DOTZON presents the seventh edition of the Digital Company Brands study. After having introduced the study in 2018, DOTZON continued to expand and enhance the underlying data to display how companies successfully use their Digital Company Brands. The Digital Company Brand is the digital dimension of a company brand and mirrors the "digitalness " of a company. For "Digital Company Brands 2024", all companies worldwide that have their own internet extension were once again analysed.

Connecting the Dots

The auctioneer's left ring finger is nearly torn off when he gets bitten by one of his French bulldogs, Louis and Jax, as he attempts to intervene in a fight between the two.

The auctioneer's left ring finger is nearly torn off when he gets bitten by one of his French bulldogs, Louis and Jax, as he attempts to intervene in a fight between the two.

Esta fue la última conversación de José González, padre del sacerdote hallado muerto en un bar de la capital antioqueña,  Javier Eduardo González Pertuz

Cristian Sánchez, Director del Instituto de Deportes y recreación de Medellín, aseguró en 10AM que no todos los conciertos están confirmados

El padre Blaster Pérez, párroco de Barrancas, La Guajira, habla sobre los operativos de liberación de Luis Manuel Díaz

En 6AM Hoy por Hoy de Caracol Radio estuvo el cantautor colombiano, Billy Pontoni, quien cumple 70 años este martes 20 de febrero, para hablar sobre su carrera artística.

Myles Anderson and Sean Lecomber troll with the punches when they discuss whether kids should use social media. Then, are stripes superior to polka dots? Rob Pue and Kathleen McGee refuse to be clothed-minded with their patter on these patterns.

CDOT warned that travel conditions could become “extreme to impossible” Friday and Saturday, expressing particular concern about I-70 east of Denver and I-25 south of Pueblo.

Bored? Forget the Snickers. What you need is a healthy serving of humor. These memes cover all the bases: nerdy, historical, relatable, and just plain dumb. As a bonus, we can guarantee they won't give you cavities or leave bits of peanuts stuck in your teeth. 

It's every cat's greatest dream to finally catch that red dot. And sometimes they do (meaning we get tired of holding down the laser and pointing). 

Gadot will play a lawyer whose son is kidnapped. Her character must run all over London, carrying out demands from a mysterious caller who has taken her child. 

Mary G. McCoy
Jun 1, 2002; 43:921-929
Research Articles

Thoracic great vessels such as the aorta and subclavian arteries are formed through dynamic remodeling of embryonic pharyngeal arch arteries (PAAs). Previous work has shown that loss of a basic helix-loop-helix transcription factor Hey1 in mice causes abnormal fourth PAA development and lethal great vessel anomalies resembling congenital malformations in humans. However, how Hey1 mediates vascular formation remains unclear. In this study, we revealed that Hey1 in vascular endothelial cells, but not in smooth muscle cells, played essential roles for PAA development and great vessel morphogenesis in mouse embryos. Tek-Cre–mediated Hey1 deletion in endothelial cells affected endothelial tube formation and smooth muscle differentiation in embryonic fourth PAAs and resulted in interruption of the aortic arch and other great vessel malformations. Cell specificity and signal responsiveness of Hey1 expression were controlled through multiple cis-regulatory regions. We found two distal genomic regions that had enhancer activity in endothelial cells and in the pharyngeal epithelium and somites, respectively. The novel endothelial enhancer was conserved across species and was specific to large-caliber arteries. Its transcriptional activity was regulated by Notch signaling in vitro and in vivo, but not by ALK1 signaling and other transcription factors implicated in endothelial cell specificity. The distal endothelial enhancer was not essential for basal Hey1 expression in mouse embryos but may likely serve for Notch-dependent transcriptional control in endothelial cells together with the proximal regulatory region. These findings help in understanding the significance and regulation of endothelial Hey1 as a mediator of multiple signaling pathways in embryonic vascular formation.

Infiltration of peripheral immune cells after blood-brain barrier dysfunction causes severe inflammation after a stroke. Although the endothelial glycocalyx, a network of membrane-bound glycoproteins and proteoglycans that covers the lumen of endothelial cells, functions as a barrier to circulating cells, the relationship between stroke severity and glycocalyx dysfunction remains unclear. In this study, glycosaminoglycans, a component of the endothelial glycocalyx, were studied in the context of ischemic stroke using a photochemically induced thrombosis mouse model. Decreased levels of heparan sulfate and chondroitin sulfate and increased activity of hyaluronidase 1 and heparanase (HPSE) were observed in ischemic brain tissues. HPSE expression in cerebral vessels increased after stroke onset and infarct volume greatly decreased after co-administration of N-acetylcysteine + glycosaminoglycan oligosaccharides as compared with N-acetylcysteine administration alone. These results suggest that the endothelial glycocalyx was injured after the onset of stroke. Interestingly, scission activity of proHPSE produced by immortalized endothelial cells and HEK293 cells transfected with hHPSE1 cDNA were activated by acrolein (ACR) exposure. We identified the ACR-modified amino acid residues of proHPSE using nano LC–MS/MS, suggesting that ACR modification of Lys139 (6-kDa linker), Lys107, and Lys161, located in the immediate vicinity of the 6-kDa linker, at least in part is attributed to the activation of proHPSE. Because proHPSE, but not HPSE, localizes outside cells by binding with heparan sulfate proteoglycans, ACR-modified proHPSE represents a promising target to protect the endothelial glycocalyx.

Sean A Burnap
Dec 7, 2020; 0:RA120.002305v1-mcp.RA120.002305
Research

The extracellular matrix encompasses a reservoir of bioactive macromolecules that modulates a cornucopia of biological functions. A prominent body of work posits matrix constituents as master regulators of autophagy and angiogenesis and provides molecular insight into how these two processes are coordinated. Here, we review current understanding of the molecular mechanisms underlying hyaluronan and HAS2 regulation and the role of soluble proteoglycan in affecting autophagy and angiogenesis. Specifically, we assess the role of proteoglycan-evoked autophagy in regulating angiogenesis via the HAS2-hyaluronan axis and ATG9A, a novel HAS2 binding partner. We discuss extracellular hyaluronan biology and the post-transcriptional and post-translational modifications that regulate its main synthesizer, HAS2. We highlight the emerging group of proteoglycans that utilize outside-in signaling to modulate autophagy and angiogenesis in cancer microenvironments and thoroughly review the most up-to-date understanding of endorepellin signaling in vascular endothelia, providing insight into the temporal complexities involved.

Bone morphogenetic protein-9 (BMP-9) is a circulating cytokine that is known to play an essential role in the endothelial homeostasis and the binding of BMP-9 to the receptor activin-like kinase 1 (ALK-1) promotes endothelial cell quiescence. Previously, using an unbiased screen, we identified ALK-1 as a high-capacity receptor for low-density lipoprotein (LDL) in endothelial cells that mediates its transcytosis in a nondegradative manner. Here we examine the crosstalk between BMP-9 and LDL and how it influences their interactions with ALK-1. Treatment of endothelial cells with BMP-9 triggers the extensive endocytosis of ALK-1, and it is mediated by caveolin-1 (CAV-1) and dynamin-2 (DNM2) but not clathrin heavy chain. Knockdown of CAV-1 reduces BMP-9–mediated internalization of ALK-1, BMP-9–dependent signaling and gene expression. Similarly, treatment of endothelial cells with LDL reduces BMP-9–induced SMAD1/5 phosphorylation and gene expression and silencing of CAV-1 and DNM2 diminishes LDL-mediated ALK-1 internalization. Interestingly, BMP-9–mediated ALK-1 internalization strongly re-duces LDL transcytosis to levels seen with ALK-1 deficiency. Thus, BMP-9 levels can control cell surface levels of ALK-1, via CAV-1, to regulate both BMP-9 signaling and LDL transcytosis.

Angiopoietin-like protein (ANGPTL)3 regulates plasma lipids by inhibiting LPL and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-C independently of the classical LDLR-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to LDLR mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic, and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3’s novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR.

We have previously shown that multimers of plasma pentraxin-3 (PTX3) were predictive of survival in patients with sepsis. To characterize the release kinetics and cellular source of plasma protein changes in sepsis, serial samples were obtained from healthy volunteers (n=10, 3 time-points) injected with low-dose endotoxin (LPS) and analyzed using data-independent acquisition (DIA) MS. The human plasma proteome response was compared to an LPS-induced endotoxemia model in mice. Proteomic analysis of human plasma revealed a rapid neutrophil degranulation signature, followed by a rise in acute phase proteins. Changes in circulating PTX3 correlated with increases in neutrophil-derived proteins following LPS injection. Time course analysis of the plasma proteome in mice showed a time-dependent increase in multimeric PTX3, alongside increases in neutrophil-derived myeloperoxidase (MPO) upon LPS treatment. The mechanisms of oxidation-induced multimerisation of PTX3 were explored in two genetic mouse models: MPO global knock-out mice and LysM CreNox2KO mice, in which NADPH oxidase 2 (Nox2) is only deficient in myeloid cells. Nox2 is the enzyme responsible for the oxidative burst in neutrophils. Increases in plasma multimeric PTX3 were not significantly different between wildtype and MPO or LysM CreNox2KO knock-out mice. Thus, PTX3 may already be stored and released in a multimeric form. Through in vivo neutrophil depletion and multiplexed vascular proteomics, PTX3 multimer deposition within the aorta was confirmed to be neutrophil-dependent. Proteomic analysis of aortas from LPS-injected mice returned PTX3 as the most upregulated protein, where multimeric PTX3 was deposited as early as 2 h post-LPS along with other neutrophil-derived proteins. In conclusion, the rise in multimeric PTX3 upon LPS injection correlates with neutrophil-related protein changes in plasma and in aortas. MPO and myeloid Nox2 are not required for the multimerisation of PTX3; instead, neutrophil extravasation is responsible for the LPS-induced deposition of multimeric PTX3 in the aorta.

Preclinical data have shown that ¹⁶¹Tb-labeled peptides targeting the somatostatin receptor are therapeutically more effective for peptide receptor radionuclide therapy than are their ¹⁷⁷Lu-labeled counterparts. To further substantiate this enhanced therapeutic effect, we performed cellular dosimetry to quantify the absorbed dose to the cell nucleus and compared dose–response curves to evaluate differences in relative biological effectiveness in vitro. Methods: CA20948 cell survival was assessed after treatment with [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTATATE (agonist) and with [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTA-LM3 (antagonist) via a clonogenic assay. Cell binding, internalization, and dissociation assays were performed up to 7 d to acquire time-integrated activity coefficients. Separate S values for each type of particle emission (Auger/internal conversion [IC] electrons and β^– particles) were computed via Monte Carlo simulations, while considering spheric cells. Once the absorbed dose to the cell nucleus was calculated, survival curves were fitted to the appropriate linear or linear-quadratic model and corresponding relative biological effectiveness was evaluated. Results: Although the radiopeptide uptake was independent of the radionuclide, [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 delivered a 3.6 and 3.8 times higher dose to the nucleus, respectively, than their ¹⁷⁷Lu-labeled counterparts on saturated receptor binding. This increased nucleus-absorbed dose was mainly due to the additional emission of IC and not Auger electrons by ¹⁶¹Tb. When activity concentrations were considered, both [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 showed a lower survival fraction than did labeling with ¹⁷⁷Lu. When the absorbed dose to the nucleus was considered, no significant difference could be observed between the dose–response curves for [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTATATE. [¹⁶¹Tb]Tb-DOTA-LM3 showed a linear-quadratic dose response, whereas [¹⁶¹Tb]Tb-DOTATATE showed only a linear dose response within the observed dose range, suggesting additional cell membrane damage by Auger electrons. Conclusion: The IC, rather than Auger, electrons emitted by ¹⁶¹Tb resulted in a higher absorbed dose to the cell nucleus and lower clonogenic survival for [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 than for the ¹⁷⁷Lu-labeled analogs. In contrast, [¹⁶¹Tb]Tb-DOTATATE showed no higher dose response than [¹⁷⁷Lu]Lu-DOTATATE, whereas for [¹⁶¹Tb]Tb-DOTA-LM3 an additional quadratic response was observed. Because of this quadratic response, potentially caused by cell membrane damage, [¹⁶¹Tb]Tb-DOTA-LM3 is a more effective radiopeptide than [¹⁶¹Tb]Tb-DOTATATE for labeling with ¹⁶¹Tb.

Our objective is to explore quantitative imaging markers for early prediction of treatment response in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) undergoing [¹⁷⁷Lu]Lu-DOTATATE therapy. By doing so, we aim to enable timely switching to more effective therapies in order to prevent time-resource waste and minimize toxicities. Methods: Patients diagnosed with unresectable or metastatic, progressive, well-differentiated, receptor-positive GEP-NETs who received 4 sessions of [¹⁷⁷Lu]Lu-DOTATATE were retrospectively selected. Using SPECT/CT images taken at the end of treatment sessions, we counted all visible tumors and measured their largest diameters to calculate the tumor burden score (TBS). Up to 4 target lesions were selected and semiautomatically segmented. Target lesion peak counts and spleen peak counts were measured, and normalized peak counts were calculated. Changes in TBS (TBS) and changes in normalized peak count (nPC) throughout treatment sessions in relation to the first treatment session were calculated. Treatment responses were evaluated using third-month CT and were binarized as progressive disease (PD) or non-PD. Results: Twenty-seven patients were included (7 PD, 20 non-PD). Significant differences were observed in TBS_second-first, TBS_third-first, and TBS_fourth-first (where second-first, third-first, and fourth-first denote scan number between the second and first, third and first, and fourth and first [¹⁷⁷Lu]Lu-DOTATATE treatment cycles), respectively) between the PD and non-PD groups (median, 0.043 vs. –0.049, 0.08 vs. –0.116, and 0.109 vs. –0.123 [P = 0.023, P = 0.002, and P < 0.001], respectively). nPC_second-first showed significant group differences (mean, –0.107 vs. –0.282; P = 0.033); nPC_third-first and nPC_fourth-first did not reach statistical significance (mean, –0.122 vs. –0.312 and –0.183 vs. –0.405 [P = 0.117 and 0.067], respectively). At the optimal threshold, TBS_fourth-first exhibited an area under the curve (AUC) of 0.957, achieving 100% sensitivity and 80% specificity. TBS_second-first and TBS_third-first reached AUCs of 0.793 and 0.893, sensitivities of 71.4%, and specificities of 85% and 95%, respectively. nPC_second-first, nPC_third-first, and nPC_fourth-first showed AUCs of 0.764, 0.693, and 0.679; sensitivities of 71.4%, 71.4%, and 100%; and specificities of 75%, 70%, and 35%, respectively. Conclusion: TBS and nPC can predict [¹⁷⁷Lu]Lu-DOTATATE response by the second treatment session.

A math specialist shares how she uses dots to allow students to see the connections between mathematical operations, like addition and multiplication.

Gal Gadot wrote, "You teach me so much about motherhood, life, and myself"

DOVER, Del. (May 11, 2023) – The Delaware Department of Transportation (DelDOT) is partnering with the Delaware Department of Agriculture’s Delaware Forest Service (DFS) to plant over 12,100 trees in support of the Forest Initiative Fund (FIF). FIF was created by the DFS to help address water quality, air quality, and overall life for all […]

Officials from the Delaware Department of Transportation (DelDOT), Delaware Emergency Management Agency (DEMA), and other state agencies are monitoring the forecast of Tropical Storm Isaias that could produce heavy rain, high wind gusts, and flash flooding throughout the day Tuesday. The National Weather Service has issued a tropical storm warning for the entire state with […]

For the second time in two weeks, a DelDOT employee was seriously injured on Harris Road near Townsend in New Castle County yesterday while mowing grass. The employee was flown to the hospital as a result of the injuries he sustained and remains hospitalized. The driver was charged with driving without a license, not having […]

From left to right: Jana Tidwell from AAA Mid-Atlantic, Delaware State Police Sergeant Heather Pepper, Lieutenant Governor Bethany Hall-Long, Daria Benson and family (DelDOT), Tom Neubauer (Kiewit), Jason Sacco (DelDOT), Sarah Powell and family (DelDOT), Secretary of Transportation Nicole Majeski at NWZAW event in Wilmington The Delaware Department of Transportation (DelDOT) encourages everyone to take […]

As the 4th of July holiday weekend approaches, the Delaware Department of Transportation (DelDOT) advises motorist to expect heavy traffic volumes on roads throughout the state. AAA Mid-Atlantic is forecasting more than 116,000 Delawareans will travel at least 50 miles during the holiday weekend. In addition, DelDOT reminds motorists that there will be many pedestrians […]

The BMW Championship begins next week at the Wilmington Country Club and will bring thousands of visitors to northern Delaware for the nearly weeklong event that concludes on Sunday, August 21, 2022. DelDOT is reminding residents and vistors to expect heavier traffic volumes on area roads during the tournament, and will be working with Delaware […]

The Delaware Department of Transportation (DelDOT) has recently installed a wrong way driving detection and alert system on the Exit 95 off-ramp from SR 1 northbound to Bay Road and SR 10 (E Lebanon Road) near the Dover Air Force Base North Gate. The alert system is the first of its kind in Delaware to […]

As the Memorial Day weekend approaches, DelDOT is reminding the public to expect crowded roads as AAA projects more than 42 million people nationally will travel 50 miles or more from home this holiday weekend. “Thousands of people will be visiting Delaware’s beaches and parks or traveling to see family and friends and we encourage […]

The Delaware Department of Transportation and Delaware Emergency Management Agency (DEMA)  are issuing a travel advisory for this afternoon and evening due to poor visibility from heavier snowfall and freezing on road surfaces tonight as temperatures drop. The advisory is not an official Level 1 Driving Warning, but is meant to caution motorists of adverse weather conditions and to stay off roads if possible. If driving is necessary, motorists are urged to use caution and common sense.

Secretary of Transportation Nicole Majeski was joined by representatives of the Delaware State Police and AAA Mid-Atlantic on Monday at the 95/896 interchange project to call attention to the importance of safe driving in our work zones across the state. National Work Zone Awareness Week is held each April at the traditional start of construction […]

Secretary of Transportation Nicole Majeski joined state and local officials to celebrate the opening of the $21 million first phase of the Park Avenue relocation project on Friday. The nearly two-mile segment of road included reconstruction of Arrow Safety Road from Route 113 to S. Bedford Street, a new roundabout at the intersection of S. […]

Monday, July 22, 2024, the U.S. Environmental Protection Agency (EPA) announced the recipients of the innovative “Climate Pollution Reduction Grant” (CPRG) program, created under the Federal Inflation Reduction Act to invest in a cleaner and safer future. The Delaware Department of Transportation (DelDOT) is proud to announce that the Clean Corridor Coalition is among the […]

The Delaware Department of Transportation’s (DelDOT) “Name That Plow Contest” returns for its fourth year! As winter approaches, we are excited to host this contest again and give kids (K-5) across Delaware the opportunity to name some of our snowplows. There were over 200 entries last year and the winning names were Ice Ice Bladey, […]

The Delaware Department of Transportation (DelDOT) announces that Moody’s Investors Service, Inc. has assigned an Aaa rating to the Delaware Transportation Authority, their highest rating, and S&P Global Ratings assigned its second highest rating of AA+ long-term rating to the department’s $150.5 million series 2024 transportation system senior revenue bond sale that will be issued […]

Read the in depth Review of Amazon Echo Dot Internet of Things. Know detailed info about Amazon Echo Dot configuration, design and performance quality along with pros & cons, Digit rating, verdict based on user opinions/feedback.

Read the in depth Review of Amazon Echo Dot (5th Gen, 2023) Audio Video. Know detailed info about Amazon Echo Dot (5th Gen, 2023) configuration, design and performance quality along with pros & cons, Digit rating, verdict based on user opinions/feedback.

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

Feeding bees edible bits of hydrogel increases their odds of surviving pesticide exposure by 30 per cent

Title: Many Who Need Opioid OD Antidote the Most Can't Afford It
Category: Health News
Created: 8/22/2022 12:00:00 AM
Last Editorial Review: 8/22/2022 12:00:00 AM

The role of gastrin-releasing peptide receptor (GRPR) in various diseases, including cancer, has been extensively studied and has emerged as a promising therapeutic target. In this study, we successfully achieved the use of [²¹²Pb]Pb-DOTAM-GRPR1, comprising the α-particle generator, ²¹²Pb, combined with a GRPR-targeting peptide, GRPR1, in a prostate cancer model. Methods: Pharmacokinetics, toxicity, radiation dosimetry, and efficacy were assessed in GRPR-positive prostate tumor–bearing mice after intravenous administration of [²¹²Pb]Pb-DOTAM-GRPR1 (where DOTAM is 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane). Results: Preclinical studies have shown tumor targeting of up to 5 percent injected dose per gram over 24 h, and optimization of the drug formulation and quantity has led to minimized oxidation and off-target binding, respectively. Particularly, an increase in peptide amount from 28 to 280 ng was shown to reduce off-target uptake, especially at the level of the pancreas, by about 30%. Furthermore, dosimetry studies confirmed the kidney as the dose-limiting organ, and toxicity studies revealed that a nontoxic dose of up to 1,665 kBq could be injected into mice. Efficacy studies indicated a median survival time of 9 wk in the control group, which received only a buffer solution, compared with 19 wk in the group that received 4 injections of 370 kBq at 3-wk intervals. Conclusion: Taken together, these combined data demonstrate the safety, tolerability, and efficacy of [²¹²Pb]Pb-DOTAM-GRPR1, thus warranting further exploration in clinical trials.