Today, the latest issue of The Domain Name Industry Brief Quarterly Report was released by DNIB.com, showing the first quarter of 2024 closed with 362.4 million domain name registrations across all top-level domains (TLDs), an increase of 2.5 million domain name registrations, or 0.7%, compared to the fourth quarter of 2023. Domain name registrations also […]

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Today, the latest issue of The Domain Name Industry Brief Quarterly Report was released by DNIB.com, showing the second quarter of 2024 closed with 362.4 million domain name registrations across all top-level domains (TLDs), unchanged compared to the first quarter of 2024. Domain name registrations increased by 5.8 million, or 1.6%, year over year. Check […]

The post Domain Name Industry Brief Quarterly Report: DNIB.com Announces 362.4 Million Domain Name Registrations in the Second Quarter of 2024 appeared first on Verisign Blog.

Today, the latest issue of The Domain Name Industry Brief Quarterly Report was released by DNIB.com, showing the third quarter of 2024 closed with 362.3 million domain name registrations across all top-level domains (TLDs), a decrease of 0.1 million domain name registrations, or less than 0.05%, compared to the second quarter of 2024. Domain name […]

The post Domain Name Industry Brief Quarterly Report: DNIB.com Announces 362.3 Million Domain Name Registrations in the Third Quarter of 2024 appeared first on Verisign Blog.

Armie Hammer takes hilarious dig at “cannibal rapist” allegations in his podcast episode with his mother Dru. The Call By Your Name actor shed light on the sexual abuse and cannibal allegations – which cost his career – in a new podcast interview with his mother.The...

New archaeological evidence shows that ancient humans ate each other surprisingly often - sometimes for compassionate reasons. The finds give us an opportunity to reassess our views on the practice

Metastatic porocarcinomas (PCs) are vanishingly rare, highly aggressive skin adnexal tumors with mortality rates exceeding 70%. Their rarity has precluded the understanding of their disease pathogenesis, let alone the conduct of clinical trials to evaluate treatment strategies. There are no effective agents for unresectable PCs. Here, we successfully demonstrate how functional precision medicine was implemented in the clinic for a metastatic PC with no known systemic treatment options. Comprehensive genomic profiling of the tumor specimen did not yield any actionable genomic aberrations. However, ex vivo drug testing predicted pazopanib efficacy, and indeed, administration of pazopanib elicited remarkable clinicoradiological response. Pazopanib and its class of drugs should be evaluated for efficacy in other cases of PC, and the rationale for efficacy should be determined when PC tumor models become available. A functional precision medicine approach could be useful to derive effective treatment options for rare cancers.

Combining two or more blood pressure medications can markedly medlinklower blood pressure/medlink in patients on ibrutinib. (!--ref1--) Targeted

Waters Corporation and NIBRT Partner to Bring Greater Control and Predictability to Biopharmaceutical Processing

Manchester : Manchester University Press, [2020]

This launch, which comes after several previous attempts, marks a major achievement as the first-ever controlled flight of a semi-cryogenic liquid engine realized through additive manufacturing

In its ninth edition this year, the festival is expected to draw at least 40,000 visitors, indicating a shift in destination tourism

[Amsterdam] : Cinema Delicatessen, [2015]

Lugduni : apud Hugonem à Porta, M. D. X L VI. [1546]

HP OmniBook Ultra Flip comes with HP Wolf Security to protect it against cyber threats

SAN DIEGO – Hoy, la Agencia de Protección Ambiental de Estados Unidos (EPA, por sus siglas en inglés), en coordinación con el Banco de Desarrollo de América del Norte (BDAN), emitió una Solicitud de Propuestas (RFP, por sus siglas en inglés) a través del Programa Frontera 2020.

Liverpool’s January transfer window of 2011 was a strange one. It was dominated by two names: Fernando Torres and Andy Carroll.

The Dominican Republic stands to benefit from integrating migration further into sectoral and national development strategies, says new joint OECD Development Centre – UNIBE report

After weathering the country’s worst recession, Candido Bracher is looking to expand

In this work, the mechanism of solvent-mediated desolvation transformation of lenvatinib mesylate (LM) was investigated. Two new solid forms of LM, a dimethyl sulfoxide (DMSO) solvate and an unsolvated form defined as form D, were discovered and characterized using powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, polarized light microscopy and Raman spectroscopy. To investigate the thermodynamic mechanism of solvent-mediated desolvation transformation (SMDT) from LM DMSO solvate to form D, solubilities of LM DMSO solvate and form D in binary solvent mixtures of DMSO and water at different water volume fractions and temperatures (293.15–323.15 K) were measured and correlated by non-random two liquids model. The solubility data were used to evaluate the thermodynamic driving force of the SMDT process from DMSO solvate to form D and the effect of the activities of water and DMSO on the transformation process. Raman spectroscopy was used to monitor in situ the solid phase compositions during the SMDT process from LM DMSO solvate to form D while the solution concentration was measured by the gravimetric method. The overall desolvation transformation experiments demonstrated that the SMDT process was controlled by the nucleation and growth of form D. Moreover, effects of operating factors on the SMDT process were studied and the results illustrated that water activity in solution was the paramount parameter in the SMDT process. Finally, a new SMDT mechanism was suggested and discussed.

The solvent-mediated desolvation process of newly discovered lenvatinib DMSO solvate to form II at different water volume fractions and temperatures was investigated. It is confirmed that the activity of water is the most important factor affecting the desolvation process: the desolvation process only occurs when the activity of water is greater than the activity of DMSO, and one new mechanism of solvent-mediated desolvation process was proposed.

A new study by a team of scientists from the Smithsonian’s National Museum of Natural History, the National University of Singapore and the Slovenian Academy of Sciences and Arts have unlocked the secret to mate binding in orb web spiders, and revealed just how it calms the cannibalistic female spider.

The post Suitor’s gentle massage soothes aggressive, cannibalistic female spiders, researchers find appeared first on Smithsonian Insider.

Douglas Owsley, the division head for physical anthropology at the Smithsonian’s National Museum of Natural History, presented today a forensic analysis of 17th-century human remains […]

The post Forensic analysis of 17th-century human remains at Jamestown, Va., reveals evidence of survival cannibalism appeared first on Smithsonian Insider.

Pullulanase (EC 3.2.1.41) is a well known starch-debranching enzyme that catalyzes the cleavage of α-1,6-glycosidic linkages in α-glucans such as starch and pullulan. Crystal structures of a type I pullulanase from Paenibacillus barengoltzii (PbPulA) and of PbPulA in complex with maltopentaose (G5), maltohexaose (G6)/α-cyclodextrin (α-CD) and β-cyclodextrin (β-CD) were determined in order to better understand substrate binding to this enzyme. PbPulA belongs to glycoside hydrolase (GH) family 13 subfamily 14 and is composed of three domains (CBM48, A and C). Three carbohydrate-binding sites identified in PbPulA were located in CBM48, near the active site and in domain C, respectively. The binding site in CBM48 was specific for β-CD, while that in domain C has not been reported for other pullulanases. The domain C binding site had higher affinity for α-CD than for G6; a small motif (FGGEH) seemed to be one of the major determinants for carbohydrate binding in this domain. Structure-based mutations of several surface-exposed aromatic residues in CBM48 and domain C had a debilitating effect on the activity of the enzyme. These results suggest that both CBM48 and domain C play a role in binding substrates. The crystal forms described contribute to the understanding of pullulanase domain–carbohydrate interactions.

Liza Botros MD., Manon C. A. Pronk PhD., Jenny Juschten MD., John Liddle, Sofia K. S. H. Morsing, Jaap D. van Buul PhD., Robert H. Bates, Pieter R. Tuinman MD. PhD., Jan S. M. van Bezu, Stephan Huveneers PhD., Harm Jan Bogaard MD. PhD., Victor W. M. van Hinsbergh PhD., Peter L. Hordijk PhD., and Jurjan Aman MD. PhD.

Aims: Endothelial barrier dysfunction leads to edema and vascular leak, carrying high morbidity and mortality. Previously, Abl kinase inhibition was shown to protect against vascular leak. Using the distinct inhibitory profiles of clinically available Abl kinase inhibitors, we aimed to provide a mechanistic basis for novel treatment strategies against vascular leakage syndromes.

Methods & Results: Bosutinib most potently protected against inflammation-induced endothelial barrier disruption. In vivo, bosutinib prevented LPS-induced alveolar protein extravasation in an acute lung injury mice model. Mechanistically, Mitogen-activated Protein 4 Kinase 4 (MAP4K4) was identified as important novel mediator of endothelial permeability, which signals via ezrin, radixin and moesin proteins to increase turnover of integrin-based focal adhesions. The combined inhibition of MAP4K4 and Arg by bosutinib preserved adherens junction integrity and reduced turnover of focal adhesions, which synergistically act to stabilize the endothelial barrier during inflammation.

Conclusion: MAP4K4 was identified as important regulator of endothelial barrier integrity, increasing focal adhesion turnover and disruption of cell-cell junctions during inflammation. Inhibiting both Arg and MAP4K4, the clinically available drug bosutinib may form a viable strategy against vascular leakage syndromes.

Pellagra, which is caused by a deficiency in vitamin B3 (niacin), showing up in hamsters because of large-scale monoculture.

James Allworth, regular contributor to HBR and coauthor of the Nieman Reports article "Breaking News: Mastering the Art of Disruptive Innovation in Journalism."

We created the program identity and website for this City of Sanibel initiative.

The present invention provides compounds for the inhibition of soluble epoxide hydrolase and associated disease conditions.

Materials and methods for treating and preventing American Foulbrood disease in honeybees, such as materials and methods for using phage lysin enzymes to lyse Paenibacillus larvae, are provided herein.

Shares of RedHill Biopharma Ltd. (RDHL) are moving up over 9% in pre-market today, after the company announced that the U.S. FDA has approved its Investigational New Drug or IND application for a Phase 2a clinical study evaluating its investigational drug, opaganib, in patients with confirmed moderate-to-severe SARS-CoV-2 infection, the cause of COVID-19.

Silicon Valley company AREVO has announced a partnership with boutique bike manufacturer Franco Bicycles to deliver the world’s first 3D printed, continuous carbon fiber single-piece unibody frame for a new line of eBikes.

Erowid Exp98591

NIH clinical trial testing antiviral remdesivir plus anti-inflammatory drug baricitinib for COVID-19 begins  National Institutes of HealthView Full coverage on Google News

The Envelope likes to judge a film's chances of winning the best picture Oscar by seeing whether it echoes any previous winners, and these do. Sort of.

Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ2 (PLCγ2). The PLCγ2 variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lck/Yes-related novel tyrosine kinase (LYN). The sensitivity of the PLCγ2 variants to BTK itself has remained unknown. Here, using genetically-modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ2-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca2+]i), we show that various CLL-specific PLCγ2 variants such as PLCγ2S707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ2 phospholipid substrate supply. At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca2+]i. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs.

Applications for the $1.3 billion in subsidies earmarked for registered owners of goods vehicles and green minibus operators under the Anti-epidemic Fund opened today, the Transport Department announced.

A one-off non-accountable subsidy of $10,000 will be provided to each registered goods vehicle owner for each goods vehicle.

From today until September 30, registered owners of goods vehicles who have received the department's letters must use the registration PIN provided in the letters for submission of registrations through GovHK.

After successful completion of registration, the subsidy will be disbursed to the designated local bank account provided in the registration through autopay in about two to three weeks.

Cross-boundary goods vehicle drivers who conduct nucleic acid tests in Hong Kong can apply for the subsidy on an accountable basis, with the maximum amount being $350 per test.

A one-off non-accountable subsidy of $30,000 per green minibus will be provided to each holder of a Passenger Service Licence-Public Light Bus (Scheduled) Service who has been approved to operate a relevant green minibus route package.

The department briefed the green minibus trade today on the subsidy arrangement and application details with the distribution of the application forms.

Green minibus operators are required to send the completed application forms to the department by post on or before September 30.

After the department has verified their submissions, the subsidy will be disbursed through autopay in about one month.

To assist the transport trades to cope with operational demands in the prevailing economic environment, the Government has rolled out the fuel subsidy and one-off subsidy measures under the first round of the Anti-epidemic Fund progressively.

As of mid-April, the department has received applications for subsidies from three franchised bus companies, 10 franchised and licensed ferry operators, Hong Kong Tramways Limited, registrations from 1,700 registered owners of non-franchised public buses, school private light buses and hire cars. Over $100 million of the subsidies have been disbursed.

Click here for details.

Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ2 (PLCγ2). The PLCγ2 variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lck/Yes-related novel tyrosine kinase (LYN). The sensitivity of the PLCγ2 variants to BTK itself has remained unknown. Here, using genetically-modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ2-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca2+]i), we show that various CLL-specific PLCγ2 variants such as PLCγ2S707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ2 phospholipid substrate supply. At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca2+]i. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs.

(NIH/National Institute of Allergy and Infectious Diseases) A randomized, controlled clinical trial evaluating the safety and efficacy of a treatment regimen of the investigational antiviral remdesivir plus the anti-inflammatory drug baricitinib for COVID-19 has begun. The trial is now enrolling hospitalized adults with COVID-19 in the United States. The trial is expected to open at approximately 100 US and international sites. Investigators currently anticipate enrolling more than 1,000 participants. The National Institute of Allergy and Infectious Diseases is sponsoring the trial.

(University of Southern Denmark) Investing in the future: Researchers show how cannibalism among the invasive comb jelly enables adults to survive severe conditions at the edge of their ecological range with implications for the use and evolutionary origins of cannibalism.

We developed a first-of-kind dasatinib-derivative imaging agent, ¹⁸F-SKI-249380 (¹⁸F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assess the feasibility of using ¹⁸F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min post-injection of ¹⁸F-SKI (mean: 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney (n = 2) or three 10-min whole-body PET/CT scans (n = 3) immediately post-injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of three patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of ¹⁸F-SKI. A total of 27 tumor lesions were analyzed with median SUVpeak 1.4 (range, 0.7–2.3) and tumor-to-blood ratios of 1.6 (range, 0.8–2.5) at 90 min post-injection. Intratumoral drug concentrations calculated for four reference lesions ranged from 0.03–0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30–90 min post-injection. Blood radio-assay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time 1.31 ± 0.81 min, plasma 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time 285 ± 148.49 min, plasma 240 ± 84.85 min; n = 2) or a small rise to plateau (n = 2). Like dasatinib, ¹⁸F-SKI underwent extensive metabolism post-administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 (SD 0.0034) mSv/MBq. Conclusion: ¹⁸F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.

In randomized clinical trials (RCTs), no survival benefit has been observed for selective internal radiotherapy (SIRT) over sorafenib in patients with advanced hepatocellular carcinoma (aHCC). This study aimed to assess by means of a meta-analysis whether overall survival (OS) with SIRT, as monotherapy or followed by sorafenib, is non-inferior to sorafenib, and compare safety profiles for patients with aHCC. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library up to February 2019 to identify RCTs comparing SIRT as monotherapy, or followed by sorafenib, to sorafenib monotherapy among patients with aHCC. The main outcomes were OS and frequency of treatment-related severe adverse events (AEs grade ≥3). The per-protocol population was the primary analysis population. A non-inferiority margin of 1.08 in terms of hazard ratio (HR) was pre-specified for the upper boundary of 95% confidence interval (CI) for OS. Pre-specified subgroup analyses were performed. Results: Three RCTs, involving 1,243 patients, comparing sorafenib with SIRT (SIRveNIB and SARAH) or SIRT followed by sorafenib (SORAMIC), were included. After randomization, 411/635 (64.7%) patients allocated to SIRT and 522/608 (85.8%) allocated to sorafenib completed the studies without major protocol deviations. Median OS with SIRT, whether or not followed by sorafenib, was non-inferior to sorafenib (10.2 and 9.2 months, [HR 0.91, 95% CI 0.78–1.05]). Treatment-related severe adverse events were reported in 149/515 patients (28.9%) who received SIRT and 249/575 (43.3%) who received sorafenib only (p<0.01). Conclusion: SIRT as initial therapy for aHCC is non-inferior to sorafenib in terms of OS, and offers a better safety profile.

Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ2 (PLCγ2). The PLCγ2 variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lck/Yes-related novel tyrosine kinase (LYN). The sensitivity of the PLCγ2 variants to BTK itself has remained unknown. Here, using genetically-modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ2-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca2+]i), we show that various CLL-specific PLCγ2 variants such as PLCγ2S707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ2 phospholipid substrate supply. At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca2+]i. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs.

Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD8+) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD8+ T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of ⁸⁹Zr-IAB22M2C, a radiolabeled minibody against CD8+ T cells, for targeted imaging of CD8+ T cells in patients with cancer. Methods: The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of ⁸⁹Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1–2, 6–8, 24, 48, and 96–144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Results: ⁸⁹Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time–activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24–48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most ⁸⁹Zr-IAB22M2C–positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Conclusion: ⁸⁹Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell–rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD8+ T-cell accumulation within tumors. Further evaluation is under way.