Investing in tomorrow while honoring the past As the nation wraps up its Memorial Day observances, Delawareans eagerly anticipate another significant celebration just two days later. May 29th marks 529 Day, a time aimed at highlighting the critical importance of saving for higher education through 529 education savings plans. These plans, named after Section 529 […]

The Delaware Natural Resources Police reports black bear was struck and killed by a vehicle in Newark, with DNREC biologists to conduct an examination of the bear.

DOVER, Del. — As the 152nd General Assembly comes to a close, Lt. Governor Bethany Hall-Long on Sunday highlighted historic investments in early education, protections for reproductive justice, and actions that support a safe, healthy, and thriving Delaware.    “As second in command for the past seven years, I’ve had the privilege of serving with […]

Hi everyone. 

I'm very a new cadence user. I'm not good at using it and quite lost in finding a way to get the results. With the topic, I would like to ask you for some suggestions to improve my cadence skills.

I have some digital decision logic. Some are combinational logic, some are sequential logic that I would like to import or generate random input combination to the inputs of my decision logic to get the maximum, minimum, and average delay power dissipation and area when feeding the different input combination.

My logic has 8-bit, 16-bit, and 32-bit input. The imported data tends to be decimal numbers.

I would like to ask you:

- which tool(s) are the most appropriate to import and feed the different combination to my decision logic?

- which tool is the most appropriate to synthesis with different number of input? - I have used Genus Synthesis Solution so far. However with my skill right now I can only let Genus synthesize my Verilog code one setup at a time. I'm not sure if I there is anyway I can feed a lot of input at a time and get those results (min, max, average of delay, power dissipation and area)

- which language or scripts I should pick up to use and achieve these results?

-where can I find information to solve my problem? which information shall I look for?

Thank you so much for your time!!

Best Regards

Hello,

I would like to create a button for my form that prompts the user to click on a cellview and draw a rectangle bounding box, exactly like the one used in the Area and Density Calculator. Can someone please help me with this?

Thanks!

Beto

Rejoice Muzamani is studying in preparation for her next paper during the end-of-term examinations at Mwenje Primary School in Chiredzi, southeast Zimbabwe. The 13-year-old girl, who is in Grade 7 or final year of primary school, is not worried about leaving school early to make the 7-kilometer journey back home before dusk, risking attacks from […]

ADB sought to understand what improving transport meant for the community. Prior to project design, consultations were conducted with residents in Ulaanbaatar’s ger areas. Design decisions were tested back to ensure that mobility pain points were addressed.

An area of the seabed north of Australia has been mapped in detail for the first time, revealing that large numbers of people could have lived there until it was inundated by rising seas

The dorsal vagal complex contains three structures: the area postrema, the nucleus tractus solitarii, and the dorsal motor nucleus of the vagus. These structures are tightly linked, both anatomically and functionally, and have important yet distinct roles in not only conveying peripheral bodily signals to the rest of the brain but in the generation of behavioral and physiological responses. Reports on the new discoveries in these structures were highlights of the symposium. In this outlook, we focus on the roles of the area postrema in mediating brain–body interactions and its potential utility as a therapeutic target, especially in cancer cachexia.

ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a membrane-bound transporter responsible for the efflux of various xenobiotics and endobiotics, including protoporphyrin IX (PPIX), an intermediate in the heme biosynthesis pathway. Certain genetic mutations and chemicals impair the conversion of PPIX to heme and/or increase PPIX production, leading to PPIX accumulation and toxicity. In mice, deficiency of ABCG2 protects against PPIX-mediated phototoxicity and hepatotoxicity by modulating PPIX distribution. In addition, in vitro studies revealed that ABCG2 inhibition increases the efficacy of PPIX-based photodynamic therapy by retaining PPIX inside target cells. In this review, we discuss the roles of ABCG2 in modulating the tissue distribution of PPIX, PPIX-mediated toxicity, and PPIX-based photodynamic therapy.

The regulation of drug-metabolizing enzymes and transporters by cytokines has been extensively studied in vitro and in clinic. Cytokine-mediated suppression of cytochrome P450 (CYP) or drug transporters may increase or decrease the systemic clearance of drug substrates that are primarily cleared via these pathways; neutralization of cytokines by therapeutic proteins may thereby alter systemic exposures of such drug substrates. The Food and Drug Administration recommends evaluating such clinical drug interactions during clinical development and has provided labeling recommendations for therapeutic proteins. To determine the clinical relevance of these drug interactions to dose adjustments, trends in steady-state exposures of CYP-sensitive substrates coadministered with cytokine modulators as reported in the University of Washington Drug Interaction Database were extracted and examined for each of the CYPs. Coadministration of cytochrome P450 family 3 subfamily A (CYP3A) (midazolam/simvastatin), cytochrome P450 subfamily 2C19 (omeprazole), or cytochrome P450 subfamily 1A2 (caffeine/tizanidine) substrates with anti-interleukin-6 and with anti-interleukin-23 therapeutics led to changes in systemic exposures of CYP substrates ranging from ~ –58% to ~35%; no significant trends were observed for cytochrome P450 subfamily 2D6 (dextromethorphan) and cytochrome P450 subfamily 2C9 (warfarin) substrates. Although none of these changes in systemic exposures have been reported as clinically meaningful, dose adjustment of midazolam for optimal sedation in acute care settings has been reported. Simulated concentration-time profiles of midazolam under conditions of elevated cytokine levels when coadministered with tocilizumab, suggest a ~six- to sevenfold increase in midazolam clearance, suggesting potential implications of cytokine–CYP drug interactions on dose adjustments of sensitive CYP3A substrates in acute care settings. Additionally, this article also provides a brief overview of nonclinical and clinical assessments of cytokine–CYP drug interactions in drug discovery and development.

The precision medicine initiative has driven a substantial change in the way scientists and health care practitioners think about diagnosing and treating disease. While it has long been recognized that drug response is determined by the intersection of genetic, environmental, and disease factors, improvements in technology have afforded precision medicine guided dosing of drugs to improve efficacy and reduce toxicity. Pharmacometabolomics aims to evaluate small molecule metabolites in plasma and/or urine to help evaluate mechanisms that predict and/or reflect drug efficacy and toxicity. In this mini review, we provide an overview of pharmacometabolomic approaches and methodologies. Relevant examples where metabolomic techniques have been used to better understand drug efficacy and toxicity in major depressive disorder and cancer chemotherapy are discussed. In addition, the utility of metabolomics in drug development and understanding drug metabolism, transport, and pharmacokinetics is reviewed. Pharmacometabolomic approaches can help describe factors mediating drug disposition, efficacy, and toxicity. While important advancements in this area have been made, there remain several challenges that must be overcome before this approach can be fully implemented into clinical drug therapy.

A STING (stimulator of interferon genes) agonist GSK3996915 under investigation in early discovery for hepatitis B was orally dosed to a mouse model for understanding the parent drug distribution in liver, the target organ. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to quantify the distribution of GSK3996915 in liver collected from mice administered a single oral dose at 90 mg/kg. GSK3996915 was detected with a zonal distribution localized in the portal triad and highly concentrated in the main bile ducts, indicating clearance through biliary excretion. High spatial resolution imaging showed the distribution of the parent drug localized to the cellular populations in the sinusoids, including the Kupffer cells. Additionally, a series of drug-related metabolites were observed to be localized in the central zones of the liver. These results exemplify the potential of utilizing MALDI IMS for measuring not only quantitative drug distribution and target exposure but also drug metabolism and elimination in a single suite of experiments.

Drug–drug interaction (DDI) assessment of therapeutic peptides is an evolving area. The industry generally follows DDI guidelines for small molecules, but the translation of data generated with commonly used in vitro systems to in vivo is sparse. In the current study, we investigated the ability of advanced human hepatocyte in vitro systems, namely HepatoPac, spheroids, and Liver-on-a-chip, to assess potential changes in regulation of CYP1A2, CYP2B6, CYP3A4, SLCO1B1, and ABCC2 in the presence of selected therapeutic peptides, proteins, and small molecules. The peptide NN1177, a glucagon and GLP-1 receptor co-agonist, did not suppress mRNA expression or activity of CYP1A2, CYP2B6, and CYP3A4 in HepatoPac, spheroids, or Liver-on-a-chip; these findings were in contrast to the data obtained in sandwich cultured hepatocytes. No effect of NN1177 on SLCO1B1 and ABCC2 mRNA was observed in any of the complex systems. The induction magnitude differed across the systems (e.g., rifampicin induction of CYP3A4 mRNA ranged from 2.8-fold in spheroids to 81.2-fold in Liver-on-a-chip). Small molecules, obeticholic acid and abemaciclib, showed varying responses in HepatoPac, spheroids, and Liver-on-a-chip, indicating a need for EC₅₀ determinations to fully assess translatability data. HepatoPac, the most extensively investigated in this study (3 donors), showed high potential to investigate DDIs associated with CYP regulation by therapeutic peptides. Spheroids and Liver-on-a-chip were only assessed in one hepatocyte donor and further evaluations are required to confirm their potential. This study establishes an excellent foundation toward the establishment of more clinically-relevant in vitro tools for evaluation of potential DDIs with therapeutic peptides.

Pregnane X receptor (PXR) belongs to the nuclear receptor superfamily that plays a crucial role in hepatic physiologic and pathologic conditions. Phase separation is a process in which biomacromolecules aggregate and condense into a dense phase as liquid condensates and coexist with a dilute phase, contributing to various cellular and biologic functions. Until now, whether PXR could undergo phase separation remains unclear. This study aimed to investigate whether PXR undergoes phase separation. Analysis of the intrinsically disordered regions (IDRs) using algorithm tools indicated a low propensity of PXR to undergo phase separation. Experimental assays such as hyperosmotic stress, agonist treatment, and optoDroplets assay demonstrated the absence of phase separation for PXR. OptoDroplets assay revealed the inability of the fusion protein of Cry2 with PXR to form condensates upon blue light stimulation. Moreover, phase separation of PXR did not occur even though the mRNA and protein expression levels of PXR target, cytochrome P450 3A4, changed after sorbitol treatment. In conclusion, for the first time, these findings suggested that exogenous PXR does not undergo phase separation following activation or under hyperosmotic stress in nucleus of cells.

Protein abundance data of drug-metabolizing enzymes and transporters (DMETs) are useful for scaling in vitro and animal data to humans for accurate prediction and interpretation of drug clearance and toxicity. Targeted DMET proteomics that relies on synthetic stable isotope-labeled surrogate peptides as calibrators is routinely used for the quantification of selected proteins; however, the technique is limited to the quantification of a small number of proteins. Although the global proteomics-based total protein approach (TPA) is emerging as a better alternative for large-scale protein quantification, the conventional TPA does not consider differential sequence coverage by identifying unique peptides across proteins. Here, we optimized the TPA approach by correcting protein abundance data by the sequence coverage, which was applied to quantify 54 DMETs for characterization of 1) differential tissue DMET abundance in the human liver, kidney, and intestine, and 2) interindividual variability of DMET proteins in individual intestinal samples (n = 13). Uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7), microsomal glutathione S-transferases (MGST1, MGST2, and MGST3) carboxylesterase 2 (CES2), and multidrug resistance-associated protein 2 (MRP2) were expressed in all three tissues, whereas, as expected, four cytochrome P450s (CYP3A4, CYP3A5, CYP2C9, and CYP4F2), UGT1A1, UGT2B17, CES1, flavin-containing monooxygenase 5, MRP3, and P-glycoprotein were present in the liver and intestine. The top three DMET proteins in individual tissues were: CES1>CYP2E1>UGT2B7 (liver), CES2>UGT2B17>CYP3A4 (intestine), and MGST1>UGT1A6>MGST2 (kidney). CYP3A4, CYP3A5, UGT2B17, CES2, and MGST2 showed high interindividual variability in the intestine. These data are relevant for enhancing in vitro to in vivo extrapolation of drug absorption and disposition and can be used to enhance the accuracy of physiologically based pharmacokinetic prediction of systemic and tissue concentration of drugs.

Hydrolases represent an essential class of enzymes indispensable for the metabolism of various clinically essential medications. Individuals exhibit marked differences in the expression and activation of hydrolases, resulting in significant variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by these enzymes. The regulation of hydrolase expression and activity involves both genetic polymorphisms and nongenetic factors. This review examines the current understanding of genetic and nongenetic regulators of six clinically significant hydrolases, including carboxylesterase (CES)-1 CES2, arylacetamide deacetylase (AADAC), paraoxonase (PON)-1 PON3, and cathepsin A (CTSA). We explore genetic variants linked to the expression and activity of the hydrolases and their effects on the PK and PD of their substrate drugs. Regarding nongenetic regulators, we focus on the inhibitors and inducers of these enzymes. Additionally, we examine the developmental expression patterns and gender differences in the hydrolases when pertinent information was available. Many genetic and nongenetic regulators were found to be associated with the expression and activity of the hydrolases and PK and PD. However, hydrolases remain generally understudied compared with other drug-metabolizing enzymes, such as cytochrome P450s. The clinical significance of genetic and nongenetic regulators has not yet been firmly established for the majority of hydrolases. Comprehending the mechanisms that underpin the regulation of these enzymes holds the potential to refine therapeutic regimens, thereby enhancing the efficacy and safety of drugs metabolized by the hydrolases.

PURPOSE

Currently, 40% of counties in the United States do not have an obstetrician or midwife, and in rural areas the likelihood of childbirth being attended to by a family medicine (FM) physician is increasing. We sought to characterize the effect of the FM presence on unit culture and a key perinatal quality metric in Iowa hospital intrapartum units.

WIDESPREAD rain fell across NSW at the weekend.

Mental health experts are hopeful about the de-stigmatization of behavioral health, the promise of AI and other areas, they shared at a recent conference.

The post 4 Areas Within Mental Health Care that Give Executives Hope appeared first on MedCity News.

Jun 11, 2015

The creation in June 2015 of a free trade area from Cape Town to Cairo is possibly the most significant event in Africa since the formation of the Organization of African Unity in 1963. It is a grand move to merge existing regional organization into a single African Economic Community.

McDowell's No.1 | #ShareAHug

Shigeru Miyamoto previews games, Golden Temple ride, more in Direct video

Brat Benatar

Highlights: India introduces the Aarogya Maitri Aid Cube, a portable hospital designed for swift deployment in

Study finds irrigation more common on city farms than rural farms, intensifying water demands in sprawling urban zones.

The post Press Release: First Global Estimate of Urban Agriculture Reveals Area Size of the EU that’s Boosting Food Security in Cities first appeared on International Water Management Institute (IWMI).

Unusual medlinkarsenic/medlink release from wildfires poses a huge threat to human and environmental health, reveals a new study. The findings of

A dental tool is created by University of Washington researchers to measure the acidity built up by the bacteria in tooth surface that leads to cavities.

Researchers discovered that medlinkchildren/medlink in highly deprived areas are three times more prone to severe tooth decay requiring hospital dental

The Uttar Pradesh health department has adopted YouTube as a platform for ongoing medical education and professional development of government doctors stationed in remote areas (!--ref1--).

While disaster-induced migration tends to be short-term, slow-onset climate-induced migration may be more permanent and on a larger scale.

The post The hidden crisis of disaster displacement and host community struggles in rural areas of Pakistan first appeared on International Water Management Institute (IWMI).

IWMI researcher says study measuring the burden of living in flood-prone areas addresses a gap in research in quantifying the broader health impacts of floods.

The post Infants at higher risk in flood-prone areas of Bangladesh first appeared on International Water Management Institute (IWMI).

While India commemorates a decade of polio-free status, sustained vigilance and vaccination efforts are essential to safeguard the nation's children.

With the peak travel rush behind them, accommodation owners are eyeing 2025 and beyond, setting their sights on strategic investments they believe will help drive and sustain positive industry growth and provide a sharp competitive edge. Where do they see they’ll get the most bang for their buck?

The WHO has issued a report urging the prioritization of health in climate action. The report, developed with over 100 organizations, calls for an end to fossil fuel reliance and investment in sustainable alternatives.

The personnel deputed for election duty were sent on Monday to 225 polling stations located in remote and inaccessible areas of five districts of the state -- West Singhbhum, Latehar, Lohardaga, Gumla and Garhwa.

The Regional Meteorological Centre (RMC) has issued a yellow alert from November 12 to November 15, warning of heavy to very heavy rainfall expected in Chennai and 15 other districts in Tamil Nadu.

Operatorul bursei elvețiene, SIX Group AG, a convenit achiziția Aquis Exchange Plc, o bursă de tranzacționare și furnizor de date din Marea Britanie, într-o tranzacție cu o valoare de aproximativ 194 milioane de lire sterline (250 milioane de dolari), potrivit Bloomberg. Conform unui comunicat de presă emis luni, consiliul Aquis a recomandat în unanimitate această ...

The post Bursa elvețiană cumpără Aquis din Marea Britanie în cea mai mare achiziție din 2020 appeared first on Forbes Romania.

Adunarea Generală a creditorilor companiei Angst a aprobat valorificarea a patru spații comerciale din București și unul din Ilfov, cu valoare totală de piață de 3,6 milioane de euro. Infinexa, companie antreprenorială românească specializată în restructurarea și finanțarea firmelor aflate în dificultate, anunță scoaterea la licitație a cinci spații comerciale ce aparțin procesatorului de carne ...

The post Creditorii companiei Angst au aprobat vânzarea unor spații comerciale în valoare de 3,6 milioane de euro appeared first on Forbes Romania.

BASF a primit aprobarea de finanțare din partea Ministerului Federal German pentru Afaceri Economice și Acțiune Climatică pentru construcția celei mai puternice pompe de căldură industriale din lume. Astfel, în următoarele luni, compania va putea începe lucrările de construcție pregătitoare pentru acest proiect la platforma sa din Ludwigshafen. Proiectul își propune să aducă o contribuție ...

The post BASF primește aprobarea de finanțare pentru construcția celei mai mari pompe de căldură industriale din lume appeared first on Forbes Romania.

The National Association of Realtors on Tuesday said that home prices in the second quarter rose in 163 out of 176 metro areas, continuing their upward trajectory even as economists warn of looming affordability problems and a limited supply of homes for sale.

Life is full of small temptations that seem harmless like hitting snooze one more time when it's time to wake up for work in the morning, scrolling endlessly when you have to get some good night's sleep. It feels satisfying at

Porsche Cars North America announces Meike Ludewig as the new Vice President for Area West, succeeding Trevor Arthur. Learn more about her career.

In some areas of the national capital, the air quality dropped to the severe category, with an AQI in the range of 400.

Several parts of east, northeast and south Delhi and areas under the New Delhi Municipal Council will be affected, it said.

London : Faber & Faber (Plays), 1999.