaptations to reduce the risk of facing energy shortages. Peripheral tissues vasoconstrict in low ambient temperatures to reduce heat loss and cold injury. Peripheral vasoconstriction has been observed with food restriction in captivity but has yet to be explored in free-ranging animals. We experimentally food restricted both wild and captive great tits (Parus major) during winter months and measured surface temperatures of the bill and eye region using thermal imaging, to investigate whether birds show rapid local heterothermic responses, which may reduce their thermoregulatory costs when facing a perceived imminent food shortage. Our results of a continuously filmed wild population showed that bill temperature was immediately reduced in response to food restriction compared with when food was available ad libitum, an apparent autonomic response. Such immediacy implies a ‘pre-emptive’ response before the bird experiences any shortfalls in energy reserves. We also demonstrate temporal variation in vasoconstriction of the bill, with bill temperature gradually rising throughout the food restriction after the initial drop. Eye-region temperature in the wild birds remained at similar levels throughout food restriction compared with unrestricted birds, possibly reflecting the need to maintain steady circulation to the central nervous and visual systems. Our findings provide evidence that birds selectively allow the bill to cool when a predictable food supply is suddenly disrupted, probably as a means of minimising depletion of body reserves for a perceived future shortage in energy.

Glycine riboswitches utilize both single- and tandem-aptamer architectures. In the tandem system, the relative contribution of each aptamer toward gene regulation is not well understood. To dissect these contributions, the effects of 684 single mutants of a tandem ON switch from Bacillus subtilis were characterized for the wild-type construct and binding site mutations that selectively restrict ligand binding to either the first or second aptamer. Despite the structural symmetry of tandem aptamers, the response to these mutations was frequently asymmetrical. Mutations in the first aptamer often significantly weakened the K_1/2, while several mutations in the second aptamer improved the amplitude. These results demonstrate that this ON switch favors ligand binding to the first aptamer. This is in contrast to the tandem OFF switch variant from Vibrio cholerae, which was previously shown to have preferential binding to its second aptamer. A bioinformatic analysis of tandem glycine riboswitches revealed that the two binding pockets are differentially conserved between ON and OFF switches. Altogether, this indicates that tandem ON switch variants preferentially utilize binding to the first aptamer to promote helical switching, while OFF switch variants favor binding to the second aptamer. The data set also revealed a cooperative glycine response when both binding pockets were maximally stabilized with three GC base pairs. This indicates a cooperative response may sometimes be obfuscated by a difference in the affinities of the two aptamers. This conditional cooperativity provides an additional layer of tunability to tandem glycine riboswitches that adds to their versatility as genetic switches.

Motor protein-based active transport is essential for mRNA localization and local translation in animal cells, yet how mRNA granules interact with motor proteins remains poorly understood. Using an unbiased yeast two–hybrid screen for interactions between murine RNA-binding proteins (RBPs) and motor proteins, here we identified protein interaction with APP tail-1 (PAT1) as a potential direct adapter between zipcode-binding protein 1 (ZBP1, a β-actin RBP) and the kinesin-I motor complex. The amino acid sequence of mouse PAT1 is similar to that of the kinesin light chain (KLC), and we found that PAT1 binds to KLC directly. Studying PAT1 in mouse primary hippocampal neuronal cultures from both sexes and using structured illumination microscopic imaging of these neurons, we observed that brain-derived neurotrophic factor (BDNF) enhances co-localization of dendritic ZBP1 and PAT1 within granules that also contain kinesin-I. PAT1 is essential for BDNF-stimulated neuronal growth cone development and dendritic protrusion formation, and we noted that ZBP1 and PAT1 co-locate along with β-actin mRNA in actively transported granules in living neurons. Acute disruption of the PAT1–ZBP1 interaction in neurons with PAT1 siRNA or a dominant-negative ZBP1 construct diminished localization of β-actin mRNA but not of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) mRNA in dendrites. The aberrant β-actin mRNA localization resulted in abnormal dendritic protrusions and growth cone dynamics. These results suggest a critical role for PAT1 in BDNF-induced β-actin mRNA transport during postnatal development and reveal a new molecular mechanism for mRNA localization in vertebrates.

3-Mercaptopyruvate sulfur transferase (MPST) catalyzes the desulfuration of 3-mercaptopyruvate (3-MP) and transfers sulfane sulfur from an enzyme-bound persulfide intermediate to thiophilic acceptors such as thioredoxin and cysteine. Hydrogen sulfide (H2S), a signaling molecule implicated in many physiological processes, can be released from the persulfide product of the MPST reaction. Two splice variants of MPST, differing by 20 amino acids at the N terminus, give rise to the cytosolic MPST1 and mitochondrial MPST2 isoforms. Here, we characterized the poorly-studied MPST1 variant and demonstrated that substitutions in its Ser–His–Asp triad, proposed to serve a general acid–base role, minimally affect catalytic activity. We estimated the 3-MP concentration in murine liver, kidney, and brain tissues, finding that it ranges from 0.4 μmol·kg−1 in brain to 1.4 μmol·kg−1 in kidney. We also show that N-acetylcysteine, a widely-used antioxidant, is a poor substrate for MPST and is unlikely to function as a thiophilic acceptor. Thioredoxin exhibits substrate inhibition, increasing the KM for 3-MP ∼15-fold compared with other sulfur acceptors. Kinetic simulations at physiologically-relevant substrate concentrations predicted that the proportion of sulfur transfer to thioredoxin increases ∼3.5-fold as its concentration decreases from 10 to 1 μm, whereas the total MPST reaction rate increases ∼7-fold. The simulations also predicted that cysteine is a quantitatively-significant sulfane sulfur acceptor, revealing MPST's potential to generate low-molecular-weight persulfides. We conclude that the MPST1 and MPST2 isoforms are kinetically indistinguishable and that thioredoxin modulates the MPST-catalyzed reaction in a physiologically-relevant concentration range.

Kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are two major, closely related receptor subtypes in the glutamate ion channel family. Excessive activities of these receptors have been implicated in a number of central nervous system diseases. Designing potent and selective antagonists of these receptors, especially of kainate receptors, is useful for developing potential treatment strategies for these neurological diseases. Here, we report on two RNA aptamers designed to individually inhibit kainate and AMPA receptors. To improve the biostability of these aptamers, we also chemically modified these aptamers by substituting their 2'-OH group with 2'-fluorine. These 2'-fluoro aptamers, FB9s-b and FB9s-r, were markedly resistant to RNase-catalyzed degradation, with a half-life of ∼5 days in rat cerebrospinal fluid or serum-containing medium. Furthermore, FB9s-r blocked AMPA receptor activity. Aptamer FB9s-b selectively inhibited GluK1 and GluK2 kainate receptor subunits, and also GluK1/GluK5 and GluK2/GluK5 heteromeric kainate receptors with equal potency. This inhibitory profile makes FB9s-b a powerful template for developing tool molecules and drug candidates for treatment of neurological diseases involving excessive activities of the GluK1 and GluK2 subunits.

Hepatocellular carcinomas (HCC) are adapted to survive extreme genomic stress conditions imposed by hyperactive DNA replication and genotoxic drug treatment. The underlying mechanisms remain unclear, but may involve intensified DNA damage response/repair programs. Here, we investigate a new role of nucleostemin (NS) in allowing HCC to survive its own malignancy, as NS was previously shown to promote liver regeneration via a damage repair mechanism. We first established that a higher NS transcript level correlates with high-HCC grades and poor prognostic signatures, and is an independent predictor of shorter overall and progression-free survival specifically for HCC and kidney cancer but not for others. Immunostaining confirmed that NS is most abundantly expressed in high-grade and metastatic HCCs. Genome-wide analyses revealed that NS is coenriched with MYC target and homologous recombination (HR) repair genes in human HCC samples and functionally intersects with those involved in replication stress response and HR repair in yeasts. In support, NS-high HCCs are more reliant on the replicative/oxidative stress response pathways, whereas NS-low HCCs depend more on the mTOR pathway. Perturbation studies showed NS function in protecting human HCC cells from replication- and drug-induced DNA damage. Notably, NS depletion in HCC cells increases the amounts of physical DNA damage and cytosolic double-stranded DNA, leading to a reactive increase of cytokines and PD-L1. This study shows that NS provides an essential mechanism for HCC to adapt to high genomic stress for oncogenic maintenance and propagation. NS deficiency sensitizes HCC cells to chemotherapy but also triggers tumor immune responses.