Malaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 (clag3) family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds and parasites can acquire resistance by silencing clag3 gene expression, thereby reducing drug uptake. We found that exposure to sub-IC50 concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in both clag3 gene expression and RBC permeability, reversing acquired resistance to the antimalarial compound blasticidin S that is transported through PSAC. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance in P. falciparum.

Earlier genetic and inhibitor studies have shown that epigenetic regulation of gene expression is critical for malaria parasite survival in multiple life stages and a promising target for new anti-malarials. We therefore evaluated the activity of 350 diverse epigenetic inhibitors against multiple stages of Plasmodium falciparum. We observed ≥90% inhibition at 10 μM for 28% of compounds against asexual blood stages and early gametocytes, of which a third retained ≥90% inhibition at 1 μM.

The charges came after police were called December 3 and told that she was damaging a Jewish neighbors apartment and defacing it with antisemitic symbols and graffiti.

Silage from the crop is one of the best feeds for the animals especially when they are three months of age and weigh more than 25kg

Coffee has been linked to changes on our DNA that affect how active certain genes are. The finding may help explain some of coffee's touted health benefits

Title: Pigs Yield Clues to Cystic Fibrosis-Related Lung Disease
Category: Health News
Created: 4/28/2010 2:10:00 PM
Last Editorial Review: 4/29/2010 12:00:00 AM

Key Points

L. donovani induces histone lysine methyltransferases/demethylases in the host.

L. donovani–induced epigenetic enzymes induce host M(IL-10) polarization.

Knockdown of epigenetic enzymes inhibited parasite multiplication in infected host.

Although substantial progress has been made in depicting the molecular pathogenesis of human immunodeficiency virus type 1 (HIV-1) infection, the comprehensive mechanism of HIV-1 latency and the most promising therapeutic strategies to effectively reactivate the HIV-1 latent reservoir to achieve a functional cure for AIDS remain to be systematically illuminated. Here, we demonstrated that piwi (P element-induced Wimpy)-like RNA-mediated gene silencing 4 (PIWIL4) played an important role in suppressing HIV-1 transcription and contributed to the latency state in HIV-1-infected cells through its recruitment of various suppressive factors, including heterochromatin protein 1α/β/, SETDB1, and HDAC4. The knockdown of PIWIL4 enhanced HIV-1 transcription and reversed HIV-1 latency in both HIV-1 latently infected Jurkat T cells and primary CD4⁺ T lymphocytes and resting CD4⁺ T lymphocytes from HIV-1-infected individuals on suppressive combined antiretroviral therapy (cART). Furthermore, in the absence of PIWIL4, HIV-1 latently infected Jurkat T cells were more sensitive to reactivation with vorinostat (suberoylanilide hydroxamic acid, or SAHA), JQ1, or prostratin. These findings indicated that PIWIL4 promotes HIV-1 latency by imposing repressive marks at the HIV-1 5' long terminal repeat. Thus, the manipulation of PIWIL4 could be a novel strategy for developing promising latency-reversing agents (LRAs).

IMPORTANCE HIV-1 latency is systematically modulated by host factors and viral proteins. During this process, the suppression of HIV-1 transcription plays an essential role in promoting HIV-1 latency. In this study, we found that PIWIL4 repressed HIV-1 promoter activity and maintained HIV-1 latency. In particular, we report that PIWIL4 can regulate gene expression through its association with the suppressive activity of HDAC4. Therefore, we have identified a new function for PIWIL4: it is not only a suppressor of endogenous retrotransposons but also plays an important role in inhibiting transcription and leading to latent infection of HIV-1, a well-known exogenous retrovirus. Our results also indicate a novel therapeutic target to reactivate the HIV-1 latent reservoir.

The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological...

Joachim Ostheim, Julia A. M. Delius, and Juan D. Delius

The visual control of pecking by pigeons (Columba livia) has latterly been thought to be restricted to the fixation stops interrupting their downward head movements because these stops prevent interference by motion blur. Pigeons were also assumed to close their eyes during the final head thrust of the peck. Here we re-examine their pecking motions using high-speed video recordings and supplementary provisions that permitted a three-dimensional spatial analysis of the movement, including measurements of their pupil diameters and eyelid slit width. The results confirm that pigeons do not close their eyes completely during the presumed optically ballistic phase of pecking. Instead their eyelids are narrowed to a slit. The width of this slit is sensitive to both the ambient illumination levels and the visual backgrounds against which seed targets have to be detected and grasped. There is also evidence of some interaction between pupil diameter and eyelid slit width. We surmise that besides being an eye-protecting reflex, the partial covering of the pupil with the eyelids may increase the depth of focus, enabling pigeons to obtain sharp retinal images of peck target items at very close range and during the beak-gape ‘handling’ of food items and occasional grit particles.

In Arabidopsis, LTR retrotransposons are activated by mutations in the chromatin gene DECREASE in DNA METHYLATION 1 (DDM1), giving rise to 21- to 22-nt epigenetically activated siRNA (easiRNA) that depend on RNA DEPENDENT RNA POLYMERASE 6 (RDR6). We purified virus-like particles (VLPs) from ddm1 and ddm1rdr6 mutants in which genomic RNA is reverse transcribed into complementary DNA. High-throughput short-read and long-read sequencing of VLP DNA (VLP DNA-seq) revealed a comprehensive catalog of active LTR retrotransposons without the need for mapping transposition, as well as independent of genomic copy number. Linear replication intermediates of the functionally intact COPIA element EVADE revealed multiple central polypurine tracts (cPPTs), a feature shared with HIV in which cPPTs promote nuclear localization. For one member of the ATCOPIA52 subfamily (SISYPHUS), cPPT intermediates were not observed, but abundant circular DNA indicated transposon "suicide" by auto-integration within the VLP. easiRNA targeted EVADE genomic RNA, polysome association of GYPSY (ATHILA) subgenomic RNA, and transcription via histone H3 lysine-9 dimethylation. VLP DNA-seq provides a comprehensive landscape of LTR retrotransposons and their control at transcriptional, post-transcriptional, and reverse transcriptional levels.

PF06821497 has been identified as an orally available small-molecule enhancer of zeste homolog 2 inhibitor. The objectives of the present study were to characterize pharmacokinetic-pharmacodynamic-disease relationships of PF06821497 in xenograft mouse models with diffuse large B-cell lymphoma (Karpas422). An indirect-response model reasonably fit dose-dependent pharmacodynamic responses [histone H3 on lysine 27 (H3K27) me3 inhibition] with an unbound EC₅₀ of 76 nM, whereas a signal-transduction model sufficiently fit dose-dependent disease responses (tumor growth inhibition) with an unbound tumor stasis concentration (T_sc) of 168 nM. Thus, effective concentration for 70% of maximal effect (EC₇₀) for H3K27me3 inhibition was roughly comparable to T_sc, suggesting that 70% H3K27me3 inhibition could be required for tumor stasis. Consistently, an integrated pharmacokinetic-pharmacodynamic-disease model adequately describing tumor growth inhibition also suggested that ~70% H3K27me3 inhibition was associated with tumor stasis. Based on these results, we would propose that an EC₇₀ estimate for H3K27me3 inhibition corresponding to tumor stasis could be considered a minimum target efficacious concentration of PF06821497 in cancer patients.

SIGNIFICANCE STATEMENT

Using a mathematical modeling approach, the quantitative relationships of an orally available anticancer small-molecule enhancer of zeste homolog 2 inhibitor, PF06821497, were characterized among pharmacokinetics, pharmacodynamic biomarker inhibition, and disease responses in nonclinical xenograft models with diffuse large B-cell lymphoma. The modeling results suggest that >70% histone H3 on lysine 27 (H3K27) me3 inhibition would be required for tumor stasis (i.e., 100% tumor growth inhibition). Accordingly, we would propose that an effective concentration for 70% of maximal effect estimate for H3K27me3 inhibition could be considered a minimum target efficacious concentration of PF06821497 in cancer patients.

Low-dose adjuvant epigenetic therapy (AET) reduced metastasis and promoted survival in mouse models.

Cruciferous vegetables have been of special interest due to the rich presence of bioactive compounds such as sulforaphane which show promising potential on cancer prevention and therapy as an epigenetic dietary strategy. Abnormal epigenetic alteration as one of the primary contributors to tumor development is closely related to breast cancer initiation and progression. In the present study, we investigated the effect of dietary broccoli sprouts (BSp), a common cruciferous vegetable, on prevention of estrogen receptor (ER)-negative mammary tumors at three different temporal exposure windows using a spontaneous breast cancer mouse model. Our findings indicate that maternal BSp treatment exhibited profound inhibitory and preventive effects on mammary cancer formation in the nontreated mouse offspring. The BSp diet administered to adult mice also showed suppressive effects on mammary cancer but was not as profound as the maternal BSp preventive effects. Moreover, such protective effects were linked with differentially expressed tumor- and epigenetic-related genes, as well as altered global histone acetylation, DNA methylation, and DNA hydroxymethylation levels. We also found that the expression changes of tumor-related genes were associated with the levels of histone methylation of H3K4 and H3K9 in the gene promoter regions. In addition, BSp-enriched sulforaphane was shown to increase protein expression of tumor suppressor genes such as p16 and p53 and inhibit the protein levels of Bmi1, DNA methyltransferases, and histone deacetylases in ERα-negative breast cancer cell lines. Collectively, these results suggest that maternal exposure to key phytochemicals may contribute to ER-negative mammary tumor prevention in their offspring through epigenetic regulations.

Although ample evidence indicates that immune cell homeostasis is an important prognostic outcome determinant in patients with cancer, few studies have examined whether it also determines cancer risk among initially healthy individuals. We performed a case–cohort study including incident cases of breast (n = 207), colorectal (n = 111), lung (n = 70), and prostate (n = 201) cancer as well as a subcohort (n = 465) within the European Prospective Investigation into Cancer and Nutrition-Heidelberg cohort. Relative counts of neutrophils, monocytes, and lymphocyte sublineages were measured by qRT-PCR. HRs and 95% confidence intervals were used to measure the associations between relative counts of immune cell and cancer risks. When relative counts of immune cell types were taken individually, a significant positive association was observed between relative counts of FOXP3+ regulatory T cells (Tregs) and lung cancer risk, and significant inverse associations were observed between relative CD8+ counts and risks of lung and breast cancer (overall and ER+ subtype). Multivariable models with mutual adjustments across immune markers showed further significant positive associations between higher relative FOXP3+ T-cell counts and increased risks of colorectal and breast cancer (overall and ER− subtype). No associations were found between immune cell composition and prostate cancer risk. These results affirm the relevance of elevated FOXP3+ Tregs and lower levels of cytotoxic (CD8+) T cells as risk factors for tumor development.Significance:This epidemiologic study supports a role for both regulatory and cytotoxic T cells in determining cancer risk among healthy individuals.See related commentary by Song and Tworoger, p. 1801

Pigeons feathers are remarkably complex and understanding how they work has led to the first robot that flies like a pigeon, dubbed PigeonBot

Coffee has been linked to changes on our DNA that affect how active certain genes are. The finding may help explain some of coffee's touted health benefits

The containment practices of outbreaks past could have lessons for modern epidemics

We're used to thinking of DNA as a rigid blueprint. Karissa Sanbonmatsu researches how our environment affects the way DNA expresses itself—especially when it comes to sex and gender.

What’s hot and what’s not in fashion this week

Kaia As in Gerber, who joins the likes of Alexa and Jane Birkin – she now has a bag named after her, by Saint Laurent. Style icon status: confirmed.

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Due to popular demand, M&S has created Percy Pig-flavoured ice cream

A Vietnamese man carrying four kilograms of pork-filled mooncakes has been turned away from Sydney Airport after failing to declare he was carrying food.

Big drugs companies have long favoured outsourcing clinical trials to poor countries with lax regulations to cut costs and maximise profit

• Coronavirus latest updates

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Last week, in Oxford, the first volunteers in the first European human trial were injected with a potential coronavirus vaccine. At the same time, Pakistan’s National Institute of Health received an offer from the Chinese pharmaceutical firm Sinopharm International Corp to take part in a trial of another potential coronavirus vaccine.

Related: Africa's Covid-19 research must be tailored to its realities – by its own scientists | Monique Wasunna

In India, many poor people were recruited to HIV trials without knowing that they were taking part in experiments

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“This settlement allows the Department of Agriculture and African-American farmers to focus on the future, and brings us one step closer to giving these farmers a chance to have their claims heard,” said Attorney General Holder.

And with that comes real fear for the environment.

The premature deaths are linked to excessive breeding.

Image credit: Duke University Duke University's Bleed Blue, Live Green campaign created a clamor of attention from fans wanting to get hold of a limited edition shirt. So much so, we had to post a follow up on where to find the green Duke shirts. I'm

Pigeons live large in these big artworks that celebrate the remarkable qualities of these overlooked birds.

If shrimp can be happy on a farm, why not pigs? For all the weekday vegetarians and omnivores out there, here is a way to obtain sausages, chorizos and bacon in a friendly way. First of all, plenty of indoor and outdoor space

more images below Matteria, good design+smart materials online store, suggest a spicy Christmas this year, without forgetting the environment. Apart from the gorgeous cork advent candle holder, the cosy Finnish red felt slippers, and giftbags to spoil

Posted by Victoria Strauss for Writer Beware®

The internet and social media have transformed writer/agent/publisher interactions in many ways, one of which is the proliferation of Twitter pitch events, such as #PitMad, #DVPit, and others.

While no online innovation has (so far) managed to supplant the traditional query-and request route, these events do attract plenty of reputable agents and publishers--unlike other purported shortcuts (*cough*Publishizer*cough*). However, inevitably, they are also stalked by marginals, amateurs, and even scammers.

For instance, Eliezer Tristan Publishing, which charged a $500 fee and went out of business just months after opening up, haunted #PitMad. Ditto for GenZ publishing, which charges authors $2,500. Burchette and Ferguson, a brand-new publisher staffed by people with zero relevant experience, participated in pitch events before they even launched (and went out of business shortly thereafter).

Then there's this:


I've gotten many, many other questions about approaches by dubious companies and individuals as a result of pitch events. All in all, therefore, it pays to be careful, and if you haven't heard of an individual or publisher who approaches you, to research them before responding. (You can contact me; I may have heard something.)

Which leads me to the subject of today's post. I might not normally devote an entire blog post to one marginal agent, but this one is such an egregious example, and seems to be so active on social media--including #PitMad--that I think she's worth a special feature.

Pigeon House Literary Agency launched just this past February. It's run by Druella Burhan, whose resume includes none (zero, zip) of the relevant background experience you typically want to see from a new literary agent--such as a professional writing resume, or having previously worked for a reputable agency or publisher.


The lofty claims Burhan does make are either unverifiable, or provably false. For instance, here's Harvard Medical's publication on its 2011 MD-PhD graduates. Surprise! There's no mention of Druella Burhan.

Here's some of Burhan's agenting philosophy:


The logo (for lack of a better word) at the top of this post provides a preview of the rest of the Pigeon House site (a Wix freebie), which is amateurishly formatted and clearly not proofread (several pages have fully-justified text, with words cut off at the end of lines--I mean, it's a Wix freebie, it's not like you have to be an expert to get it right) and rife with typos, grammatical errors, and bizarre word use. For instance,


That's bad, but here's what it originally looked like. Burhan changed it shortly after I tweeted about it:


There's more: the Who We Are page, which bafflingly proclaims that the agency will "strive to bring a supreme appealingness and picturesque style of books from darkness to life"; the Foreign Rights page, which erroneously cautions writers that "If a literary agent does not agree to take you on as an international client/author, you will not be able to sell books overseas"; the Referrals page, where Burhan bizarrely invites other agents to send her clients. And here's the contract she is sending out, which includes the same formatting/proofreading errors as her website, and is really just an embarrassment.

It's a perfect carnival of amateurism.

Am I being mean here? Maybe, but before you whip out the "everyone has to start somewhere" argument, consider Burhan's false claims about herself and her aggressive use of social media to recruit clients despite her obvious ignorance and complete lack of relevant qualifications (I first heard of her because she was trolling on Reddit, and she is actively inviting queries on her Twitter feed).

The damage an amateur agent can do is considerable--squandering clients' chances with substandard submissions, submitting to disreputable or incompetent publishers, inadequately understanding publishing contract language and therefore not capable of effectively negotiating it. An amateur agent may not drain a writer's bank account the way a scammer would, but the bottom line isn't that different: no sale, and lots of wasted time.

Writer Beware.

Roko no

Coffee has been linked to changes on our DNA that affect how active certain genes are. The finding may help explain some of coffee's touted health benefits

A potentially fatal viral infection that affects pigs can readily find its way into human cells, say scientists, raising concerns about the potential for outbreaks that threaten our health. Researchers at Ohio State University in the US and Utrecht University in the Netherlands collaborated to better understand the new virus and its potential reach.

The study, published in the in the journal PNAS, is the first to point to possible transmission of this virus between species. Porcine deltacoronavirus was first identified in 2012 in pigs in China, but it was not associated with disease. It was first detected in the US in 2014 during a diarrhea outbreak in Ohio pigs and has since been detected in various countries. Young, infected pigs experience acute diarrhea and vomiting. The disease can be fatal.

As of yet, no human cases have been documented, but scientists are concerned about the possibility. "Before it was found in pigs ¿ including in the Ohio outbreak ¿ it had only been found in various birds," said Linda Saif, a professor in Ohio State University in the US. "We're very concerned about emerging coronaviruses and worry about the harm they can do to animals and their potential to jump to humans," said Saif.

Emergence of the new virus is especially worrisome to veterinary and public-health experts because of its similarity to the life-threating viruses responsible for SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) outbreaks. The potential for a virus to jump from one species to another is highly dependent on its ability to bind to receptors on the cells of the animal or human, said Scott Kenney, an assistant professor at Ohio State University.

"A receptor is like a lock in the door. If the virus can pick the lock, it can get into the cell and potentially infect the host," he said. The study looked at a particular cellular receptor called aminopeptidase N that the researchers suspected might be involved. "We know from other coronaviruses that these receptors on the cells are used and that they're found in the respiratory and digestive tracts of a number of different animals," Kenney said.

"Now we know that this new virus could go into cells of different species, including humans," he added. For now, the only known infection in humans and other species is in the laboratory, using cultured cells. The study confirmed that the virus could bind to human cells, and to cells from cats and chickens. "This doesn't prove that this virus can infect and cause disease in these other species, but that's something we obviously want to know," Saif said.

The next step in understanding this virus and its potential for human infection will be a study looking for antibodies in the blood that would serve as evidence that the pig virus has already infected people.

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Highlights: Unique surgery leaves a 100kg man with two beating hearts by a technique called the 'Piggyba

Flavonoid quercetin intake can significantly decrease blood pressure, reports a new study. The findings of the study are published in the journal iNutrition Reviews/i.

Exports of (bop) - Dyes and Pigments, Petrochemic in Canada decreased to 263.60 CAD Million in March from 266.30 CAD Million in February of 2020. Exports of (bop) - Dyes and Pigments, Petrochemic in Canada averaged 211.17 CAD Million from 1988 until 2020, reaching an all time high of 455.80 CAD Million in July of 2008 and a record low of 46 CAD Million in June of 1992. This page includes a chart with historical data for Canada Exports of (bop) - Dyes And Pigments, Petrochemic.

Exports of Pigment in Switzerland increased to 130.66 CHF Million in March from 121.49 CHF Million in February of 2020. Exports of Pigment in Switzerland averaged 124.08 CHF Million from 2014 until 2020, reaching an all time high of 173.39 CHF Million in March of 2017 and a record low of 98.93 CHF Million in December of 2019. This page includes a chart with historical data for Switzerland Exports of Pigment.

Iggy Azalea is at war with the British cartoon character Peppa Pig.

Iggy Azalea has expressed fears that Peppa Pig is going to outsell her comeback album on the charts.

Fancy singer Iggy Azalea had beef with cartoon character Peppa Pig back in June.

Every now and again - but not often - a player will make the brave decision to move from his current club to their biggest rivals. Here, Sportsmail takes a look at ten transfers between rival clubs.

WARNING GRAPHIC CONTENT Jenny was walking through the Beelu National Park, around 40km east of Perth on Monday when she saw something lying inside a cage.