A selection of some of the most striking sports photographs taken around the world over the past seven days.

Andy Bailey has been photographing bins in his Cheshire town, giving them a rating out of 25.

A selection of photographs sent in by our readers on the theme of "railways".

A selection of readers' photographs on the theme of 'arches.'

Each week, we ask you to send in your pictures on a set theme and a selection of these are then published each Thursday on our In pictures page

A selection of pictures sent in by our readers on the theme of 'in the air'.

A selection of pictures on the theme of 'road trip'.

Members of Canada women's coaching staff "objected" to flying drones over training sessions before the scandal at Paris 2024.

It's time for you to be the boss as you select your Northern Ireland starting XI to take on Belarus in Belfast on Friday.

In what seems like the work of a typical Democrat, Kama Harris raised one billion dollars for her campaign… and finished it $20 million in debt. Imagine what she would have done to the United States which would have started out bankrupt if Harris had entered the White House. How do you have an actual […]

The post Typical Democrat: Harris Raised One BILLION for her Campaign… Ended it $20 Million In Debt appeared first on The Lid.

With so few words, most of them kid-friendly, it should be a piece of cake. But it depends on who’s holding the whisk. Translator Daniel Hahn say,"I believe my job as a translator is to preserve all the dimensions of a book, not just one of them. When I find complexity, my job is to keep complexity, or more accurately to reconstruct it. And some of the most complex books I’ve reconstructed have been children’s picture books."

The latest investment insights and market developments.

If you have ever thought, "I wish I could play as an 8-bit version of Janet Weiss or Brad Majors," you are in luck. You can "Jump to the left and dodge to the right" in the upcoming video game adaptation of everyone's favorite midnight movie. — Read the rest

The post The Rocky Horror Picture Show is now a video game appeared first on Boing Boing.

The following article, INTERNal Stupidity: Pentagon Interns Post Pic of Chinese Plane on Veteran’s Day, was first published on Conservative Firing Line.

A knock-off Chinese plane similar to the US F-35 was inadvertently posted by the F-35 JPO (Joint Program Office) on Veteran’s Day. Somebody needs to help this administration figure out some basics …oh wait, a new administration is coming in January. Good. The JPO Strike Force account had no clue what they did until an …

Continue reading INTERNal Stupidity: Pentagon Interns Post Pic of Chinese Plane on Veteran’s Day ...

Rome is magnificent in every way possible, from the millennia of history made here to the deliciousness of a perfect cacio e pepe pasta. There are so many things to do in Rome, from the Colosseum to the Vatican Museums to the Trevi Fountain and the Spanish Steps. Rome is so overwhelming, in a good […]

The post 30+ Epic Things to Do in Rome, Italy appeared first on Adventurous Kate.

Merry belated Christmas and happy Hanukkah, friends! It’s been a crazy last few months of 2016. I’ve had some new work projects keeping me busy, plus some family health scares, fear for my country’s future, and yes, these goddamn celebrity deaths (I watched Love Actually for the first time last weekend since Alan Rickman died. Then pre-teen crush […]

The article Spicy Cranberry Salsa Recipe originated at EverInTransit.com

Shamelessly, Big Media doesn't even try to hide their Democrat preferences anymore. They are happy to lie. But even the lies they tell can point indirectly to the truth.

The post EPIC: When AI Swaps ‘Democracy’ For THIS Word, Journos Start Telling The Truth appeared first on Clash Daily.

Kamala was right about one thing: this election really DID deliver 'joy'... just not the way she expected.

The post EPIC: The ‘Songify’ Trend Of Clipping Speeches To Music Is Back… And AWESOME! appeared first on Clash Daily.

One of the best parts about the first days after a Trump win is how the left has begun to devour themselves.

The post WATCH: Carville Has NO ‘Effs’ Left To Give — Blasts ‘Woke’ In Epic ‘I Told You So’ Rant appeared first on Clash Daily.

President-elect Donald Trump is expected to nominate Florida Sen. Marco Rubio as his secretary of state, reports late Monday indicate. According to The Wall Street Journal, while the nomination isn’t […]

The post Trump to Pick Senator Marco Rubio for Crucial Cabinet Position: Report appeared first on The Western Journal.

In a surprise move that broke in the early hours of Tuesday morning, President-elect Donald Trump has reportedly picked South Dakota Gov. Kristi Noem as his nominee to head the […]

The post Trump Makes His Pick for Secretary of the Department of Homeland Security Secretary: Report appeared first on The Western Journal.

Shortly after President-elect Donald Trump appointed Tom Homan as “border czar,” the immigration hardliner’s hilarious 2019 smackdown of Democratic Rep. Alexandria Ocasio-Cortez of New York went viral on social media. […]

The post Flashback: Video of Tom Homan Taking Down AOC Resurfaces, Showing Why Trump Picked Him appeared first on The Western Journal.

President-elect Donald Trump announced Tuesday that former Arkansas Gov. Mike Huckabee is his pick to be the next U.S. ambassador to Israel. “Mike has been a great public servant, Governor, […]

The post Trump Makes His Pick for US Ambassador to Israel as Conflict in Gaza Remains Heated appeared first on The Western Journal.

President-elect Donald Trump has chosen the next director of the CIA. Trump tapped former Texas congressman and director of national intelligence John Ratcliffe for the job. According to a statement […]

The post 'Warrior for Truth': Trump Has Chosen His Next CIA Director, Crediting Pick for 'Exposing Russian Collusion' Hoax appeared first on The Western Journal.

Epoxide hydrolases (EHs) have been characterized and engineered as biocatalysts that convert epoxides to valuable chiral vicinal diol precursors of drugs and bioactive compounds. Nonetheless, the regioselectivity control of the epoxide ring opening by EHs remains challenging. Alp1U is an α/β-fold EH that exhibits poor regioselectivity in the epoxide hydrolysis of fluostatin C (compound 1) and produces a pair of stereoisomers. Herein, we established the absolute configuration of the two stereoisomeric products and determined the crystal structure of Alp1U. A Trp-186/Trp-187/Tyr-247 oxirane oxygen hole was identified in Alp1U that replaced the canonical Tyr/Tyr pair in α/β-EHs. Mutation of residues in the atypical oxirane oxygen hole of Alp1U improved the regioselectivity for epoxide hydrolysis on 1. The single site Y247F mutation led to highly regioselective (98%) attack at C-3 of 1, whereas the double mutation W187F/Y247F resulted in regioselective (94%) nucleophilic attack at C-2. Furthermore, single-crystal X-ray structures of the two regioselective Alp1U variants in complex with 1 were determined. These findings allowed insights into the reaction details of Alp1U and provided a new approach for engineering regioselective epoxide hydrolases.

Expert

Cheng Chu
Proc. Amer. Math. Soc. 152 (), 5289-5297.
Abstract, references and article information

The dimeric ectonucleotidase CD73 catalyzes the hydrolysis of AMP at the cell surface to form adenosine, a potent suppressor of the immune response. Blocking CD73 activity in the tumor microenvironment can have a beneficial effect on tumor eradication and is a promising approach for cancer therapy. Biparatopic antibodies binding different regions of CD73 may be a means to antagonize its enzymatic activity. A panel of biparatopic antibodies representing the pairwise combination of 11 parental monoclonal antibodies against CD73 was generated by Fab-arm exchange. Nine variants vastly exceeded the potency of their parental antibodies with ≥90% inhibition of activity and subnanomolar EC50 values. Pairing the Fabs of parents with nonoverlapping epitopes was both sufficient and necessary whereas monovalent antibodies were poor inhibitors. Some parental antibodies yielded potent biparatopics with multiple partners, one of which (TB19) producing the most potent. The structure of the TB19 Fab with CD73 reveals that it blocks alignment of the N- and C-terminal CD73 domains necessary for catalysis. A separate structure of CD73 with a Fab (TB38) which complements TB19 in a particularly potent biparatopic shows its binding to a nonoverlapping site on the CD73 N-terminal domain. Structural modeling demonstrates a TB19/TB38 biparatopic antibody would be unable to bind the CD73 dimer in a bivalent manner, implicating crosslinking of separate CD73 dimers in its mechanism of action. This ability of a biparatopic antibody to both crosslink CD73 dimers and fix them in an inactive conformation thus represents a highly effective mechanism for the inhibition of CD73 activity.

14 September 2020

The EGFR tyrosine kinase inhibitor gefitinib is commonly used for lung cancer patients. However, some patients eventually become resistant to gefitinib and develop progressive disease. Here, we indicate that ecto-ATP synthase, which ectopically translocated from mitochondrial inner membrane to plasma membrane, is considered as a potential therapeutic target for drug-resistant cells. Quantitative multi-omics profiling reveals that ecto-ATP synthase inhibitor mediates CK2-dependent phosphorylation of DNA topoisomerase IIα (topo IIα) at serine 1106 and subsequently increases the expression of long noncoding RNA, GAS5. Additionally, we also determine that downstream of GAS5, p53 pathway, is activated by ecto-ATP synthase inhibitor for regulation of programed cell death. Interestingly, GAS5-proteins interactomic profiling elucidates that GAS5 associates with topo IIα and subsequently enhancing the phosphorylation level of topo IIα. Taken together, our findings suggest that ecto-ATP synthase blockade is an effective therapeutic strategy via regulation of CK2/phospho-topo IIα/GAS5 network in gefitinib-resistant lung cancer cells.

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There is nothing quite like the excitement of discovery in science—of finding something no one else knew and seeing a story unfold. One has to be part of an emerging picture to feel the elation. These moments in a lifetime are few and far between, but they fuel enthusiasm and keep one going. They are embedded in struggles and joys of everyday life, years of establishing what Louis Pasteur called “the prepared mind,” working with mentors, trainees, and colleagues, failures and successes. This article recalls 1) how I got to be a biochemist; 2) my contributions as an educator and researcher, especially regarding meprin metalloproteases; and 3) my participation in communities of science. Perhaps my reflections will help an aspiring scientist see how fulfilling a career in science can be.

To date, the imaging and diagnosis of hepatocellular carcinoma (HCC) rely on CT/MRI, which have well-known limitations. Glypican-3 (GPC3) is a cell surface receptor highly expressed by HCC but not by normal or cirrhotic liver tissue. Here we report initial clinical results of GPC3-targeted PET imaging with [⁶⁸Ga]Ga-DOTA-RYZ-GPC3 (RAYZ-8009), a peptide-based GPC3 ligand in patients with known or suspected HCC. Methods: [⁶⁸Ga]Ga-RAYZ-8009 was obtained after labeling the peptide precursor with ⁶⁸Ga from a ⁶⁸Ge/⁶⁸Ga generator and heating at 90°C for 10 min followed by sterile filtration. After administration of [⁶⁸Ga]Ga-RAYZ-8009, a dynamic or static PET/CT scan was acquired between 45 min and 4 h after administration. Radiotracer uptake was measured by SUVs for the following tissues: suspected or actual HCC or hepatoblastoma lesions, non–tumor-bearing liver, renal cortex, blood pool in the left ventricle, and gastric fundus. Additionally, tumor–to–healthy-liver ratios (TLRs) were calculated. Results: Twenty-four patients (5 patients in the dynamic protocol; 19 patients in the static protocol) were scanned. No adverse events occurred. Two patients had no lesion detected and did not have HCC during follow-up. In total, 50 lesions were detected and analyzed. The mean SUV_max of these lesions was 19.6 (range, 2.7–95.3), and the mean SUV_mean was 10.1 (range, 1.0–49.2) at approximately 60 min after administration. Uptake in non–tumor-bearing liver and blood pool rapidly decreased over time and became negligible 45 min after administration (mean SUV_mean, <1.6), with a continuous decline to 4 h after administration (mean SUV_mean, 1.0). The opposite was observed for HCC lesions, for which SUVs and TLRs continuously increased for up to 4 h after administration. In individual lesion analysis, TLR was the highest between 60 and 120 min after administration. Uptake in the gastric fundus gradually increased for up to 45 min (to an SUV_max of 31.3) and decreased gradually afterward. Conclusion: [⁶⁸Ga]Ga-RAYZ-8009 is safe and allows for high-contrast imaging of GPC3-positive HCC, with rapid clearance from most normal organs. Thereby, [⁶⁸Ga]Ga-RAYZ-8009 is promising for HCC diagnosis and staging. Further research is warranted.

CHANDLER, Ariz., Oct. 23, 2024 — The global edge computing market is expected to grow by more than 30 percent in the next five years, serving mission-critical applications in the […]

The post Microchip Expands 64-Bit Portfolio with High-Performance PIC64HX Microprocessors for Edge Computing appeared first on HPCwire.

It will cost $55.7 million to repair Tropicana Field, home to the MLB Tampa Bay Rays, in time for the 2026 home opener, St. Petersburg., Fla., city officials said Tuesday.

"Gladiator II" has even more crowd-pleasing combat events than the original and an operatic story showcasing flamboyant performances.

President-elect Donald Trump says that he wants ex-Arkansas Gov. Mike Huckabee to represent America's interests in the troubled Middle East region as U.S. Ambassador to Israel.

President-elect Donald Trump on Tuesday night announced his nomination of Fox News host and Army veteran Pete Hegseth to head the Department of Defense.

The days are a technology overload, mixed with the joy of seeing her students' faces and worry about her own family's health and safety, New York City teacher Ariel Sacks writes.

Washington sent a 2025 fifth-round pick and a 2027 third-round pick to Pittsburgh on Tuesday for Eller.

The latest update of the College Football Playoff rankings was officially released Tuesday night on ESPN, with the Alabama Crimson Tide seeing some movement as a result of their dominant 42-13 road win over the LSU Tigers on Saturday. In the rankings

No. 1 Oregon will travel to Madison this weekend to take on the Wisconsin Badgers at Camp Randall Stadium.

Texas A&M's Week 11 bye week was (hopefully) successful in terms of fixing the issues that plagued the Aggies, especially the defensive issues that led to 25 missed tackles in the 44-20 loss to South Carolina, which dropped the Aggies to No. 14 in the first Col

Georgia and Miami misery translates into joy for the Texas Longhorns. Thanks to losses by the 'Canes and Bulldogs on Saturday, the Horns move up two spots in the college football playoff ranki

The second release of College Football Playoff rankings changes the projected bracket. Here's what it looks like if the season ended today.