The Nobel prize in physics has been jointly awarded to  James Peebles, Michel Mayor and Didier Queloz for their contributions to our understanding of the evolution of the universe and Earth’s place in the cosmos.

It has been identified that arginine vasopressin (AVP), vasopressin receptor 2(V2R), and the aquaporin 2 (AQP2) signaling pathway in the inner ear play important roles in hearing and balance functions through regulating the endolymph equilibrium; however, the contributions of this signaling pathway to the development of motion sickness are unclear. The present study was designed to investigate whether the activation of the AVP-V2R-AQP2 signaling pathway in the inner ear is involved in the induction of motion sickness and whether mozavaptan, a V2R antagonist, could reduce motion sickness. We found that both rotatory stimulus and intraperitoneal AVP injection induced conditioned taste aversion (a confirmed behavioral index for motion sickness) in rats and activated the AVP-V2R-AQP2 signaling pathway with a responsive V2R downregulation in the inner ears, and AVP perfusion in cultured epithelial cells from rat endolymphatic sacs induced similar changes in this pathway signaling. Vestibular training, V2R antagonist mozavaptan, or PKA inhibitor H89 blunted these changes in the V2R-AQP2 pathway signaling while reducing rotatory stimulus– or DDAVP (a V2R agonist)-induced motion sickness in rats and dogs. Therefore, our results suggest that activation of the inner ear AVP-V2R-AQP2 signaling pathway is potentially involved in the development of motion sickness; thus, mozavaptan targeting AVP V2Rs in the inner ear may provide us with a new application option to reduce motion sickness.

Metastatic breast cancer is prevalent worldwide, and one of the most common sites of metastasis is long bones. Of patients with disease, the major symptom is pain, yet current medications fail to adequately result in analgesic efficacy and present major undesirable adverse effects. In our study, we investigate the potential of a novel monoacylglycerol lipase (MAGL) inhibitor, MJN110, in a murine model of cancer-induced bone pain. Literature has previously demonstrated that MAGL inhibitors function to increase the endogenous concentrations of 2-arachydonylglycerol, which then activates CB1 and CB2 receptors to inhibit inflammation and pain. We demonstrate that administration of MJN110 significantly and dose dependently alleviates spontaneous pain behavior during acute administration compared with vehicle control. In addition, MJN110 maintains its efficacy in a chronic-dosing paradigm over the course of 7 days without signs of receptor sensitization. In vitro analysis of MJN110 demonstrated a dose-dependent and significant decrease in cell viability and proliferation of 66.1 breast adenocarcinoma cells to a greater extent than KML29, an alternate MAGL inhibitor, or the CB2 agonist JWH015. Chronic administration of the compound did not appear to affect tumor burden, as evidenced by radiograph or histologic analysis. Together, these data support the application for MJN110 as a novel therapeutic for cancer-induced bone pain.

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.

Glucagon-like peptide-2 (GLP-2) agonists have therapeutic potential in clinical indications in which the integrity or absorptive function of the intestinal mucosa is compromised, such as in short bowel syndrome (SBS). Native hGLP-2, a 33–amino acid peptide secreted from the small intestine, contributes to nutritional absorption but has a very short half-life because of enzymatic cleavage and renal clearance and thus is of limited therapeutic value. The GLP-2 analog teduglutide (Revestive/Gattex; Shire Inc.) has been approved for use in SBS since 2012 but has a once-daily injection regimen. Pharmacokinetic (PK) and pharmacodynamic studies confirm that apraglutide, a novel GLP-2 analog, has very low clearance, long elimination half-life, and high plasma protein binding compared with GLP-2 analogs teduglutide and glepaglutide. Apraglutide and teduglutide retain potency and selectivity at the GLP-2 receptor comparable to native hGLP-2, whereas glepaglutide was less potent and less selective. In rat intravenous PK studies, hGLP-2, teduglutide, glepaglutide, and apraglutide had clearances of 25, 9.9, 2.8, and 0.27 ml/kg per minute, respectively, and elimination half-lives of 6.4, 19, 16, and 159 minutes, respectively. The unique PK profile of apraglutide administered via intravenous and subcutaneous routes was confirmed in monkey and minipig and translated into significantly greater in vivo pharmacodynamic activity, measured as small intestinal growth in rats. Apraglutide showed greater intestinotrophic activity than the other peptides when administered at less-frequent dosing intervals because of its prolonged half-life. We postulate that apraglutide offers several advantages over existing GLP-2 analogs and is an excellent candidate for the treatment of gastrointestinal diseases, such as SBS.

Abicipar pegol (abicipar) is a novel DARPin therapeutic and highly potent vascular endothelial growth factor (VEGF) inhibitor intended for the treatment of neovascular age-related macular degeneration (nAMD). Here we develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for abicipar to guide dosing regimens in the clinic. The model incorporated abicipar-VEGF binding kinetics, VEGF expression levels, and VEGF turnover rates to describe the ocular and systemic PK data collected from the vitreous, aqueous humor (AH), choroid, retina, and serum of rabbits after a 1-mg abicipar intravitreal (IVT) dose. The model was translated to humans using human-specific mechanistic parameters and refitted to human serum and AH concentrations from patients with diabetic macular edema and nAMD. The model was then used to simulate 8-, 12- (quarterly), and 16-week dosing intervals in the clinic. Simulations of 2 mg abicipar IVT at 8-week or quarterly dosing in humans indicates minimum steady-state vitreal concentrations are maintained above both in vitro IC₅₀ and in vivo human IC₅₀ values. The model predicted virtually complete VEGF inhibition for the 8-week and quarterly dosing schedule during the 52-week treatment period. In the 16-week schedule, clinically significant VEGF inhibition was maintained during the 52-week period. The model quantitatively described abicipar-VEGF target engagement leading to rapid reduction of VEGF and a long duration of VEGF inhibition demonstrating the clinical feasibility of up to a 16-week dosing interval. Abicipar is predicted to reduce IVT dosing compared with other anti-VEGF therapies with the potential to lessen patient treatment burden.

Ubiquitin (UB) transfer cascades consisting of E1, E2, and E3 enzymes constitute a complex network that regulates a myriad of biologic processes by modifying protein substrates. Deubiquitinating enzymes (DUBs) reverse UB modifications or trim UB chains of diverse linkages. Additionally, many cellular proteins carry UB-binding domains (UBDs) that translate the signals encoded in UB chains to target proteins for degradation by proteasomes or in autophagosomes, as well as affect nonproteolytic outcomes such as kinase activation, DNA repair, and transcriptional regulation. Dysregulation of the UB transfer pathways and malfunctions of DUBs and UBDs play causative roles in the development of many diseases. A greater understanding of the mechanism of UB chain assembly and the signals encoded in UB chains should aid in our understanding of disease pathogenesis and guide the development of novel therapeutics. The recent flourish of protein-engineering approaches such as unnatural amino acid incorporation, protein semisynthesis by expressed protein ligation, and high throughput selection by phage and yeast cell surface display has generated designer proteins as powerful tools to interrogate cell signaling mediated by protein ubiquitination. In this study, we highlight recent achievements of protein engineering on mapping, probing, and manipulating UB transfer in the cell.

Advances in synthetic biology have enabled the production of a variety of compounds using bacteria as a vehicle for complex compound biosynthesis. Violacein, a naturally occurring indole pigment with antibiotic properties, can be biosynthetically engineered in Escherichia coli expressing its nonnative synthesis pathway. To explore whether this synthetic biosynthesis platform could be used for drug discovery, here we have screened bacterially derived violacein against the main causative agent of human malaria, Plasmodium falciparum. We show the antiparasitic activity of bacterially derived violacein against the P. falciparum 3D7 laboratory reference strain as well as drug-sensitive and -resistant patient isolates, confirming the potential utility of this drug as an antimalarial agent. We then screen a biosynthetic series of violacein derivatives against P. falciparum growth. The varied activity of each derivative against asexual parasite growth points to the need to further develop violacein as an antimalarial. Towards defining its mode of action, we show that biosynthetic violacein affects the parasite actin cytoskeleton, resulting in an accumulation of actin signal that is independent of actin polymerization. This activity points to a target that modulates actin behavior in the cell either in terms of its regulation or its folding. More broadly, our data show that bacterial synthetic biosynthesis could become a suitable platform for antimalarial drug discovery, with potential applications in future high-throughput drug screening with otherwise chemically intractable natural products.

The MaMTH-DS assay detected inhibitors of mutant EGFR in non–small cell lung cancer cells.

Evidence points to London being a ceremonial site from the fourth millennium BC

A new discovery in mice shows the innate immune system has 'memory,' previously thought to be a unique feature of the adaptive immune system. Blocking this memory prevented transplanted organs from being rejected, providing a way to more specific drugs that could lengthen organ transplant survival.

AI drug discovery firm Exscientia has announced the appointment of Dr David Hallett as its Chief Operating Officer and Head of Drug Discovery.

Bringing 20 years of experience to the role, Dr Hallett’s primary remit will see him take responsibility for the company’s entire drug discovery portfolio, as well as managing pharma collaborations, joint ventures and pipeline projects. He will report to Exscientia Founder and CEO Professor Andrew Hopkins.

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The partnership will focus on generating novel small-molecule inhibitors against specific DUB targets for treatment of a range of diseases.

The position was established as part of the Department’s ongoing efforts, initiated last year at the direction of the Attorney General, to review and improve its criminal discovery and case management policies and procedures.

A new process for seeing how electricity flows at the surface of electrodes will give a boost to efforts to improve rechargeable batteries

Our photo of the day comes from Lee County, Florida.

Conoce a la familia Méndez, pionera en la transformación extrema de camiones. Texas Trocas, nueva serie de Discovery en Español. Estreno 15 de septiembre a las 10PM E/P.

Conoce al legendario restaurador y mecánico Martín Vaca quien construye autos fuera de serie desde hace más de 50 años. MEXICÁNICOS, estreno el 2 de marzo a las 10PM

New evidence from neutrinos points to one of several theories about why the cosmos is made of matter and not antimatter

-- Read more on ScientificAmerican.com

YouTube is becoming more than just a great ally during the Coronavirus-caused lockdown. On Friday, ace cricket statistician Mohandas Menon stumbled upon something that could force a change in the record books if dug deeper.

Menon happened to watch a Pathe Films news clip of the 1936-37 Ashes Test in Brisbane, where Gubby Allen’s Englishmen were in early trouble against Don Bradman’s Australia on a sticky wicket.

Arthur Fagg, who came in at the fall of TS Worthington’s wicket, is seen being caught by a short midwicket fielder. However, in the scorecard of that Test, Fagg is mentioned as caught behind by Bert Oldfield off Ernest McCormick for four.

Worthington departed, caught by Oldfield off the first ball in the Test.

Arthur Fagg

“While watching the 1936/37 #Ashes series - the 1st Test at Brisbane (4 Dec 1936), I find that England’s Arthur Fagg in the first innings was caught by a fielder at short mid-wicket and not by wicketkeeper Bert Oldfield. But all sources since then, ie in the last 83-and-a-half years have recorded it in the scorebooks as ‘caught Oldfield’. Time to change this error,” wrote Menon on his Facebook page. When this writer asked Menon what made him compare the footage to the scorecard, he replied: “Usually, when I watch old film clippings, I keep the scorecard ready so I can match the unknown players who are batting, bowling or fielding.”

There is a small possibility that the producers of the newsreel may have got the batsman wrong and the scorecard is right, but with Australians being no slouches when it comes to digging up archives (one Aussie recently found coloured footage of Bradman’s last competitive game at the Sydney Cricket Ground in February 1949 in his garage), this case is worth digging up. If the footage is right, will there be a change in Oldfield’s 130 Test dismissals?

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Mid-Day is now on Telegram. Click here to join our channel (@middayinfomedialtd) and stay updated with the latest news

HIV genetic code was read in two different ways by cells the virus has infected, stated findings published today in Science. The result is that infected

Newly developed insulin compound could offer fresh hope of better diabetes treatment to millions of diabetics, reports a new study. The findings of the

EastEnders spoilers reveal Lola will be stunned to learn former fling Peter has joined her boyfriend Jay at work as she frets their secret one-night stand will be revealed.

The 21-year-old, who just finished his junior year at St. Mary’s University in Minnesota, was preparing a stack of old papers to be logged in a database and put into storage.

JJ Abrams has revealed that unseen footage made it possible for the late Carrie Fisher to appear in the upcoming film, Star Wars: The Rise Of Skywalker. 

Heartbreak can be the best teacher, as arts journalist Alice Vincent learns in her hopeful memoir of self-discovery and horticulture.

Beloved of intrepid explorers and school run mums alike, the one millionth Land Rover Discovery rolled off the production line today before embarking on an epic 8,000 mile fund-raising expedition miles to China.

Priced from £32,395 to £42,995, the baby 'Disco' goes on sale in January alongside the existing full-size sevenseater Discovery.

RAY MASSEY tests the new Land Rover Discovery Sport on the snowy roads of Iceland. With an impressive seven seats avilable and fantastic flexibilty this car is perfect for families.

London's Tower Bridge has reopened after it was sealed off today at around 12.20pm by armed police as they examined a package, which has since been found to be non-suspicious.

Scientists say they've discovered an antibody that blocks infection by SARS-CoV-2, the coronavirus behind the current global health crisis.

लैंड रोवर डिस्कवरी स्पोर्ट (Land Rover Discovery Sport) को उसकी बेमिसाल पावर के लिए जाना जाता है. इसका 2.0-लीटर बीएस-6 कम्प्लाइंट D180 डीजल इंजन 180 हॉर्स पावर की ताकत और 430Nm का टॉर्क जेनरेट करता है