La enseñanza bíblica en profundidad de John MacArthur lleva la verdad transformadora de la Palabra de Dios a millones de personas cada día.

La enseñanza bíblica en profundidad de John MacArthur lleva la verdad transformadora de la Palabra de Dios a millones de personas cada día.

La enseñanza bíblica en profundidad de John MacArthur lleva la verdad transformadora de la Palabra de Dios a millones de personas cada día.

La enseñanza bíblica en profundidad de John MacArthur lleva la verdad transformadora de la Palabra de Dios a millones de personas cada día.

The government has decided to give support to North Korea worth US$8 million in programs helping its vulnerable people including children and pregnant women indirectly through international organizations. It, however, has not decided when to start sending money and exactly how. This is interpreted as a choice to deflect criticism that it is undertaking an aid project at a time when North Korea is causing an international storm by launching a series of missile tests. On September 21, the gover...

Alger -Huit (8) personnes sont...

The Netherlands Authority for Consumers and Markets (the “ACM”) has ruled that arrangments concerning a new form of sustainably reared chicken, known as the ‘Chicken of Tomorrow’, which lead to other forms of chicken being re...

On Thursday, 7 May, the IOPC launched an independent investigation into the full circumstances of an incident in Haringey on 4 May in which a man sustained serious injuries. We fully support this investigation and continue to co-operate with the IOPC's...

Musasizi, who was riding a motorcycle, had come to pick up Nagasha who was in Byansi Clinic located along Elgin Street in Masaka town, for a pregnancy test

[Dalsan Radio] The African Union Mission in Somalia, AMISOM, expresses its heartfelt condolences to the families of those who perished in the plane crash of 4th May, 2020. The aircraft which left Baidoa, had six people on board and was approaching Bardale, south of Somalia and 300km northwest of the capital Mogadishu when it crashed.

In the Halle attack, two people were killed near the synagogue when the alleged gunman could not enter the building.

Commercial Court rules that St Philip's Hospital owner Frank Portelli cannot decide the hospital's fate on his own as HSBC Bank seeks repayment of €11.5 million in loans, appoints two provisional administrators

Kylie Moore-Gilbert is among the many foreigners held in Iran's notorious Evin prison on espionage charges.

MANSEHRA: Two persons were killed and three others sustained injuries when a pickup vehicle plunged into a ravine in Shahshi Gigal area of Lower Kohistan on Friday.The vehicle was on way to Kokai from Gijal when it met to accident while negotiating a sharp turn.The local rushed to scene and...

WeChat, the Chinese messaging app, is systematically monitoring the content sent by international users to build up its censorship algorithms applied against accounts registered in China, a new study has found.Researchers at Citizen Lab, an academic research lab at the University of Toronto, determined that WeChat screens images and documents shared by accounts registered outside China after they are sent, then adds the digital signature – or “hash” – of any files deemed sensitive to a…

Eight-time Grand Slam winner Ivan Lendl said whoever ends up winning the most majors among the ‘Big Three’ of Roger Federer, Rafa Nadal and Novak Djokovic should be considered the greatest male tennis player of the Open era. The ‘GOAT’ (greatest of all time) debate in men’s tennis has divided...

The post Grand Slam tally should decide ‘GOAT’ debate, says Lendl appeared first on Cyprus Mail.

Katrina Kaif accidentally started a live video on Instagram, winning audience’s hearts with her adorable expressions

MANSEHRA: Two persons were killed and three others sustained injuries when a pickup vehicle plunged into a ravine in Shahshi Gigal area of Lower Kohistan on Friday.The vehicle was on way to Kokai...

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SUKKUR: The DG NAB has decided to file corruption references against some government officials allegedly involved in corruption, including Anees-ur-Rehman Mahar the-then deputy director food Sukkur,...

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Ariel Winter shocked her fans after revealing a harrowing accident she had once while cooking at her place

Health and safety on the jobsite involves more than simply enforcing rules and regulations. A culture of prevention, as well as innovative digital solutions, are needed to keep workers alive and healthy.

The Sindh High Court has directed the home department to decide the representation of a proscribed organisation’s activist against his 90 days’ detention under the Maintenance of Public Order within a week.The activist, Abdul Hameed Bugti, had been recently released in the Pakistan...

Two people were wounded in two separate firing incidents on Friday. A 40-year-old man, Feroz, son of Salman, was injured near Mauripur’s Gate No. 15. The man was taken to the Civil Hospital for medical attention.The Jackson police said that the incident took place when a traffic police cop...

A Reuters examination has found that widespread crop damage covering millions of acres of Midwestern farmland has its roots in weak regulatory oversight and corporate secrecy.

A number of ant species produce acid in a poison gland in their abdomen to spray at enemies, and now it seems they also drink it to kill pathogens in their food

Everyone seems to agree trees are a major solution to climate change, but there is a danger that mass reforestation could see us to continue pumping carbon into the atmosphere

Is our love affair with AI really about building a new kind of deity to meet human needs no amount of rationality can fill? Max Barry's disturbing novel Providence lays out the case, says Sally Adee

Eight-time Grand Slam winner Ivan Lendl said whoever ends up winning the most majors among the 'Big Three' of Roger Federer, Rafa Nadal and Novak Djokovic should be considered the greatest male tennis player of the Open era.

The United States' Federal Aviation Administration (FAA) is investigating an incident in which actor Harrison Ford was piloting a small plane that wrongly crossed a runway where another aircraft was landing, U.S. media reported late on Wednesday citing an FAA statement.

Title: Teens With Migraines at Greater Risk of Suicide
Category: Health News
Created: 5/4/2007 2:00:00 AM
Last Editorial Review: 5/4/2007 12:00:00 AM

Title: Folic Acid Might Offer Allergy Relief
Category: Health News
Created: 5/1/2009 2:00:00 AM
Last Editorial Review: 5/1/2009 12:00:00 AM

Title: Happiest States Have Most Suicides
Category: Health News
Created: 4/23/2011 11:00:00 AM
Last Editorial Review: 4/25/2011 12:00:00 AM

Title: Prenatal Pesticide Exposure May Harm Kids' Brains
Category: Health News
Created: 5/1/2012 11:01:00 AM
Last Editorial Review: 5/1/2012 12:00:00 AM

Title: Steep Rise in Suicides Among Middle-Aged Americans, CDC Says
Category: Health News
Created: 5/2/2013 12:35:00 PM
Last Editorial Review: 5/3/2013 12:00:00 AM

Title: Higher Doses of Antidepressants Linked to Suicidal Behavior in Young Patients: Study
Category: Health News
Created: 4/28/2014 4:36:00 PM
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Title: News Coverage of Teen Suicides May Have Ripple Effect
Category: Health News
Created: 5/2/2014 7:35:00 AM
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Title: Health Tip: Needing Folic Acid
Category: Health News
Created: 4/27/2015 12:00:00 AM
Last Editorial Review: 4/27/2015 12:00:00 AM

Title: Teens With History of Self-Poisoning Face Greater Suicide Risk
Category: Health News
Created: 4/25/2015 12:00:00 AM
Last Editorial Review: 4/27/2015 12:00:00 AM

Title: Health Visits May Offer Chance to Prevent Suicide
Category: Health News
Created: 4/24/2015 12:00:00 AM
Last Editorial Review: 4/27/2015 12:00:00 AM

Title: Young Gay, Bisexual Men May Be at Higher Risk for Suicide, Study Finds
Category: Health News
Created: 4/26/2016 12:00:00 AM
Last Editorial Review: 4/27/2016 12:00:00 AM

Title: Teen Suicide Thoughts, Self-Harm Cases Double in a Decade
Category: Health News
Created: 5/4/2017 12:00:00 AM
Last Editorial Review: 5/4/2017 12:00:00 AM

Title: U.S. Youth Suicide Rates Hit 19-Year High After '13 Reasons Why'
Category: Health News
Created: 4/30/2019 12:00:00 AM
Last Editorial Review: 4/30/2019 12:00:00 AM

Title: 'Ringing in the Ears' May Drive Some to the Brink of Suicide
Category: Health News
Created: 5/2/2019 12:00:00 AM
Last Editorial Review: 5/3/2019 12:00:00 AM

Title: Pepcid Ingredient Famotidine Being Tested as COVID-19 Treatment
Category: Health News
Created: 4/27/2020 12:00:00 AM
Last Editorial Review: 4/27/2020 12:00:00 AM

KRAS mutation is a negative predictive biomarker of anti-EGFR agents in patients with metastatic colorectal cancer (mCRC), and remains an elusive target. Pelareorep, a double-stranded RNA virus selectively replicates in KRAS-mutated cells, and is synergistic with irinotecan. A dose escalation trial of FOLFIRI/bevacizumab [irinotecan (150–180 mg/m²) and pelareorep (1 x 10¹⁰ TCID₅₀–3 x 10¹⁰ TCID₅₀)] was implemented in adult patients with oxaliplatin refractory/intolerant, KRAS-mutant mCRC. Pelareorep was administered intravenously over 1 hour on days 1–5 every 4 weeks. Additional studies included pharmacokinetics, tumor morphology, and immune responses. Among FOLFIRI-naïve patients, the highest dose of FOLFIRI/bevacizumab (180 mg/m² irinotecan) and pelareorep (3 x 10¹⁰ TCID₅₀) was well tolerated, without a dose-limiting toxicity. At the recommended phase II dose, 3 of 6 patients (50%) had a partial response; the median progression-free and overall survival (PFS, OS) were 65.6 weeks and 25.1 months, respectively. Toxicities included myelosuppression, fatigue, and diarrhea. Transmission electron microscopy revealed viral factories (viral collections forming vesicular structures), at various stages of development. Immunogold staining against viral capsid -1 protein demonstrated viral "homing" in the tumor cells. The nucleus displayed sufficient euchromatin regions suggestive of active transcription. Flow cytometry revealed rapid dendritic cell maturation (48 hours) with subsequent activation of cytotoxic T cells (7 days). The combination of pelareorep with FOLFIRI/bevacizumab is safe. The PFS and OS data are encouraging and deserve further exploration. Pelareorep leads to a clear recurrent immune stimulatory response with cytotoxic T-cell activation, and homes and replicates in the tumor.

Geranylgeranoic acid (GGA) originally was identified in some animals and has been developed as an agent for preventing second primary hepatoma. We previously have also identified GGA as an acyclic diterpenoid in some medicinal herbs. Recently, we reported that in human hepatoma-derived HuH-7 cells, GGA is metabolically labeled from ¹³C-mevalonate. Several cell-free experiments have demonstrated that GGA is synthesized through geranylgeranial by oxygen-dependent oxidation of geranylgeraniol (GGOH), but the exact biochemical events giving rise to GGA in hepatoma cells remain unclear. Monoamine oxidase B (MOAB) has been suggested to be involved in GGOH oxidation. Here, using two human hepatoma cell lines, we investigated whether MAOB contributes to GGA biosynthesis. Using either HuH-7 cell lysates or recombinant human MAOB, we found that: 1) the MAO inhibitor tranylcypromine dose-dependently downregulates endogenous GGA levels in HuH-7 cells; and 2) siRNA-mediated MAOB silencing reduces intracellular GGA levels in HuH-7 and Hep3B cells. Unexpectedly, however, CRISPR/Cas9-generated MAOB-KO human hepatoma Hep3B cells had GGA levels similar to those in MAOB-WT cells. A sensitivity of GGA levels to siRNA-mediated MAOB downregulation was recovered when the MAOB-KO cells were transfected with a MAOB-expression plasmid, suggesting that MAOB is the enzyme primarily responsible for GGOH oxidation and that some other latent metabolic pathways may maintain endogenous GGA levels in the MAOB-KO hepatoma cells. Along with the previous findings, these results provide critical insights into the biological roles of human MAOB and provide evidence that hepatic MAOB is involved in endogenous GGA biosynthesis via GGOH oxidation.

Adipocytes take up long chain FAs through diffusion and protein-mediated transport, whereas FA efflux is considered to occur by diffusion. To identify potential membrane proteins that are involved in regulating FA flux in adipocytes, the expression levels of 55 membrane transporters without known function were screened in subcutaneous adipose samples from obese patients before and after bariatric surgery using branched DNA methodology. Among the 33 solute carrier (SLC) transporter family members screened, the expression of 14 members showed significant changes before and after bariatric surgery. One of them, Slc43a3, increased about 2.5-fold after bariatric surgery. Further investigation demonstrated that Slc43a3 is highly expressed in murine adipose tissue and induced during adipocyte differentiation in primary preadipocytes and in OP9 cells. Knockdown of Slc43a3 with siRNA in differentiated OP9 adipocytes reduced both basal and forskolin-stimulated FA efflux, while also increasing FA uptake and lipid droplet accumulation. In contrast, overexpression of Slc43a3 decreased FA uptake in differentiated OP9 cells and resulted in decreased lipid droplet accumulation. Therefore, Slc43a3 seems to regulate FA flux in adipocytes, functioning as a positive regulator of FA efflux and as a negative regulator of FA uptake.

ABSTRACT

Production of metallo-β-lactamases (MBLs), which hydrolyze carbapenems, is a cause of carbapenem resistance in Enterobacteriaceae. Development of effective inhibitors for MBLs is one approach to restore carbapenem efficacy in carbapenem-resistant Enterobacteriaceae (CRE). We report here that sulfamoyl heteroarylcarboxylic acids (SHCs) can competitively inhibit the globally spreading and clinically relevant MBLs (i.e., IMP-, NDM-, and VIM-type MBLs) at nanomolar to micromolar orders of magnitude. Addition of SHCs restored meropenem efficacy against 17/19 IMP-type and 7/14 NDM-type MBL-producing Enterobacteriaceae to satisfactory clinical levels. SHCs were also effective against IMP-type MBL-producing Acinetobacter spp. and engineered Escherichia coli strains overproducing individual minor MBLs (i.e., TMB-2, SPM-1, DIM-1, SIM-1, and KHM-1). However, SHCs were less effective against MBL-producing Pseudomonas aeruginosa. Combination therapy with meropenem and SHCs successfully cured mice infected with IMP-1-producing E. coli and dually NDM-1/VIM-1-producing Klebsiella pneumoniae clinical isolates. X-ray crystallographic analyses revealed the inhibition mode of SHCs against MBLs; the sulfamoyl group of SHCs coordinated to two zinc ions, and the carboxylate group coordinated to one zinc ion and bound to positively charged amino acids Lys224/Arg228 conserved in MBLs. Preclinical testing revealed that the SHCs showed low toxicity in cell lines and mice and high stability in human liver microsomes. Our results indicate that SHCs are promising lead compounds for inhibitors of MBLs to combat MBL-producing CRE.

IMPORTANCE Carbapenem antibiotics are the last resort for control of severe infectious diseases, bloodstream infections, and pneumonia caused by Gram-negative bacteria, including Enterobacteriaceae. However, carbapenem-resistant Enterobacteriaceae (CRE) strains have spread globally and are a critical concern in clinical settings because CRE infections are recognized as a leading cause of increased mortality among hospitalized patients. Most CRE produce certain kinds of serine carbapenemases (e.g., KPC- and GES-type β-lactamases) or metallo-β-lactamases (MBLs), which can hydrolyze carbapenems. Although effective MBL inhibitors are expected to restore carbapenem efficacy against MBL-producing CRE, no MBL inhibitor is currently clinically available. Here, we synthesized 2,5-diethyl-1-methyl-4-sulfamoylpyrrole-3-carboxylic acid (SPC), which is a potent inhibitor of MBLs. SPC is a remarkable lead compound for clinically useful MBL inhibitors and can potentially provide a considerable benefit to patients receiving treatment for lethal infectious diseases caused by MBL-producing CRE.