DOVER, DEL. (Sept. 16, 2024) – The Delaware Coalition for Injury Prevention’s Falls Prevention Team asks Delawareans to reduce broken bones, head injuries, and disabilities by preventing falls. Governor John Carney and Lieutenant Governor Bethany Hall-Long proclaimed Sep. 23 to 27, 2024 as Falls Prevention Awareness Week. A fall can impact a person’s mobility, functionality, and […]

A series of community engagement sessions in late October is planned to gather input on updating the state’s Climate Action Plan.

Fight back against sophisticated money launderers with these 3 techniques.

The post 3 techniques to improve AML transaction monitoring strategies appeared first on The Data Roundtable.

Read this blog for an overview to the Circuit physical verification and parasitic extraction design stage in the Custom IC Design methodology and the key design steps which can help you achieve this.(read more)

Research by fDi Intelligence reveals which cities received the most tech start-up FDI relative to their population between 2016 and 2018, with European cities coming out on top.

From historically underperforming when compared with its peers, the German federal state of Rhineland-Palatinate is now attracting major investment projects on the back of its auto and electrification expertise.

Giant investment firm BlackRock throwing its weight behind sustainability issues is sending a signal to the corporate world to respond urgently to global calls for action, writes Gregg Wassmansdorf.

United Nations — The U.N. Secretary-General appealed Monday to developed nations to make good on their promise of $100 billion a year to support climate action in developing countries, ahead of a November climate review conference in Egypt.   “Funding for adaptation and resilience must represent at least half of all climate finance,” Antonio Guterres told reporters.    Ministers, climate experts and civil society representatives are meeting this week in the Congolese capital, Kinshasa, to prepare the agenda for the November meeting, known as COP27, which will take place in the Red Sea resort of Sharm el-Sheikh from November 6 to 18.    The United Nations says G-20 countries account for 80% of global emissions, but they have been slow to deliver on their $100 billion annual pledge.   “Taken together, current pledges and policies are shutting the door on our chance to limit global temperature rise to 2 degrees Celsius, let alone meet the 1.5-degree goal,” he said of the benchmarks set in the 2015 Paris Climate Agreement.    The U.N. warns that failure to reach those goals would spell climate catastrophe.   “The world can’t wait,” he added. “Emissions are at an all-time high and rising.”   Guterres said every government, business, investor and institution must step up with concrete climate action plans.    “I am urging leaders at the highest level to take full part in COP27 and tell the world what climate action they will take nationally and globally,” the U.N. chief said.    U.S. Special Presidential Envoy for Climate John Kerry is among the leaders in Kinshasa this week.   

By staying silent, these bystanders betray themselves, their communities, and democratic ideals—abandoning Amsterdam’s Israeli and Jewish guests.

The situation of local fruit vendors has gone from bad to worse after the Thai Pesticide Alert Network (Thai-PAN) released its finding two weeks ago, revealing chemical contamination in popular Shine Muscat grapes.

The act of planting trees offers more than shade and fruit. It symbolizes a deeper mission—restoring soil, preserving water, and, for these students, living in Tanzania’s northern Rorya district, delivering a form of climate justice. The reforestation efforts are in step with Tanzania's broader plans to fortify its agriculture and water systems against the advancing climate crisis.

The United Nations Environment Programme’s (UNEP) 2024 Adaptation Gap Report has warned that adaptation actions are not keeping pace with the surging demands of a warming planet. Released ahead of the COP29 climate conference in Baku, Azerbaijan, the report—titled Come Hell and High Water—projected a bleak future where vulnerable communities bear the brunt of climate-induced hardships.  […]

The Paris Agreement on climate change is a decade old this month. While there has been progress – with new net zero pledges and new technological solutions, we are still grappling with the reality that global temperatures continue to soar. 2023 was the hottest year ever on record. This alarming trend poses grave consequences for […]

Scientists warn of vastly higher impacts on billions of people’s livelihood and cost to the global economy by the accelerating losses in the world’s snow and ice regions, aka the cryosphere. Over 50 leading cryosphere scientists released an annual report on the status of the world’s ice stores on Tuesday (November 12) at the UN […]

This infographic examines how extreme heat disproportionately impacts women in Asia and the Pacific, presenting data on health and economic vulnerabilities shaped by intersecting factors like age, hormonal influences, caregiving roles, and limited cooling access.

Bamboo value chain can be developed and scaled up to support climate action, create green jobs, resilient businesses, and financial health, especially for the region's rural communities.

Climate change poses an increasing threat to people and their livelihoods. Record heat waves, catastrophic floods, prolonged droughts, and other extreme weather events in Asia and the Pacific are becoming more frequent.

Inclusive sports can empower women with disabilities, and foster accessibility, social integration, and gender equality in the Pacific. Recent Paralympic milestones and policy examples illustrate the ongoing need for supportive infrastructures and greater representation to create equitable opportunities in sports.

These charts illustrate that despite the broader adoption of disaster risk reduction strategies, escalating greenhouse gas emissions and intensified disaster impacts underscore the urgent need for more robust climate action and support across the region.

to write a reaction paper book

This publication provides updated statistics on a comprehensive set of economic, financial, social, and environmental measures as well as select indicators for the Sustainable Development Goals (SDGs).

Experiments in a wind tunnel have revealed why the sling action bowling technique made famous by Sri Lankan cricketer Lasith Malinga is so effective at hoodwinking whoever is batting

The books, TV, games and more that New Scientist staff have enjoyed this week

Title: Fast Action Can Prevent Sepsis Death: CDC
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Title: Serious Reactions to Vaccines Rarely Recur: Review
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Title: Tourist With Measles Visited Southern California Attractions
Category: Health News
Created: 8/26/2019 12:00:00 AM
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Most studies of genome organization have focused on intrachromosomal (cis) contacts because they harbor key features such as DNA loops and topologically associating domains. Interchromosomal (trans) contacts have received much less attention, and tools for interrogating potential biologically relevant trans structures are lacking. Here, we develop a computational framework that uses Hi-C data to identify sets of loci that jointly interact in trans. This method, trans-C, initiates probabilistic random walks with restarts from a set of seed loci to traverse an input Hi-C contact network, thereby identifying sets of trans-contacting loci. We validate trans-C in three increasingly complex models of established trans contacts: the Plasmodium falciparum var genes, the mouse olfactory receptor "Greek islands," and the human RBM20 cardiac splicing factory. We then apply trans-C to systematically test the hypothesis that genes coregulated by the same trans-acting element (i.e., a transcription or splicing factor) colocalize in three dimensions to form "RNA factories" that maximize the efficiency and accuracy of RNA biogenesis. We find that many loci with multiple binding sites of the same DNA-binding proteins interact with one another in trans, especially those bound by factors with intrinsically disordered domains. Similarly, clustered binding of a subset of RNA-binding proteins correlates with trans interaction of the encoding loci. We observe that these trans-interacting loci are close to nuclear speckles. These findings support the existence of trans-interacting chromatin domains (TIDs) driven by RNA biogenesis. Trans-C provides an efficient computational framework for studying these and other types of trans interactions, empowering studies of a poorly understood aspect of genome architecture.

As a major type of structural variants, tandem duplication plays a critical role in tumorigenesis by increasing oncogene dosage. Recent work has revealed that noncoding enhancers are also affected by duplications leading to the activation of oncogenes that are inside or outside of the duplicated regions. However, the prevalence of enhancer duplication and the identity of their target genes remains largely unknown in the cancer genome. Here, by analyzing whole-genome sequencing data in a non-gene-centric manner, we identify 881 duplication hotspots in 13 major cancer types, most of which do not contain protein-coding genes. We show that the hotspots are enriched with distal enhancer elements and are highly lineage-specific. We develop a HiChIP-based methodology that navigates enhancer–promoter contact maps to prioritize the target genes for the duplication hotspots harboring enhancer elements. The methodology identifies many novel enhancer duplication events activating oncogenes such as ESR1, FOXA1, GATA3, GATA6, TP63, and VEGFA, as well as potentially novel oncogenes such as GRHL2, IRF2BP2, and CREB3L1. In particular, we identify a duplication hotspot on Chromosome 10p15 harboring a cluster of enhancers, which skips over two genes, through a long-range chromatin interaction, to activate an oncogenic isoform of the NET1 gene to promote migration of gastric cancer cells. Focusing on tandem duplications, our study substantially extends the catalog of noncoding driver alterations in multiple cancer types, revealing attractive targets for functional characterization and therapeutic intervention.

The analysis of extractables and leachables and subsequent risk assessment is an important aspect of the determination of biocompatibility for many medical devices. Leachable chemicals have the potential to pose a toxicological risk to patients, and therefore it is required that they be adequately characterized and assessed for potential safety concerns. One important consideration in the assessment of leachables is the choice of a suitable simulating solvent intended to replicate the use condition for the device and its biological environment. This aspect of study design is especially difficult for blood-contacting medical devices due to the complexity of simulating the biological matrix. This publication reports a comparison of the extracting power of different binary solvent mixtures and saline in comparison with whole blood for a bloodline tubing set connected to a hemodialyzer. Ten different known extractables, spanning a range of physicochemical properties and molecular weights, were quantified. The results indicated that for low-molecular-weight analytes, a suitable exaggeration for whole blood can be obtained using a low-concentration ethanol/water mixture (20%), and in general, extracted quantity increases with the concentration of alcohol cosolvent. For polyvinylpyrrolidone, the opposite trend was observed, as solubility of the polymer was found to decrease with increasing alcohol concentration, resulting in lower extracted quantities at high alcohol concentrations. Analysis of ethanol/water concentrations in the extract solutions post extraction indicated no change in solvent composition.

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.

End-to-end RNA-sequencing methods that capture 5'-sequence content without cumbersome library manipulations are of great interest, particularly for analysis of long RNAs. While template-switching methods have been developed for RNA sequencing by distributive short-read RTs, such as the MMLV RTs used in SMART-Seq methods, they have not been adapted to leverage the power of ultraprocessive RTs, such as those derived from group II introns. To facilitate this transition, we dissected the individual processes that guide the enzymatic specificity and efficiency of the multistep template-switching reaction carried out by RTs, in this case, by MarathonRT. Remarkably, this is the first study of its kind, for any RT. First, we characterized the nucleotide specificity of nontemplated addition (NTA) reaction that occurs when the RT extends past the RNA 5'-terminus. We then evaluated the binding specificity of specialized template-switching oligonucleotides, optimizing their sequences and chemical properties to guide efficient template-switching reaction. Having dissected and optimized these individual steps, we then unified them into a procedure for performing RNA sequencing with MarathonRT enzymes, using a well-characterized RNA reference set. The resulting reads span a six-log range in transcript concentration and accurately represent the input RNA identities in both length and composition. We also performed RNA-seq from total human RNA and poly(A)-enriched RNA, with short- and long-read sequencing demonstrating that MarathonRT enhances the discovery of unseen RNA molecules by conventional RT. Altogether, we have generated a new pipeline for rapid, accurate sequencing of complex RNA libraries containing mixtures of long RNA transcripts.

Early detection of drug-drug interactions (DDIs) can facilitate timely drug development decisions, prevent unnecessary restrictions on patient enrollment, resulting in clinical study populations that are not representative of the indicated study population, and allow for appropriate dose adjustments to ensure safety in clinical trials. All of these factors contribute to a streamlined drug approval process and enhanced patient safety. Here we describe a new approach for early prediction of the magnitude of change in exposure for cytochrome P450 (P450) CYP3A4-related DDIs of small-molecule anticancer drugs based on the model-based extrapolation of human-CYP3A4-transgenic mice pharmacokinetics to humans. Victim drugs brigatinib and lorlatinib were evaluated with the new approach in combination with the perpetrator drugs itraconazole and rifampicin. Predictions of the magnitude of change in exposure deviated at most 0.99- to 1.31-fold from clinical trial results for inhibition with itraconazole, whereas exposure predictions for the induction with rifampicin were less accurate, with deviations of 0.22- to 0.48-fold. Results for the early prediction of DDIs and their clinical impact appear promising for CYP3A4 inhibition, but validation with more victim and perpetrator drugs is essential to evaluate the performance of the new method.

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.

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.

The -aminobutyric acid type A (GABA_A) receptor is modulated by a number of neuroactive steroids. Sulfated steroids and 3β-hydroxy steroids inhibit, while 3α-hydroxy steroids typically potentiate the receptor. Here, we have investigated inhibition of the α1β32L GABA_A receptor by the endogenous neurosteroid 3α-hydroxy-5β-pregnan-20-one (3α5βP) and the synthetic neuroactive steroid 3α-hydroxy-5α-androstane-17β-carbonitrile (ACN). The receptors were expressed in Xenopus oocytes. All experiments were done using two-electrode voltage-clamp electrophysiology. In the presence of low concentrations of GABA, 3α5βP and ACN potentiate the GABA_A receptor. To reveal inhibition, we conducted the experiments on receptors activated by the combination of a saturating concentration of GABA and propofol to fully activate the receptors and mask potentiation, or on mutant receptors in which potentiation is ablated. Under these conditions, both steroids inhibited the receptor with IC₅₀s of ~13 μM and maximal inhibitory effects of 70–90%. Receptor inhibition by 3α5βP was sensitive to substitution of the α1 transmembrane domain (TM) 2-2' residue, previously shown to ablate inhibition by pregnenolone sulfate. However, results of coapplication studies and the apparent lack of state dependence suggest that pregnenolone sulfate and 3α5βP inhibit the GABA_A receptor independently and through distinct mechanisms. Mutations to the neurosteroid binding sites in the α1 and β3 subunits statistically significantly, albeit weakly and incompletely, reduced inhibition by 3α5βP and ACN.

This review explores the concept of synergy in pharmacology, emphasizing its importance in optimizing treatment outcomes through the combination of drugs with different mechanisms of action. Synergy, defined as an effect greater than the expected additive effect elicited by individual agents according to specific predictive models, offers a promising approach to enhance therapeutic efficacy while minimizing adverse events. The historical evolution of synergy research, from ancient civilizations to modern pharmacology, highlights the ongoing quest to understand and harness synergistic interactions. Key concepts, such as concentration-response curves, additive effects, and predictive models, are discussed in detail, emphasizing the need for accurate assessment methods throughout translational drug development. Although various mathematical models exist for synergy analysis, selecting the appropriate model and software tools remains a challenge, necessitating careful consideration of experimental design and data interpretation. Furthermore, this review addresses practical considerations in synergy assessment, including preclinical and clinical approaches, mechanism of action, and statistical analysis. Optimizing synergy requires attention to concentration/dose ratios, target site localization, and timing of drug administration, ensuring that the benefits of combination therapy detected bench-side are translatable into clinical practice. Overall, the review advocates for a systematic approach to synergy assessment, incorporating robust statistical analysis, effective and simplified predictive models, and collaborative efforts across pivotal sectors, such as academic institutions, pharmaceutical companies, and regulatory agencies. By overcoming critical challenges and maximizing therapeutic potential, effective synergy assessment in drug development holds promise for advancing patient care.

With 420,000 Quebec public sector workers on strike on Monday, and with little progress in negotiations, the Front Commun promises further strike action.

The post Hundreds of thousands of Quebec public sector workers vow further strike action appeared first on rabble.ca.

I was excited for Slitterhead, an action adventure game by Bokeh Studio, a studio founded by none other than your boy Keiichiro Toyama: the creator of Silent Hill, Gravity Rush, and the Siren series. And within that first hour, Slitterhead's body-possessing and Hong Kong-inspired streets had me thinking, "Is this it, the sleeper hit of 2024?!"

No, sadly not. It's no doubt built a compelling universe filled with brain-sucking aliens that masquerade as humans, and it attempts plenty else besides: bouncing between bodies as you stealth around dingy apartment blocks, fighting with blood katanas, and gorging on pools of red plasma to refuel skills, many of which require more body-flitting. Thing is, they are ultimately just attempts, attempts that fall victim to an emptiness and jitteriness that quickly reveals Slitterhead's true, irritating form.

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Warframe developers Digital Extremes have announced a new round of early access for their 2025-bound fantasy action-RPG Soulframe, which I saw a bit of last year and think is pretty promising. They're now adding 2000 players to a Preludes build of the game every week, with each invite email including an additional four invite codes, so you can get your friends involved.

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A virtual private network is a service that encrypts your internet connection, ensuring your online activity remains private and secure.