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.

The antitumor effect of cardiotonic steroids (CTS) has stimulated the search for new methods to evaluate both kinetic and thermodynamic aspects of their binding to Na⁺/K⁺-ATPase (IUBMB Enzyme Nomenclature). We propose a real-time assay based on a chromogenic substrate for phosphatase activity (pNPPase activity), using only two concentrations with an inhibitory progression curve, to obtain the association rate (k_on), dissociation rate (k_off), and equilibrium (K_i) constants of CTS for the structure-kinetics relationship in drug screening. We show that changing conditions (from ATPase to pNPPase activity) resulted in an increase of K_i of the cardenolides digitoxigenin, essentially due to a reduction of k_on. In contrast, the K_i of the structurally related bufadienolide bufalin increased much less due to the reduction of its k_off partially compensating the decrease of its k_on. When evaluating the kinetics of 15 natural and semisynthetic CTS, we observed that both k_on and k_off correlated with K_i (Spearman test), suggesting that differences in potency depend on variations of both k_on and k_off. A rhamnose in C3 of the steroidal nucleus enhanced the inhibitory potency by a reduction of k_off rather than an increase of k_on. Raising the temperature did not alter the k_off of digitoxin, generating a H (k_off) of –10.4 ± 4.3 kJ/mol, suggesting a complex dissociation mechanism. Based on a simple and inexpensive methodology, we determined the values of k_on, k_off, and K_i of the CTS and provided original kinetics and thermodynamics differences between CTS that could help the design of new compounds.

Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact blood-brain barrier (BBB). GBM has a poor prognosis despite aggressive treatment, in part due to the lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemosensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA-damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent temozolomide; however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro–in vivo disconnect was explored to understand factors influencing central nervous system (CNS) distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-glycoprotein efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for interspecies differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited.

Simplified methods of acquisition and quantification would facilitate the use of synaptic density imaging in multicenter and longitudinal studies of Alzheimer disease (AD). We validated a simplified tissue-to-reference ratio method using SUV ratios (SUVRs) for estimating synaptic density with [¹¹C]UCB-J PET. Methods: Participants included 31 older adults with AD and 16 with normal cognition. The distribution volume ratio (DVR) using simplified reference tissue model 2 was compared with SUVR at short scan windows using a whole-cerebellum reference region. Results: Synaptic density was reduced in AD participants using DVR or SUVR. SUVR using later scan windows (60–90 or 70–90 min) was minimally biased, with the strongest correlation with DVR. Effect sizes using SUVR at these late time windows were minimally reduced compared with effect sizes with DVR. Conclusion: A simplified tissue-to-reference method may be useful for multicenter and longitudinal studies seeking to measure synaptic density in AD.

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.

Karolinska Institutet is a medical university encompassing 21 departments distributed across three departmental or campus groups. Pharmacological research has a long and successful tradition at the institute with a multitude of seminal findings in the areas of neuronal control of vasodilatation, cardiovascular pharmacology, neuropsychopharmacology, receptor pharmacology, and pharmacogenomics that resulted in, among many other recognitions, two Nobel prizes in Physiology and Medicine, one in 1970 to Ulf von Euler for his discovery of the processes involved in storage, release, and inactivation of neurotransmitters and the other in 1982 to Sune Bergström and Bengt Samuelsson for their work on prostaglandins and the discovery of leukotrienes. Pharmacology at Karolinska Institutet has over the last decade been ranked globally among the top 10 according to the QS World University Ranking. With the Department of Physiology and Pharmacology now celebrating its 75-year anniversary, we wanted to take this as an opportunity to showcase recent research achievements and how they paved the way for current activities at the department. We emphasize examples from preclinical and clinical research where the dpartment's integrative environment and robust infrastructure have successfully facilitated the translation of findings into clinical applications and patient benefits. The close collaboration between preclinical scientists and clinical researchers across various disciplines, along with a strong network of partnerships within the department and beyond, positions us to continue leading world-class pharmacological research at the Department of Physiology and Pharmacology for decades to come.

BACKGROUND AND PURPOSE:

There has been a distinction made in the 2001 Canadian C-Spine Rule regarding patients 65 and older and younger than 65 years of age as far as indications for cervical spine CT scanning. We sought to determine if there are differences in the symptoms, mechanisms of injury, fracture locations, and types that are still relevant in 2024.

Bone marrow transplantation, now often known as haematopoietic stem cell transplantation (HSCT), is a complex choreographed procedure used to treat both acquired and inherited disorders of the bone marrow. It has proven invaluable as therapy for haematological and immunological disorders, and more recently in the treatment of metabolic and enzyme disorders. As the number of performed transplants grows annually, and with patients enjoying improved survival, a knowledge of both early and late complications of HSCT is essential for respiratory trainees and physicians in practice. This article highlights the spectrum of respiratory complications, both infectious and non-infectious, the timeline of their likely occurrence, and the approaches used for diagnosis and treatment, keeping in mind that more than one entity may occur simultaneously. As respiratory issues are often a leading cause of short- and long-term morbidity, consideration of a combined haematology/respiratory clinic may prove useful in this patient population.

Palliative care pertains to the holistic multidimensional concept of "patient-centred" care. It is an interprofessional specialty, primarily aiming to improve quality of care for cancer patients and their families, from the time of diagnosis of malignant disease, over the continuum of cancer care, and extending after the patient's death to the period of bereavement to support the patient's family. There are various complex and frequently unmet needs of lung cancer patients and their families/caregivers, not only physical but also psychological, social, spiritual and cultural. Systematic monitoring of patients’ symptoms using validated questionnaires and patient-reported outcomes (PROs), on a regular basis, is highly encouraged and recommended in recent guidelines on the role of PRO measures in the continuum of cancer clinical care. It improves patient–physician communication, physician awareness of symptoms, symptom control, patient satisfaction, health-related quality of life and cost-effectiveness. This implies that all treating physicians should improve their skills in communication with lung cancer patients/relatives and become more familiar with this multidimensional assessment, repeatedly screening patients for palliative care needs. Therefore, they should receive education and training to develop palliative care knowledge, skills and attitudes. This review is dedicated to lung cancer palliative care essentials that should be within the competences of treating physicians, i.e. pneumologists/thoracic oncologists.

Sega has sold Humankind and Endless developer Amplitude Studios to members of its internal team, announced the developer in a community post. This means the studio is now independent.

"Our studio is backed by strong and meaningful franchises and our team is committed to creating the best games possible," said Amplitude Studios founder Romain de Waubert de Genlis.

"With our extensive experiences in strategy game development and two exciting titles currently in progress, we are confident in our ability to deliver outstanding experience to players. This decision allows us to be more agile in our approach while continuing to shape the vision that has been ours from the very beginning, empowering us to push boundaries and be closer as ever of our community."

Sega in its own statement said: "Sega Europe has today announced the sale of Amplitude Studios following a management buyout from senior leaders and employees at the Parisian studio. The move will see Amplitude go back to its roots as an independent organisation and concludes the structural reforms that have been taking place in Sega’s European business.  

"The decision to part ways follows a period of close consultation between Sega Europe and Amplitude. As an independent studio once more, Amplitude will focus on its in-development projects and growing its own franchises, while Sega will continue to advance its strong and diverse stable of Japanese and Western IP. 

“Sega Europe acquired Amplitude in 2016, and together have released epic strategy titles like Endless Space 2 and Humankind, along with Endless Dungeon, the successor to 2014’s indie hit, Dungeon of the Endless.

"While Amplitude is no longer a part of the Sega family of studios, the two entities will continue to work together on the smooth transition of services and operations, ensuring minimum disruption for Amplitude employees and continuity of service for players of Amplitude games."

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463024/sega-sells-humankind-developer-amplitude-studios/

Our Future Chronicles column explores an imagined history of inventions and developments yet to come. This time, Rowan Hooper takes us to the early 2030s, when a technological step change enabled us to produce all the food we needed without the use of animals

Here’s everything you need to know about the allegations, diss tracks, and that $12 million NDA.

Video Friday is your weekly selection of awesome robotics videos, collected by your friends at IEEE Spectrum robotics. We also post a weekly calendar of upcoming robotics events for the next few months. Please send us your events for inclusion.

ICRA@40: 23–26 September 2024, ROTTERDAM, NETHERLANDS

IROS 2024: 14–18 October 2024, ABU DHABI, UAE

ICSR 2024: 23–26 October 2024, ODENSE, DENMARK

Cybathlon 2024: 25–27 October 2024, ZURICH

Enjoy today’s videos!

Zipline has (finally) posted some real live footage of its new Platform 2 drone, and while it’s just as weird looking as before, it seems to actually work really well.

[ Zipline ]

I appreciate Disney Research’s insistence on always eventually asking, “okay, but can we get this to work on a real robot in the real world?”

[ Paper from ETH Zurich and Disney Research [PDF] ]

In this video, we showcase our humanoid robot, Nadia, being remotely controlled for boxing training using a simple VR motion capture setup. A remote user takes charge of Nadia’s movements, demonstrating the power of our advanced teleoperation system. Watch as Nadia performs precise boxing moves, highlighting the potential for humanoid robots in dynamic, real-world tasks.

[ IHMC ]

Guide dogs are expensive to train and maintain—if available at all. Because of these limiting factors, relatively few blind people use them. Computer science assistant professor Donghyun Kim and Ph.D candidate Hochul Hwang are hoping to change that with the help of UMass database analyst Gail Gunn and her guide dog, Brawny.

[ University of Massachusetts, Amherst ]

Thanks Julia!

The current paradigm for motion planning generates solutions from scratch for every new problem, which consumes significant amounts of time and computational resources. Our approach builds a large number of complex scenes in simulation, collects expert data from a motion planner, then distills it into a reactive generalist policy. We then combine this with lightweight optimization to obtain a safe path for real world deployment.

[ Neural MP ]

A nice mix of NAO and AI for embodied teaching.

[ Aldebaran ]

When retail and logistics giant Otto Group set out to strengthen its operational efficiency and safety, it turned to robotics and automation. The Otto Group has become the first company in Europe to deploy the mobile case handling robot Stretch, which unloads floor-loaded trailers and containers.

[ Boston Dynamics ]

From groceries to last-minute treats, Wing is here to make sure deliveries arrive quickly and safely. Our latest aircraft design features a larger, more standardized box and can carry a higher payload which came directly from customer and partner feedback.

[ Wing ]

It’s the jacket that gets me.

[ Devanthro ]

In this video, we introduce Rotograb, a robotic hand that merges the dexterity of human hands with the strength and efficiency of industrial grippers. Rotograb features a new rotating thumb mechanism, allowing for precision in-hand manipulation and power grasps while being adaptable. The robotic hand was developed by students during “Real World Robotics”, a master course by the Soft Robotics Lab at ETH Zurich.

[ ETH Zurich ]

A small scene where Rémi, our distinguished professor, is teaching chess to the person remotely operating Reachy! The grippers allow for easy and precise handling of chess pieces, even the small ones! The robot shown in this video is the Beta version of Reachy 2, our new robot coming very soon!

[ Pollen ]

Enhancing the adaptability and versatility of unmanned micro aerial vehicles (MAVs) is crucial for expanding their application range. In this article, we present a bimodal reconfigurable robot capable of operating in both regular quadcopter flight mode and a unique revolving flight mode, which allows independent control of the vehicle’s position and roll-pitch attitude.

[ City University Hong Kong ]

The Parallel Continuum Manipulator (PACOMA) is an advanced robotic system designed to replace traditional robotic arms in space missions, such as exploration, in-orbit servicing, and docking. Its design emphasizes robustness against misalignments and impacts, high precision and payload capacity, and sufficient mechanical damping for stable, controlled movements.

[ DFKI Robotics Innovation Center ]

Even the FPV pros from Team BlackSheep do, very occasionally, crash.

[ Team BlackSheep ]

This is a one-hour uninterrupted video of a robot cleaning bathrooms in real time. I’m not sure if it’s practical, but I am sure that it’s impressive, honestly.

[ Somatic ]

Loneliness was long thought to cause health conditions ranging from diabetes to cardiovascular disease, but new research paints a more nuanced picture

<a href="https://bluetechker.com/" rel="nofollow ugc">Blue Techker</a> Nice post. I learn something totally new and challenging on websites

The actor is getting some support from his ex-wife, Lindsay Hartley, and daughter, Bella.

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Dry ice is becoming an essential resource for various industries in Lakeland, Florida. Made from carbon dioxide in its solid form, dry ice sublimates directly into gas without leaving any liquid residue. This characteristic makes it a highly effective cooling solution, ideal for transporting perishable goods, supporting medical needs, and industrial cleaning. With the right […]

The post Essential Guide to Choosing the Best Lakeland Dry Ice Supplier for Your Business Needs appeared first on Chart Attack.

Reports indicate that Chauhaan may have died by suicide, a claim supported by a social media post from his former co-star Vibhuti Thakur, who expressed her shock and sorrow over his untimely death

Following yesterday’s big Disney Dreamlight Valley update on Apple Arcade and other platforms, a few more notable games on Apple’s …

Continue reading "Apple Arcade Weekly Round-Up: New Content and Feature Updates Are Now Live for TMNT Splintered Fate, Temple Run: Legends, Vampire Survivors, Simon’s Cat, and More"

Hello everyone, and welcome to the week! It’s time once again for our look back at the noteworthy updates of …

Continue reading "Best iPhone Game Updates: ‘TMNT Splintered Fate’, ‘Subway Surfers’, ‘Another Eden’, and More"

As-yet unnamed “NewCo” will handle IBM’s “managed infrastructure services.”

The grant program provides hardware startups with reimbursement for working with local manufacturers.

The Department of Pharmaceuticals (DoP) has upheld the retail price fixation of National Pharmaceutical Pricing Authority (NPPA) for Mumbai─based Aristo Pharmaceuticals for its multivitamin tablets with

Oversimplification about integration of traditional and modern treatment systems often creates confusion among the stakeholders, and nobody understands the reality of the integration and what it is meant for, said Dr.

Joe Anderson, product and promotional marketing manager at Harland, explores the role of surface preparation in the application of hydrophilic and hydrophobic coatings.

<p>In May 2024, Malaysia’s National Pharmaceutical Regulatory Agency (NPRA) announced that it will trial new timelines for variation applications&nbsp;of registered pharmaceutical products and natural health supplements (TMHS).</p>

Community pharmacies able to administer up to 400 COVID-19 vaccines per week can now apply to become designated vaccination sites, NHS England has said.

Pharmaceutical and biotech companies breathed a sigh of relief Monday when the Federal Circuit unanimously ruled in a precedential opinion that the mere sale of manufacturing services to create embodiments of a patented product is not a “commercial sale” of the invention that triggers the on-sale bar of 35 U.S.C. § 102(b) (pre-AIA).[1]  The en banc opinion...… Continue Reading

This SAS Usage Note illustrates fitting a model containing a spline effect in PROC GLIMMIX. It discusses the spline basis output, the interpretation of the output, how to use the spline model to make predictions, and how to use the LSMEANS and ESTIMATE statements to compute quantities of interest.

SINGAPORE – The police are investigating deepfake nude photos of Singapore Sports School (SSP) students that were created and spread by other students. In response to queries from The Straits Times, school principal Ong Kim Soon said SSP is “aware of the incident involving the creation and sharing of deepfake photos by our student-athletes”. “The school does not condone such harmful behaviour,” he said, adding that it has launched an investigation and lodged a police report. The police, in response to queries from ST, confirmed that a report was lodged and investigations are ongoing. A reader who identified himself as a parent of a victim had alerted ST in an e-mail on Nov 12 about the deepfake nude images that were being circulated. “Many parents of affected female students in Singapore Sports School are making police reports about deepfake nude photos of their daughters generated by male students from the school,” the parent said. When contacted, the parent said that female teachers were also targeted, and that the school has offered affected students counselling.

Apr 18, 2024

The fourth session addressed the pressing issue of climate change and its political implications in Africa. This session highlighted the disproportionate impact of climate change effects on African nations and how governments are responding through policy measures. A significant focus of the discussion was placed on current climate financial models and the challenges to accessing funding for renewable energy and electrification projects in Africa. The study group counted with the presence of external expert speaker Ely Sandler, Fellow at the Belfer Center. Ely has worked as a senior consultant at the World Bank and previously at Morgan Stanley for nearly a decade. Policy proposals that Ely developed at Harvard were presented at COP27 and are now being adopted by the World Bank and UAE COP28 Presidency, with the hope of catalyzing trillions of dollars of green investment, in part through Article 6 of the Paris Agreement.

Elliott Vichinsky, MD, University of California, San Francisco (UCSF) Benioff Children's Hospital Oakland

They created their own path. Will you create yours?

GST Returns which are to be filed in November month, those returns are very important as in this month you need to reconcile them thoroughly.

My client purchased a property from an NRI and we have deducted 20% Plus Cess and Surcharge. Later the TDS processed with defaults and intimated that the applicable rate is 30%. They have raised demand for short deduction.1.What is the actual rate of TDS when we are buying

The AAAR, Tamil Nadu in the case of M/s Faiveley Transport Rail Technologies India (P.) Ltd., In Re [A.R. Appeal No. 03/2024 AAAR dated July 10, 2024] upheld the ruling passed by AAR Tamil Nadu wherein it was ruled that GST would be applicable on Car facility extended to employees when the amount of

The Hon'ble Delhi High Court in the case of M/s Sanjay Sales India v. Principal Commissioner of Department of Trade and Taxes, Government of NCT, Delhi [Writ Petition (Civil) No. 10234 of 2024 dated July 26, 2024] held that the application for the cancellation of the GST registration cannot be denie

If assessee had agriculture income in inheritance, then such agriculture land converted into non-agriculture land i.e. commercial land and make his sub plots and sale to others, so what is treatment of such income arise on sale whether capital gain applicable in such case or consider in PGBP, if considered in PGBP, then how to provide effect in that i.e. Treat as direct income under Trading account or treat as indirect income in P&L Account?