The transfer of a phosphate from ATP to a protein substrate, a modification known as protein phosphorylation, is catalyzed by protein kinases. Protein kinases play a crucial role in virtually every cellular activity. Recent studies of atypical protein kinases have highlighted the structural similarity of the kinase superfamily despite notable differences in primary amino acid sequence. Here, using a bioinformatics screen, we searched for putative protein kinases in the intracellular bacterial pathogen Legionella pneumophila and identified the type 4 secretion system effector Lpg2603 as a remote member of the protein kinase superfamily. Employing an array of biochemical and structural biology approaches, including in vitro kinase assays and isothermal titration calorimetry, we show that Lpg2603 is an active protein kinase with several atypical structural features. Importantly, we found that the eukaryote-specific host signaling molecule inositol hexakisphosphate (IP6) is required for Lpg2603 kinase activity. Crystal structures of Lpg2603 in the apo-form and when bound to IP6 revealed an active-site rearrangement that allows for ATP binding and catalysis. Our results on the structure and activity of Lpg2603 reveal a unique mode of regulation of a protein kinase, provide the first example of a bacterial kinase that requires IP6 for its activation, and may aid future work on the function of this effector during Legionella pathogenesis.

VOLUME 295 (2020) PAGES 4079–4092There was an error in the abstract. “The pyridinium cation hampers uptake of OPs into the central nervous system (CNS)” should read as “The pyridinium cation hampers uptake into the central nervous system (CNS).”

Fascism -- History -- 21st century.

Mass media -- Political aspects -- United States.

Paris : J.-B. Baillière, 1877.

Georgia is one of four states that doesn't have a hate crime law. Arbery's killing has reignited calls for legislation.

London : Cleanair, Smoke-free Environment (33 Stillness Rd, London, SE23 1NG), [198-?]

Suddenly, the White House loves Bernie Sanders.

Hate crimes against Vancouver's Asian communities have increased since the early days of the outbreak and the #Elimin8hate campaign is an effort to combat that and comfort victims.

UN Secretary General Antonio Guterres said Friday the coronavirus pandemic keeps unleashing "a tsunami of hate and xenophobia, scapegoating and scaremongering" and appealed for "an all-out effort to end hate speech globally."

Volker (OM Montenegro) describes how their outdoor lessons for Roma kids were threatened by bad weather. Then God provided not only the solution - building a carport as a shelter - but also the funds and manpower needed to build it.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an important risk factor for neonatal jaundice in Nigeria. It is associated with severe hyperbilirubinemia among infants exposed to icterogenic agents. Elevated bilirubin levels have occasionally been demonstrated in G6PD-deficient infants without exposure to icterogenic agents.

Even without exposure to known icterogens, G6PD-deficient infants have a more rapid hematocrit decline and higher bilirubin levels than their G6PD-intermediate and G6PD-normal counterparts throughout the first week of life. (Read the full article)

Glucose-6-phosphate dehydrogenase deficiency remains a global as well as a North American burden for extreme hyperbilirubinemia and kernicterus and is often unpredictable during the first few days after birth. Newborn screening for this enzyme deficiency is not universally available but debated.

Point-of-care screening, using digital microfluidics, provides accurate, low blood volume, and affordable technology for rapid newborn glucose-6-phosphate dehydrogenase enzyme screening that could guide clinicians before infants’ discharge from well-child nurseries and meet existing American Academy of Pediatrics’ recommendations. (Read the full article)

Members of the Scottish Parliament’s Justice Committee have launched a call for views on the Scottish Government’s plans to update hate crime laws.

Read Full Article at RT.com

It also passed a string of directions on safe passage for the bodies of the victims, their proper burial/cremation, adequate number of helplines and help desks, besides rehabilitation of those affected.

Unlike Wednesday, when Justices Muralidhar and Talwant Singh questioned the Solicitor General repeatedly over the delay in lodging FIRs and had video clips of the hate speeches played in open court with proceedings lasting through the day, the hearing Thursday was over in less than an hour.

The Supreme Court on Wednesday sent the plea to the Delhi High Court with the direction that it be listed for March 6 along with other petitions on the matter.

Matthew Berry gives players the Love/Hate treatment coming out of the 2020 NFL draft, identifying those who have gained or lost the most fantasy football value.

U.N. Secretary-General Antonio Guterres called on May 8 for an "all-out effort" to end the "tsunami of hate and xenophobia" sparked by the novel coronavirus pandemic, without naming specific countries.

We will never fully know what Iran and Russia actually think of Assad or each other’s historic role in Syria.

UN Secretary General Antonio Guterres on Friday said the coronavirus pandemic keeps unleashing “a tsunami of hate and xenophobia, scapegoating and scaremongering” and appealed for “an all-out effort to end hate speech globally”.The UN chief said “anti-foreigner sentiment has surged online and in the streets, anti-Semitic conspiracy theories have spread, and Covid-19-related anti-Muslim attacks have occurred”. Migrants and refugees “have been vilified as a source of the virus – and then denied…

The International Criminal Court (ICC) on Tuesday highlighted crimes against humanity and grave mismanagement of the law in Libya during a release of their latest report on the North African nation.  Fatou Bensouda, Chief Prosecutor of the ICC, said enforced disappearances, arbitrary detentions, hate speech, and severe maltreatment of detainees remains a massive concern in […]

The post Enforced Disappearances, Arbitrary Detentions, Hate Speech & Attacks on Civilians – ICC Report on Libya appeared first on Inter Press Service.

Bold action is required by policymakers and central bankers to keep the region’s economies afloat and contain the pandemic.

Julia Ebner infiltrated the hidden forums that extremists use. Her experiences lay bare how they hijack social media and video games to spread hate – and how to beat them

The Netscape co-founder and high-profile venture capitalist tells Reuters' Felix Salmon that he hates selling companies -- nearly as much as he hates taking them public. What will his investors say?

They’re safer than other kinds of road junction, require less energy for lights and result in less pollution from vehicles. But will they ever conquer the world?

Julia Ebner infiltrated the hidden forums that extremists use. Her experiences lay bare how they hijack social media and video games to spread hate – and how to beat them

Title: Hate Meat? It May Be in Your Genes
Category: Health News
Created: 5/3/2012 11:01:00 AM
Last Editorial Review: 5/3/2012 12:00:00 AM

ABSTRACT

The Candida albicans high-affinity phosphate transporter Pho84 is required for normal Target of Rapamycin (TOR) signaling, oxidative stress resistance, and virulence of this fungal pathogen. It also contributes to C. albicans’ tolerance of two antifungal drug classes, polyenes and echinocandins. Echinocandins inhibit biosynthesis of a major cell wall component, beta-1,3-glucan. Cells lacking Pho84 were hypersensitive to other forms of cell wall stress beyond echinocandin exposure, while their cell wall integrity signaling response was weak. Metabolomics experiments showed that levels of phosphoric intermediates, including nucleotides like ATP and nucleotide sugars, were low in pho84 mutant compared to wild-type cells recovering from phosphate starvation. Nonphosphoric precursors like nucleobases and nucleosides were elevated. Outer cell wall phosphomannan biosynthesis requires a nucleotide sugar, GDP-mannose. The nucleotide sugar UDP-glucose is the substrate of enzymes that synthesize two major structural cell wall polysaccharides, beta-1,3- and beta-1,6-glucan. Another nucleotide sugar, UDP-N-acetylglucosamine, is the substrate of chitin synthases which produce a stabilizing component of the intercellular septum and of lateral cell walls. Lack of Pho84 activity, and phosphate starvation, potentiated pharmacological or genetic perturbation of these enzymes. We posit that low substrate concentrations of beta-d-glucan- and chitin synthases, together with pharmacologic inhibition of their activity, diminish enzymatic reaction rates as well as the yield of their cell wall-stabilizing products. Phosphate import is not conserved between fungal and human cells, and humans do not synthesize beta-d-glucans or chitin. Hence, inhibiting these processes simultaneously could yield potent antifungal effects with low toxicity to humans.

IMPORTANCE Candida species cause hundreds of thousands of invasive infections with high mortality each year. Developing novel antifungal agents is challenging due to the many similarities between fungal and human cells. Maintaining phosphate balance is essential for all organisms but is achieved completely differently by fungi and humans. A protein that imports phosphate into fungal cells, Pho84, is not present in humans and is required for normal cell wall stress resistance and cell wall integrity signaling in C. albicans. Nucleotide sugars, which are phosphate-containing building block molecules for construction of the cell wall, are diminished in cells lacking Pho84. Cell wall-constructing enzymes may be slowed by lack of these building blocks, in addition to being inhibited by drugs. Combined targeting of Pho84 and cell wall-constructing enzymes may provide a strategy for antifungal therapy by which two sequential steps of cell wall maintenance are blocked for greater potency.

Plants have evolved complex physiological and biochemical mechanisms to adapt to a heterogeneous soil phosphorus environment. PHOSPHATE2 (PHO2) is a phosphate (Pi) starvation-signaling regulator involved in maintaining Pi homeostasis in plants. Arabidopsis (Arabidopsis thaliana) PHO2 targets PHOSPHATE TRANSPORTER1 (PHT1) and PHO1 for degradation, whereas rice (Oryza sativa) PHO2 is thought to mediate PHOSPHATE TRANSPORTER TRAFFIC FACILITATOR1 degradation. However, it is unclear whether and how PHO2 is post-translationally regulated. Here, we show that in rice, the CASEIN KINASE2 (OsCK2) catalytic subunit OsCK2α3 interacts with OsPHO2 in vitro and in vivo in vascular tissues cells, and phosphorylates OsPHO2 at Ser-841. Phosphorylated OsPHO2 is degraded more rapidly than native OsPHO2 in cell-free degradation assays. OsPHO2 interacts with OsPHO1 and targets it for degradation through a multivesicular body-mediated pathway. PHO1 mutation partially rescued the pho2 mutant phenotype. Further genetic analysis showed that a nonphosphorylatable version of OsPHO2 rescued the Ospho2 phenotype of high Pi accumulation in leaves better than native OsPHO2. In addition to the previously established role of OsCK2 in negatively regulating endoplasmic reticulum exit of PHT1 phosphate transporters, this work uncovers a role for OsCK2α3 in modulating Pi homeostasis through regulating the phosphorylation status and abundance of OsPHO2 in rice.

Functions of eukaryotic mRNAs are characterized by intramolecular interactions between their ends. We have addressed the question whether 5' and 3' ends meet by diffusion-controlled encounter "through solution" or by a mechanism involving the RNA backbone. For this purpose, we used a translation system derived from Drosophila embryos that displays two types of 5'–3' interactions: Cap-dependent translation initiation is stimulated by the poly(A) tail and inhibited by Smaug recognition elements (SREs) in the 3' UTR. Chimeric RNAs were made consisting of one RNA molecule carrying a luciferase coding sequence and a second molecule containing SREs and a poly(A) tail; the two were connected via a protein linker. The poly(A) tail stimulated translation of such chimeras even when disruption of the RNA backbone was combined with an inversion of the 5'–3' polarity between the open reading frame and poly(A) segment. Stimulation by the poly(A) tail also decreased with increasing RNA length. Both observations suggest that contacts between the poly(A) tail and the 5' end are established through solution, independently of the RNA backbone. In the same chimeric constructs, SRE-dependent inhibition of translation was also insensitive to disruption of the RNA backbone. Thus, tracking of the backbone is not involved in the repression of cap-dependent initiation. However, SRE-dependent repression was insensitive to mRNA length, suggesting that the contact between the SREs in the 3' UTR and the 5' end of the RNA might be established in a manner that differs from the contact between the poly(A) tail and the cap.

VOLUME 295 (2020) PAGES 4079–4092There was an error in the abstract. “The pyridinium cation hampers uptake of OPs into the central nervous system (CNS)” should read as “The pyridinium cation hampers uptake into the central nervous system (CNS).”

Diadenosine tetraphosphate (Ap₄A) is a dinucleotide found in both prokaryotes and eukaryotes. In bacteria, its cellular levels increase following exposure to various stress signals and stimuli, and its accumulation is generally correlated with increased sensitivity to a stressor(s), decreased pathogenicity, and enhanced antibiotic susceptibility. Ap₄A is produced as a by-product of tRNA aminoacylation, and is cleaved to ADP molecules by hydrolases of the ApaH and Nudix families and/or by specific phosphorylases. Here, considering evidence that the recombinant protein YqeK from Staphylococcus aureus copurified with ADP, and aided by thermal shift and kinetic analyses, we identified the YqeK family of proteins (COG1713) as an unprecedented class of symmetrically cleaving Ap₄A hydrolases. We validated the functional assignment by confirming the ability of YqeK to affect in vivo levels of Ap₄A in B. subtilis. YqeK shows a catalytic efficiency toward Ap₄A similar to that of the symmetrically cleaving Ap₄A hydrolases of the known ApaH family, although it displays a distinct fold that is typical of proteins of the HD domain superfamily harboring a diiron cluster. Analysis of the available 3D structures of three members of the YqeK family provided hints to the mode of substrate binding. Phylogenetic analysis revealed the occurrence of YqeK proteins in a consistent group of Gram-positive bacteria that lack ApaH enzymes. Comparative genomics highlighted that yqeK and apaH genes share a similar genomic context, where they are frequently found in operons involved in integrated responses to stress signals.

IMPORTANCE Elevation of Ap₄A level in bacteria is associated with increased sensitivity to heat and oxidative stress, reduced antibiotic tolerance, and decreased pathogenicity. ApaH is the major Ap₄A hydrolase in gamma- and betaproteobacteria and has been recently proposed as a novel target to weaken the bacterial resistance to antibiotics. Here, we identified the orphan YqeK protein family (COG1713) as a highly efficient Ap₄A hydrolase family, with members distributed in a consistent group of bacterial species that lack the ApaH enzyme. Among them are the pathogens Staphylococcus aureus, Streptococcus pneumoniae, and Mycoplasma pneumoniae. By identifying the player contributing to Ap₄A homeostasis in these bacteria, we disclose a novel target to develop innovative antibacterial strategies.

Subjects with low serum HDL cholesterol levels are reported to be susceptible to diabetes, with insulin resistance believed to be the underlying pathological mechanism. Apolipoprotein M (apoM) is a carrier of sphingosine-1-phosphate (S1P), a multifunctional lipid mediator, on HDL, and the pleiotropic effects of HDL are believed to be mediated by S1P. In the current study, we attempted to investigate the potential association between apoM/S1P and insulin resistance. We observed that the serum levels of apoM were lower in patients with type 2 diabetes and that they were negatively correlated with BMI and the insulin resistance index. While deletion of apoM in mice was associated with worsening of insulin resistance, overexpression of apoM was associated with improvement of insulin resistance. Presumably, apoM/S1P exerts its protective effect against insulin resistance by activating insulin signaling pathways, such as the AKT and AMPK pathways, and also by improving the mitochondrial functions through upregulation of SIRT1 protein levels. These actions of apoM/S1P appear to be mediated via activation of S1P1 and/or S1P3. These results suggest that apoM/S1P exerts protective roles against the development of insulin resistance.

Julia Ebner infiltrated the hidden forums that extremists use. Her experiences lay bare how they hijack social media and video games to spread hate – and how to beat them

This week RPG Cast welcomes Kelley to the show! Together with Anna Marie and Chris, they uncover the truth about Vita DRPGs. They unravel the...

Director Josh Trank opens up about the bitterness and resentment he felt towards comic book movies following the critical and commercial failure of his 2015 film Fantastic Four, and praises superhero filmmakers James Gunn and Zack Snyder.

Follow our live coronavirus updates here Coronavirus: the symptoms

Piers Morgan today hit out at the Government's "spectacular failure" for doing fewer coronavirus tests than 12 days ago.

UN secretary-general Antonio Guterres has called for an "all-out effort to end hate speech globally" amid what he called a "tsunami of hate and xenophobia, scapegoating and scare-mongering" unleashed during the coronavirus pandemic.

The actor on walking the red carpet while having an allergic reaction, her controversial Calvin Klein campaign and dressing like Michael Jackson

I’m not known for wearing outfits that are as completely covered up as this. Often, you are uncomfortable on the red carpet, worried that something is going to pop out, unzip or break. There was something about this look that felt like protection and armour to me. I wore it to the 2018 CFDA fashion awards and I loved how extreme it felt: chic and strong, slightly androgynous but with a femininity to it. It came together nicely with no stress – until I was in the car, when I realised I was having some kind of allergic reaction to my makeup! One of my eyes swelled up right before I was stepping out on to the red carpet. I panicked and put on my reading glasses to camouflage the fact that one eye was almost completely shut!

As a teenager, my relationship with apparel was fraught because I never cultivated my own style. My mom and I bought everything from thrift shops – I would wear the same jeans all year and then cut them into shorts – but every time I would go on a set I would be decked out in designer clothes. There was a disconnect: clothes were just something belonging to other people that I would embody, and then shed.

Labour was embroiled in recriminations today over the leak of an internal report that apparently exonerated Jeremy Corbyn's team of failing to crack down on anti-Semitism and instead blamed his opponents for stoking up controversy to damage him.

The Speaker is presiding over his first virtual PMQs. Susannah Butter meets him (on FaceTime)

Manchester City striker Sergio Aguero is certain that Argentina team-mate Lionel Messi will stay at Barcelona – whatever happens at the Catalan club.

Lawmakers are reacting with outrage to the February killing