The histone demethylase JMJD1A plays a key functional role in spermatogenesis, sex determination, stem cell renewal, and cancer via removing mono- and di-methyl groups from H3K9 to epigenetically control gene expression. However, its role in prostate cancer progression remains unclear. Here, we found JMJD1A was significantly elevated in prostate cancer tissue compared with matched normal tissue. Ectopic JMJD1A expression in prostate cancer cells promoted proliferation, migration, and invasion in vitro, and tumorigenesis in vivo; JMJD1A knockdown exhibited the opposite effects. Mechanically, we revealed that JMJD1A directly interacted with the Snail gene promoter and regulated its transcriptional activity, promoting prostate cancer progression both in vitro and in vivo. Furthermore, we found that JMJD1A transcriptionally activated Snail expression via H3K9me1 and H3K9me2 demethylation at its special promoter region. In summary, our studies reveal JMJD1A plays an important role in regulating proliferation and progression of prostate cancer cells though Snail, and thus highlight JMJD1A as potential therapeutic target for advanced prostate cancer.

Decreased release of palmitic acid methyl ester (PAME), a vasodilator, from perivascular adipose tissue (PVAT) might contribute to hypertension pathogenesis. However, the PAME biosynthetic pathway remains unclear. In this study, we hypothesized that PAME is biosynthesized from palmitic acid (PA) via human catechol-O-methyltransferase (COMT) catalysis and that decreased PAME biosynthesis plays a role in hypertension pathogenesis. We compared PAME biosynthesis between age-matched normotensive Wistar Kyoto (WKY) rats and hypertensive spontaneously hypertensive rats (SHRs) and investigated the effects of losartan treatment on PAME biosynthesis. Computational molecular modeling indicated that PA binds well at the active site of COMT. Furthermore, in in vitro enzymatic assays in the presence of COMT and S-5'-adenosyl-L-methionine (AdoMet), the stable isotope [¹³C₁₆]-PA was methylated to form [¹³C₁₆]-PAME in incubation medium or the Krebs–Henseleit solution containing 3T3-L1 adipocytes or rat PVAT. The adipocytes and PVATs expressed membrane-bound (MB)-COMT and soluble (S)-COMT proteins. [¹³C₁₆]-PA methylation to form [¹³C₁₆]-PAME in 3T3-L1 adipocytes and rat PVAT was blocked by various COMT inhibitors, such as S-(5'-adenosyl)-L-homocysteine, adenosine-2',3'-dialdehyde, and tolcapone. MB- and S-COMT levels in PVATs of established SHRs were significantly lower than those in PVATs of age-matched normotensive WKY rats, with decreased [¹³C₁₆]-PA methylation to form [¹³C₁₆]-PAME. This decrease was reversed by losartan, an angiotensin II (Ang II) type 1 receptor antagonist. Therefore, PAME biosynthesis in rat PVAT is dependent on AdoMet, catalyzed by COMT, and decreased in SHRs, further supporting the role of PVAT/PAME in hypertension pathogenesis. Moreover, the antihypertensive effect of losartan might be due partly to its increased PAME biosynthesis.

Covalent chemical modifications of cellular RNAs directly impact all biological processes. However, our mechanistic understanding of the enzymes catalyzing these modifications, their substrates and biological functions, remains vague. Amongst RNA modifications N⁶-methyladenosine (m⁶A) is widespread and found in messenger (mRNA), ribosomal (rRNA), and noncoding RNAs. Here, we undertook a systematic screen to uncover new RNA methyltransferases. We demonstrate that the methyltransferase-like 5 (METTL5) protein catalyzes m⁶A in 18S rRNA at position A₁₈₃₂. We report that absence of Mettl5 in mouse embryonic stem cells (mESCs) results in a decrease in global translation rate, spontaneous loss of pluripotency, and compromised differentiation potential. METTL5-deficient mice are born at non-Mendelian rates and develop morphological and behavioral abnormalities. Importantly, mice lacking METTL5 recapitulate symptoms of patients with DNA variants in METTL5, thereby providing a new mouse disease model. Overall, our biochemical, molecular, and in vivo characterization highlights the importance of m⁶A in rRNA in stemness, differentiation, development, and diseases.

ABSTRACTThe Standard Days Method (SDM), a modern fertility awareness-based family planning method, has been introduced in 30 countries since its development in 2001. It is still unclear to what extent the SDM was mainstreamed within the family planning method mix, particularly in low- and middle-income country (LMIC) settings, where the SDM had been introduced by donors and implementing partners. This review of implementation science publications on the SDM in LMICs first looked at community pilot studies of the SDM to determine the acceptability of the method; correct use and efficacy rates; demographics of users; and changes to contraceptive prevalence rates and family planning behaviors, especially among men and couples. Then, we examined the status of the SDM in the 16 countries that had attempted to scale up the method within national family planning protocols, training, and service delivery. At the community level, evidence demonstrated a high level of acceptability of the method; efficacy rates comparable to the initial clinical trials; diversity in demographic characteristics of users, including first-time or recently discontinued users of family planning; increased male engagement in family planning; and improved couple's communication. Nationally, few countries had scaled up the SDM due to uneven stakeholder engagement, lackluster political will, and competing resource priorities. Results of this review could help policy makers determine the added value of the SDM in the contraceptive method mix and identify potential barriers to its implementation moving forward.

Yan Xing, Hongling Wei, Xiumei Xiao, Zekun Chen, Hui Liu, Xiaomei Tong, and Wei Zhou

Infants with intrauterine growth retardation (IUGR) have a high risk of developing bronchial asthma in childhood, but the underlying mechanisms remain unclear. This study aimed to disclose the role of vascular non-inflammatory molecule 1 (vannin-1, encoded by the Vnn1 gene) and its downstream signaling in IUGR asthmatic mice induced by ovalbumin. Significant histological alterations and an increase of vannin-1 expression were revealed in IUGR asthmatic mice, accompanied by elevated methylation of Vnn1 promoter regions. In IUGR asthmatic mice, we also found (i) a direct binding of HNF4α and PGC1α to Vnn1 promoter by ChIP assay; (ii) a direct interaction of HNF4α with PGC1α; (iii) upregulation of phospho-PI3K p85/p55 and phospho-Akt^Ser473 and downregulation of phospho-PTENT^yr366, and (iv) an increase in nuclear NFB p65 and a decrease in cytosolic IB-α. In primary cultured bronchial epithelial cells derived from the IUGR asthmatic mice, knockdown of Vnn1 prevented upregulation of phospho-Akt^Ser473 and an increase of reactive oxygen species (ROS) and TGF-β production. Taken together, we demonstrate that elevated vannin-1 activates the PI3K/Akt/NFB signaling pathway, leading to ROS and inflammation reactions responsible for asthma occurrence in IUGR individuals. We also disclose that interaction of PGC1α and HNF4α promotes methylation of Vnn1 promoter regions and then upregulates vannin-1 expression.

BackgroundPolycystic ovary syndrome (PCOS) is a common lifelong metabolic condition with serious associated comorbidities. Evidence points to a delay in diagnosis and inconsistency in the information provided to women with PCOS.AimTo capture women’s experiences of how PCOS is diagnosed and managed in UK general practice.Design and settingThis was a mixed-methods study with an online questionnaire survey and semi-structured telephone interviews with a subset of responders.MethodAn online survey to elicit women’s experiences of general practice PCOS care was promoted by charities and BBC Radio Leicester. The survey was accessible online between January 2018 and November 2018. A subset of responders undertook a semi-structured telephone interview to provide more in-depth data.ResultsA total of 323 women completed the survey (average age 35.4 years) and semi-structured interviews were conducted with 11 women. There were five key themes identified through the survey responses. Participants described a variable lag time from presentation to PCOS diagnosis, with a median of 6–12 months. Many had experienced mental health problems associated with their PCOS symptoms, but had not discussed these with the GP. Many were unable to recall any discussion about associated comorbidities with the GP. Some differences were identified between the experiences of women from white British backgrounds and those from other ethnic backgrounds.ConclusionFrom the experiences of the women in this study, it appears that PCOS in general practice is not viewed as a long-term condition with an increased risk of comorbidities including mental health problems. Further research should explore GPs’ awareness of comorbidities and the differences in PCOS care experienced by women from different ethnic backgrounds.

Background:

Historically, some chiropractors have been critical of vaccination, and this has been the subject of recent media attention in Canada. We explored the association between media attention and public dissemination of vaccination information on Canadian chiropractors’ websites.

Addition of sodium bicarbonate (NaHCO₃) to standard antimicrobial susceptibility testing medium reveals certain methicillin-resistant Staphylococcus aureus (MRSA) strains to be highly susceptible to β-lactams. We investigated the prevalence of this phenotype (NaHCO₃ responsiveness) to two β-lactams among 58 clinical MRSA bloodstream isolates. Of note, ~75% and ~36% of isolates displayed the NaHCO₃ responsiveness phenotype to cefazolin (CFZ) and oxacillin (OXA), respectively. Neither intrinsic β-lactam MICs in standard Mueller-Hinton broth (MHB) nor population analysis profiles were predictive of this phenotype. Several genotypic markers (clonal complex 8 [CC8]; agr I and spa t008) were associated with NaHCO₃ responsiveness for OXA.

Tedizolid (TZD) and daptomycin (DAP) were assessed in a rat endocarditis model against Enterococcus faecalis, Enterococcus faecium (resistant to vancomycin and ampicillin), and Staphylococcus aureus. As a monotherapy, TZD for 5 days was not effective in a comparison with no-treatment controls, while DAP for 5 days was significantly effective against these bacteria. Step-down therapy (DAP for 3 days followed by TZD for 2 days) was as effective as DAP for 5 days and was comparable to 3 days of DAP plus ceftriaxone against all bacteria and to 3 days of DAP plus gentamicin against E. faecalis OG1RF.

A new method called MicroMapping can identify nanoscale protein–protein interactions on live cells.

Background:

Relatives of patients with bladder cancer have been shown to be at increased risk for kidney, lung, thyroid, and cervical cancer after correcting for smoking-related behaviors that may concentrate in some families. We demonstrate a novel approach to simultaneously assess risks for multiple cancers to identify distinct multicancer configurations (multiple different cancer types that cluster in relatives) surrounding patients with familial bladder cancer.

High-throughput sequencing methods have created exciting opportunities to explore the regulatory landscape of the entire genome. Here we introduce methods to characterize the genomic locations of bound proteins, open chromatin, and sites of DNA–DNA contact in Xenopus embryos. These methods include chromatin immunoprecipitation followed by sequencing (ChIP-seq), a combination of DNase I digestion and sequencing (DNase-seq), the assay for transposase-accessible chromatin and sequencing (ATAC-seq), and the use of proximity-based DNA ligation followed by sequencing (Hi-C).

BACKGROUND AND PURPOSE:

Conventional nonadhesive liquid embolic agents currently are the criterion standard for endovascular embolization of cerebral AVMs. However, inadequate distal penetration into the nidus and unstable proximal plug formation are the major limitations of this approach and of the currently available embolic materials. The aim of this study was to evaluate the hypothetic efficacy of combining liquid embolic agents with different properties and viscosities for use in endovascular embolization of cerebral AVMs.

SAVANNAH, Georgia—Allegations Friday that a Georgia district attorney blocked police officers from arresting the killers of 25-year-old Ahmaud Arbery were just the latest blow to a local law enforcement apparatus that has been rocked by a series of troubling and deadly scandals.

Brunswick DA Jackie Johnson’s office allegedly prevented the Glynn County Police Department from arresting Travis and Gregory McMichael in connection with the shooting death of Arbery, an unarmed black man, in late February, the Atlanta Journal-Constitution reported. Johnson has recused herself from that case. But one Glynn County commissioner suggested she personally intervened in early plans to make arrests “to protect her friend” Gregory McMichael. McMichael was a former cop and investigator in the Brunswick DA’s office for 25 years who had reportedly investigated Arbery in the past. 

It is far from the first time the office—and local law enforcement more generally—had come under scathing scrutiny. 

Read more at The Daily Beast.

Given the overall strength of this top six, it’s surprising how messy these one-queen shows turn out to be.

A new computational method for assigning the donor in single cell RNA sequencing experiments provides an accurate way to unravel data from a mixture of people. The Souporcell method could help study how genetic variants in different people affect which genes are expressed during infection or response to drugs, and help research into transplants, personalized medicine and malaria.

He’s played a revolutionary hero, a horny teen – now Gael García Bernal is a reptilian choreographer in Ema, and locked down in Mexico city. Just don’t ask him to move to LA when all this is over

At the start of the century, the director Alfonso Cuarón was casting Y Tu Mamá También, the bawdy but plangent road movie he had written with his brother Carlos about two oversexed Mexican teenagers, the wealthy Tenoch and his poorer, grungier friend Julio. “Alfonso called me very excitedly,” recalls Carlos Cuarón. “He said: ‘I know who’s going to play Julio! I’ve seen him in Alejandro’s movie.’” Alejandro González Iñárritu, that is, whose ferocious dog-fighting drama Amores Perros was about to be released. “I said: ‘No, no, I’ve found Julio; I saw the perfect actor in this short film, De Tripas, Corazón. He’s incredible: his eyes, the way he manages silence ...’”

Eventually, the brothers realised they were talking about the same person: Gael García Bernal, who was then just 21. The son of theatre actors, he had become a star in his early teens on the Mexican soap opera El Abuelo y Yo (Grandpa and I) before decamping to London to study at the Royal Central School of Speech and Drama. Iñárritu plucked him out mid-term for Amores Perros and he stole that movie as the twitchy-hipped tearaway who was every bit as feral as his champion rottweiler. His mutable features could switch from cherubic to lupine to gravely smouldering; his nerve endings felt exposed like frayed electrical wires.

Trump administration whistleblower Rick Bright teared up while ripping the Trump's response to the coronavirus: "We could've done something and we didn't."

While Jackbox clearly owes a great deal of its current popularity to the shelter-in-place policies, they've also been honing their craft for years. It's worth looking at what makes them work.

The grime star is convinced the highly-contagious disease was deliberately introduced in China as a “control method” and a way to kill huge numbers within society.

Scientists have presented a non-contact method for detecting the state of charge and any defects in lithium-ion batteries.

Follow our live Covid-19 updates HERE Coronavirus: The symptoms

Police have launched an investigation after an officer was filmed threatening to "make something up" in order to arrest a man.

'Reinvention' of ceramics firing process could be used by artificial intelligence to create new materials with wide range of possible applications

The new 'Hercules' may not even be a musical, according to the Russo Brothers.

As authors from Chaucer to Hollinghurst have shown, sex reveals our emotions, instincts and morals. The question is not why write about sex, claims author Garth Greenwell, it’s why write about anything else?

There is a widely held belief, among English-language writers, that sex is impossible to write about well – or at least much harder to write about well than anything else. I once heard a wonderful writer, addressing students at the Iowa Writers’ Workshop, say that her ideal of a sex scene would be the sentence: “They sat down on the sofa …” followed by white space. This is a prejudice I can’t understand. One of the glories of being a writer in English is that two of our earliest geniuses, Chaucer and Shakespeare, wrote of the sexual body so exuberantly, claiming it for literature and bringing its vocabulary – including all those wonderful four-letter words – into the texture of our literary language. This is a gift not all languages have received; a translator once complained to me that in her language there was only the diction of the doctor’s office or of pornography, neither of which felt native to poetry.

More than this, surely it is absurd to claim that a central activity of human life, a territory of feeling and drama, is off-limits to art. Sex is a uniquely useful tool for a writer, a powerful means not just of revealing character or exploring relationships, but of asking the largest questions about human beings.

Brooker says he's coping with the crisis "far better than I would have anticipated"

Mikel Arteta insists summer signing Kieran Tierney will bring Arsenal "something special" when the Premier League restarts following its suspension due to the coronavirus pandemic.

Cross-laminated timber draws praise -- and skeptics.

Vanessa Bryant opened a card from her late husband Kobe on her birthday. "It gave me something to look forward to today," she writes.

A new study has found the oil and gas industry has had a far worse impact on the climate than previously believed.

What do Barrie Cassidy, Annika Smethurst, Tony Wright and Sean Murphy have in common? They all got their start on country newspapers. And recent mass closures have had a visceral impact on each of them.

Energy and Commerce Chairman Frank Pallone, Jr. (D-NJ) and Ways and Means Chairman Richard E. Neal (D-MA) sent a letter to Health and Human Services (HHS) Secretary Alex Azar and Centers for Medicare & Medicaid Services (CMS) Administrator Seema Verma today raising a series of concerns over the methodology used to distribute and the lack of transparency into how COVID-19 relief funds and loans for health care providers are being spent.  “We write to raise serious concerns about the Provider Relief Fund and the Accelerated and Advance Payment Programs,” Pallone and Neal wrote.  “With respect to each, we are concerned about the lack of transparency with Congress and the American people about how funds are being spent or loans are being made.  We also have grave concerns regarding the methodology being used to distribute $175 billion Congress appropriated for the Provider Relief Fund.” The Chairmen’s letter documents concerns with how the programs are being run, in particular the Administration’s methodologies for distributing funding that has shortchanged a number of critical providers and makes clear that more transparency is needed for Congress to accurately assess the ongoing needs of health care providers as the COVID-19 crisis unfolds. “The Administration’s efforts to establish the Provider Relief Fund to date has been at best, a series of missteps, and at worst, a disregard of Congress’ intent for the program,” Pallone and Neal continued in their letter. Pallone and Neal wrote that when Congress passed the CARES Act, it was clear that the funding provided to HHS for the Provider Relief Fund was for the express purpose, “to prevent, prepare for, and respond to coronavirus.”  The two Chairs voiced concern that some of the funding formulas adopted to date fail to target funding based on the statutory framework relating to COVID-19 driven costs.  In fact, the Chairs write that the level of funding appears to be, “completely disconnected from need.” The Chairmen requested an immediate response from HHS regarding documents and information pertaining to the Provider Relief Fund and the Accelerated and Advanced Payment Program.  Pallone and Neal also wrote that if HHS is unable to immediately provide the information, it should provide a timeline of when the Committees would receive the requested information. While recognizing the incredible demands on the Department at this difficult time, the Chairmen emphasized that, “This crisis demands that we work swiftly and based on the best data available.  Currently, despite repeated requests, this Administration has prevented Congress from obtaining the data that the Department has available on funding for our health care system, data that is necessary to inform near future legislation.  We look forward to receiving this information so that we can conduct the business the American people expect of us.  We look forward to having you join us at the earliest possible date in each of our Committees to discuss these and other COVID-related issues.” To read the full letter, click HERE. ###

Pharmacists will be allowed to give out medication to patients who have already been receiving it

Pharmacists are to be allowed to hand out a range of super-strength medicines, including the heroin substitute methadone, without prescription during the Covid-19 crisis, under emergency measures that official drug policy advisers have warned could trigger a spike in drug misuse.

The Advisory Council for Misuse of Drugs (ACMD), which makes recommendations to the government on the control of dangerous drugs, was asked by the home secretary to consider the risks of lifting restrictions on certain substances controlled under the Misuse of Drugs Act.

Methodist Hospital in Houston has agreed to pay the United States $9.99 million to settle allegations that it defrauded the federal Medicare program. The settlement resolves allegations that Methodist improperly increased charges to Medicare patients in order to obtain enhanced reimbursement from Medicare.

The United States has sued four Certified Public Accounts (CPA), 27 tax preparers and one other individual, seeking to bar them from promoting an alleged tax scam involving bogus income tax credits claimed for sham sales of methane from landfills.

A federal judge in Tampa, Fla., has permanently barred eight men – including five tax preparers and two Certified Public Accountants (CPA) – from promoting an alleged tax fraud scheme involving bogus income tax credits.

A federal judge in Beaumont, Texas, has permanently barred 12 people from promoting an alleged tax fraud scheme involving bogus income tax credits.

The Justice Department has reached an agreement with Stonecleave Village Association, Inc. to resolve allegations that Stonecleave engaged in a pattern or practice of familial status discrimination by imposing excessive fines on residents with children for alleged violations of Stonecleave’s rules.

The Justice Department today announced that it has filed a lawsuit alleging that Air Methods Corp. and LifeMed Alaska LLC willfully violated the Uniformed Services Employment and Reemployment Rights Act of 1994 (USERRA) by discriminating against and failing to reemploy Chief Warrant Officer Third Class Jonathon L. Goodwin of Wasilla, Alaska.

A federal court in Beaumont, Texas, has permanently barred two men from promoting an alleged tax fraud scheme involving bogus tax credits for the production of methane gas from landfills.

The Justice Department today announced that it has resolved a lawsuit alleging that Air Methods Corp. and LifeMed Alaska, LLC willfully violated the Uniformed Services Employment and Reemployment Rights Act of 1994 (USERRA) by discriminating against and failing to reemploy Chief Warrant Officer Third Class Jonathon L. Goodwin of Wasilla, Alaska. The suit was filed in federal district court in Alaska.

Attorney General Eric Holder and Director of National Intelligence James Clapper released the following joint statement Monday.