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The focus of this paper is to review hybrid recursive-complementarity formulations for multibody systems characterized by a large number of bilateral constraints which are frequently encountered in robotics. Here, hybrid implies the use of complementarity contact models with recursive forward dynamics schemes. Such formulations have a common underlying structure which can be applied to multibody systems with a constrained tree-type topology. These common steps are pointed out. Theoretical formulation is given for systems using three important classes (O(n), O(n), and O(log (n))) of multibody algorithms. Further, numerical comparison for the efficiency is given for rigid multibody systems. The paper makes recommendations on the choice of hybrid complementarity formulations which would result in the most efficient simulation. The paper further gives a non-iterative approach to allow the use of explicit higher order integrators for frictionless contacts. The difficulties in extending this approach to allow for frictional contact are also discussed. The focus of this paper is to review hybrid recursive-complementarity formulations for multibody systems characterized by a large number of bilateral constraints which are frequently encountered in robotics. Here, hybrid implies the use of complementarity contact models with recursive forward dynamics schemes. Such formulations have a common underlying structure which can be applied to multibody systems with a constrained tree-type topology. These common steps are pointed out. Theoretical formulation is given for systems using three important classes (O(n3), O(n), and O(log(n))) of multibody algorithms. Further, numerical comparison for the efficiency is given for rigid multibody systems. The paper makes recommendations on the choice of hybrid complementarity formulations which would result in the most efficient simulation. [ABSTRACT FROM AUTHOR]

Debra J Tompson,1 Christopher S Crean,2 Mauro Buraglio,1 Thangam Arumugham3 1Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, Hertfordshire, UK; 2Clinical Pharmacology and Pharmacokinetics, Valeant Pharmaceuticals North America, Durham, NC, USA; 3Clinical Statistics, GlaxoSmithKline, Raleigh-Durham, NC, USA Introduction: The potential for ezogabine/retigabine (EZG/RTG) and its N-acetyl metabolite (NAMR) to inhibit the transporter protein P-glycoprotein-(P-gp)-mediated digoxin transport was tested in vitro. EZG/RTG did not inhibit P-gp. However, NAMR inhibited P-gp in a concentration-dependent manner. Based on these in vitro results, NAMR had the potential to inhibit P-gp at therapeutic doses of EZG/RTG (600–1,200 mg/day). As digoxin has a narrow therapeutic index, inhibition of digoxin clearance may have an impact on its safety. Methods: An open-label, single-center, two session, fixed-sequence study was conducted to assess the effect of co-administration of therapeutic doses of EZG/RTG on digoxin pharmacokinetics in healthy adults. In session 1, subjects received a single dose of digoxin 0.25 mg. In session 2, EZG/RTG was up-titrated over 6 weeks. Digoxin 0.25 mg was co-administered at EZG/RTG steady-state doses of 600, 900, and, based on tolerability, 1,050/1,200 mg/day. Blood samples were collected over 144 hours for determination of digoxin, EZG/RTG, and NAMR concentrations. Urine samples were collected over 48 hours for determination of digoxin concentrations. Results: Of 30 subjects enrolled, 29 were included in the pharmacokinetic analysis. Compared with digoxin alone, co-administration with EZG/RTG led to small increases in the digoxin plasma area under the concentration–time curve (AUC)0–120 at doses of 600, 900, and 1,050/1,200 mg (geometric mean ratio 1.08, 90% confidence interval [CI] 1.01–1.15; 1.18, 90% CI 1.10–1.27; 1.13, 90% CI 1.05–1.21, respectively). Safety was consistent with previous repeat-dose studies of EZG/RTG in healthy subjects. Conclusion: Co-administration of EZG/RTG across the therapeutic range resulted in small, non-dose-dependent and non-clinically relevant increases in digoxin systemic exposure, suggesting that digoxin dose adjustment is not necessary. Keywords: digoxin, retigabine, ezogabine, drug–drug interactions

Presents a letter to the editor which states that tumor necrosis factor alpha resistance in MCF-7 breast cancer cells is associated with altered subcellular localization of p2lCIP1 and p27KIP1.

Presents a letter to the editor which states that tumor necrosis factor alpha resistance in MCF-7 breast cancer cells is associated with altered subcellular localization of p2lCIP1 and p27KIP1.

Background: Myeloproliferative neoplasms (MPNs) are a group of chronic disorders of the bone marrow characterised by the overproduction of clonal myeloid stem cells. The most common driver mutation found in MPNs is a point mutation on exon 14 of the JAK2 gene, JAK2 V617F . Various studies have suggested that measuring the variable allele frequency (VAF) of JAK2 V617F may provide useful insight regarding diagnosis, treatment, risks and outcomes in MPN patients. In particular, JAK2 V617F has been associated with increased risk of thrombotic events, a leading cause of mortality in MPNs., Aims: The aim of this study was to determine if JAK2 V617F VAF was associated with clinical outcomes in patients with MPN., Methods: JAK2 V617F VAF was determined by quantitative PCR (qPCR) in a cohort of 159 newly diagnosed MPN patients, and the association of JAK2 V617F VAF and risk of thrombosis was examined in this cohort., Results: We observed a significantly higher JAK2 V617F VAF in PV and PMF versus ET. A significant association was observed between JAK2 V617F VAF and risk of thrombotic events. When patients were stratified by thrombotic events prior to and post diagnosis, an association with JAK2 V617F VAF was only observed with post diagnosis thrombotic events. Of note, these associations were not observed when looking at each MPN subtype in isolation., Conclusions: We have shown that a higher JAK2 V617F VAF is associated with thrombotic events post MPN diagnosis. JAK2 V617F VAF may therefore provide a valuable prognostic indicator for risk of thrombosis in MPNs., Competing Interests: Declarations. Patient Consent: Not required. Provence and Peer review: Not commissioned; externally peer reviewed. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The utilization of ambient ionization (AI) techniques for mass spectrometry (MS) has significantly grown due to their ability to facilitate rapid and direct sample analysis with minimal sample preparation. This study investigates the performance of various AI techniques, including atmospheric solids analysis probe (ASAP), thermal desorption corona discharge (TDCD), direct analysis in real time (DART), and paper spray coupled to a Waters QDa mass spectrometer. The focus is on evaluating the linearity, repeatability, and limit of detection (LOD) of these techniques across a range of analytes, including amino acids, drugs, and explosives. The results show that each AI technique exhibits distinct advantages and limitations. ASAP and DART cover high concentration ranges, which may make them suitable for semiquantitative analysis. TDCD demonstrates exceptional linearity and repeatability for most analytes, while paper spray offers surprising LODs despite its complex setup (between 80 and 400 pg for most analytes). The comparison with electrospray ionization (ESI) as a standard method shows that ambient ionization techniques can achieve competitive LODs for various compounds such as PETN (80 pg ESI vs 100 pg ASAP), TNT (9 pg ESI vs 4 pg ASAP), and RDX (4 pg ESI vs 10 pg ASAP). This study underscores the importance of selecting the appropriate ambient ionization technique based on the specific analytical requirements. This comprehensive evaluation contributes valuable insights into the selection and optimization of AI techniques for diverse analytical applications.

Ambient ionization (AI) is a rapidly growing field in mass spectrometry (MS). It allows for the direct analysis of samples without any sample preparation, making it a promising technique for the detection of explosives. Previous studies have shown that AI can be used to detect a variety of explosives, but the exact gas-phase reactions that occur during ionization are not fully understood. This is further complicated by differences in mass spectrometers and individual experimental set ups between researchers. This study investigated the gas-phase ion reactions of five different explosives using a variety of AI techniques coupled to a Waters QDa mass spectrometer to identify selective ions for explosive detection and identification based on the applied ambient ionization technique. The results showed that the choice of the ion source can have a significant impact on the number of ions observed. This can affect the sensitivity and selectivity of the data produced. The findings of this study provide new insights into the gas-phase ion reactions of explosives and could lead to the development of more sensitive and selective AI-based methods for their detection.

We report a facile, solvent-free surfactant-dependent mechanochemical synthesis of highly luminescent CsPbBr 3 nanocrystals (NCs) and study their scintillation properties. A small amount of surfactant oleylamine (OAM) plays an important role in the two-step ball milling method to control the size and emission properties of the NCs. The solid-state synthesized perovskite NCs exhibit a high photoluminescence quantum yield (PLQY) of up to 88% with excellent stability. CsPbBr 3 NCs capped with different amounts of surfactant were dispersed in toluene and mixed with polymethyl methacrylate (PMMA) polymer and cast into scintillator discs. With increasing concentration of OAM during synthesis, the PL yield of CsPbBr 3 /PMMA nanocomposite was increased, which is attributed to reduced NC aggregation and PL quenching. We also varied the perovskite loading concentration in the nanocomposite and studied the resulting emission properties. The most intense PL emission was observed from the 2% perovskite-loaded disc, while the 10% loaded disc exhibited the highest radioluminescence (RL) emission from 50 kV X-rays. The strong RL yield may be attributed to the deep penetration of X-rays into the composite, combined with the large interaction cross-section of the X-rays with the high-Z atoms within the NCs. The nanocomposite disc shows an intense RL emission peak centered at 536 nm and a fast RL decay time of 29.4 ns. Further, we have demonstrated the X-ray imaging performance of a 10% CsPbBr 3 NC-loaded nanocomposite disc., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

While there is great demand for effective, affordable radiation detectors in various applications, many commonly used scintillators have major drawbacks. Conventional inorganic scintillators have a fixed emission wavelength and require expensive, high-temperature synthesis; plastic scintillators, while fast, inexpensive, and robust, have low atomic numbers, limiting their X-ray stopping power. Formamidinium lead halide perovskite nanocrystals show promise as scintillators due to their high X-ray attenuation coefficient and bright luminescence. Here, we used a room-temperature, solution-growth method to produce mixed-halide FAPbX3 (X = Cl, Br) nanocrystals with emission wavelengths that can be varied between 403 and 531 nm via adjustments to the halide ratio. The substitution of bromine for increasing amounts of chlorine resulted in violet emission with faster lifetimes, while larger proportions of bromine resulted in green emission with increased luminescence intensity. By loading FAPbBr3 nanocrystals into a PVT-based plastic scintillator matrix, we produced 1 mm-thick nanocomposite scintillators, which have brighter luminescence than the PVT-based plastic scintillator alone. While nanocomposites such as these are often opaque due to optical scattering from aggregates of the nanoparticles, we used a surface modification technique to improve transmission through the composites. A composite of FAPbBr3 nanocrystals encapsulated in inert PMMA produced even stronger luminescence, with intensity 3.8× greater than a comparative FAPbBr3/plastic scintillator composite. However, the luminescence decay time of the FAPbBr3/PMMA composite was more than 3× slower than that of the FAPbBr3/plastic scintillator composite. We also demonstrate the potential of these lead halide perovskite nanocomposite scintillators for low-cost X-ray imaging applications.

Polymeric drug carriers are widely used for providing temporal and/or spatial control of drug delivery, with corticosteroids being one class of drugs that have benefitted from their use for the treatment of inflammatory-mediated conditions. However, these polymer-based systems often have limited drug-loading capacity, suboptimal release kinetics, and/or promote adverse inflammatory responses. This manuscript investigates and describes a strategy for achieving controlled delivery of corticosteroids, based on a discovery that low molecular weight corticosteroid dimers can be processed into drug delivery implant materials using a broad range of established fabrication methods, without the use of polymers or excipients. These implants undergo surface erosion, achieving tightly controlled and reproducible drug release kinetics in vitro. As an example, when used as ocular implants in rats, a dexamethasone dimer implant is shown to effectively inhibit inflammation induced by lipopolysaccharide. In a rabbit model, dexamethasone dimer intravitreal implants demonstrate predictable pharmacokinetics and significantly extend drug release duration and efficacy (>6 months) compared to a leading commercial polymeric dexamethasone-releasing implant.

Competing Interests: The authors have no competing interests to declare.

Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

Flexible wearable chemical sensors are emerging tools which target diagnosis and monitoring of medical conditions. One of the potential applications of wearable chemical sensors is therapeutic drug monitoring for drugs that have a narrow therapeutic range such as lithium. We have investigated the possibility of developing a fibre-based device for non-invasive lithium drug monitoring in interstitial fluid. A flexible cotton-based lithium sensor was coupled with a carbon fibre-based reference electrode to obtain a potentiometric device. In vitro reverse iontophoresis experiments were performed to extract Li + from under porcine skin by applying a current density of 0.4 mA cm -2 via two electrodes. Carbon fibre-based reverse iontophoresis electrodes were fabricated and used instead of a conventional silver wire-based version and comparable results were obtained. The fibre-based Li + sensor and reference electrodes were capable of determining the Li + concentration in samples collected via reverse iontophoresis and the results compared well to those obtained by ion chromatography. Additionally, biocompatibility of the materials used have been tested. Promising results were obtained which confirm the possibility of monitoring lithium in interstitial fluid using a wearable sensor., (Copyright © 2019. Published by Elsevier B.V.)

There is a growing desire for wearable sensors in health applications. Fibers are inherently flexible and as such can be used as the electrodes of flexible sensors. Fiber-based electrodes are an ideal format to allow incorporation into fabrics and clothing and for use in wearable devices. Electrically conducting fibers were produced from a dispersion of poly (3,4-ethylenedioxythiophene)-poly (styrenesulfonate) (PEDOT: PSS). Fibers were wet spun from two PEDOT: PSS sources, in three fiber diameters. The effect of three different chemical treatments on the fibers were investigated and compared. Short 5 min treatment times with dimethyl sulfoxide (DMSO) on 20 μm fibers produced from Clevios PH1000 were found to produce the best overall treatment. Up to a six-fold increase in electrical conductivity was achieved, reaching 800 S cm -1 , with no loss of mechanical strength (150 MPa). With a pH-sensitive polyaniline coating, these fibers displayed a Nernstian response across a pH range of 3.0 to 7.0, which covers the physiologically critical pH range for skin. These results provide opportunities for future wearable, fiber-based sensors including real-time, on-body pH sensing to monitor skin disease., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

A miniaturized, flexible fiber-based lithium sensor was fabricated from low-cost cotton using a simple, repeatable dip-coating technique. This lithium sensor is highly suited for ready-to-use wearable applications and can be used directly without the preconditioning steps normally required with traditional ion-selective electrodes. The sensor has a stable, rapid, and accurate response over a wide Li + concentration range that spans over the clinically effective and the toxic concentration limits for lithium in human serum. The sensor is selective to Li + in human plasma even in the presence of a high concentration of Na + ions. This novel sensor concept represents a significant advance in wearable sensor technology which will target lithium drug monitoring from under the skin.

The phenomenon of new psychoactive substances (NPS), which came to the attention of the wider international community at the beginning of the 2010s, has been unprecedented in terms of the sheer number of substances, their rate of emergence, chemical diversity, and range of pharmacological effects. In particular, the chemical diversity has been a challenge to promoting a better understanding of the NPS market - a fundamental requirement for effective policy decisions and interventions. This manuscript highlights the significant chemical diversity of NPS and describes an alternative, complementary, and pragmatic classification based on pharmacological effects, which aligns NPS to traditional controlled drugs and enhances understanding of the phenomenon. It further reviews actions taken at the international level to address the NPS issue, including changes in the scope of control of some NPS and the enhancement of the United Nations Early Warning Advisory on NPS to deal with the dynamics and evolution of the market.

The nature of the global drugs market has evolved rapidly and has become more complex with the emergence of new psychoactive substances (NPS), some of which have been associated with increased abuse, hospital emergency admissions and sometimes fatalities. NPS are characterized by geographic heterogeneity, with some only transient in nature and others not satisfying the criteria for harm required for international control. Consequently, a pragmatic response of the international community is to prioritize the most harmful, persistent and prevalent substances for action - an objective, which is hampered by the paucity of data on harms. The report describes a United Nations Office on Drugs and Crime (UNODC) initiative, in collaboration with the International Association of Forensic Toxicologists (TIAFT), to collect, analyze and share toxicology data at a global level to reinforce the ability of the international community in making informed decisions using a scientific evidence-based approach, in identifying the most harmful NPS., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Multiple myeloma is incurable once osteolytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here, we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in multiple myeloma cell lines and primary bone marrow cells from patients. CD166 + multiple myeloma cells homed more efficiently than CD166 - cells to the bone marrow of engrafted immunodeficient NSG mice. CD166 silencing in multiple myeloma cells enabled longer survival, a smaller tumor burden, and less osteolytic lesions, as compared with mice bearing control cells. CD166 deficiency in multiple myeloma cell lines or CD138 + bone marrow cells from multiple myeloma patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Furthermore, CD166 deficiency in multiple myeloma cells also reduced the formation of osteolytic disease in vivo after intratibial engraftment. Mechanistic investigation revealed that CD166 expression in multiple myeloma cells inhibited osteoblastogenesis of bone marrow-derived osteoblast progenitors by suppressing Runx2 gene expression. Conversely, CD166 expression in multiple myeloma cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in multiple myeloma cell homing to the bone marrow and multiple myeloma progression, rationalizing its further study as a candidate therapeutic target for multiple myeloma treatment. Cancer Res; 76(23); 6901-10. ©2016 AACR., Competing Interests: The authors declare no conflict of interest., (©2016 American Association for Cancer Research.)

The analysis of substances of abuse remains one of the most matured areas in forensic science with a strong scientific basis, namely analytical chemistry. The current evolving drug markets, characterized by the global emergence of new psychoactive substances (NPS) and the need for forensic scientists to identify an unprecedented and ever-increasing number of NPS, presents a unique challenge to this discipline. This article looks at the current situation with NPS at the global level, and the challenges posed to the otherwise technically robust forensic science discipline of analysis of substances of abuse. It discusses the preparedness of forensic science to deal with the current situation and identifies the need for a shift in forensic science practice, especially one which embraces research and looks beyond normal casework in order to provide the much needed data for developing effective policy responses to the NPS problem., (© 2015 The Author(s) Published by the Royal Society. All rights reserved.)

Purpose: An understanding of how hematopoietic cells respond to therapy that causes myelosuppression will help develop approaches to prevent this potentially life-threatening toxicity. The goal of this study was to determine how human myeloid precursor cells respond to temozolomide (TMZ)-induced DNA damage., Experimental Design: We developed an ex vivo primary human myeloid precursor cells model system to investigate the involvement of cell-death pathways using a known myelosuppressive regimen of O(6)-benzylguanine (6BG) and TMZ., Results: Exposure to 6BG/TMZ led to increases in p53, p21, γ-H2AX, and mitochondrial DNA damage. Increases in mitochondrial membrane depolarization correlated with increased caspase-9 and -3 activities following 6BG/TMZ treatment. These events correlated with decreases in activated AKT, downregulation of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT), and increased cell death. During myeloid precursor cell expansion, FAS/CD95/APO1(FAS) expression increased over time and was present on approximately 100% of the cells following exposure to 6BG/TMZ. Although c-flipshort, an endogenous inhibitor of FAS-mediated signaling, was decreased in 6BG/TMZ-treated versus control, 6BG-, or TMZ alone-treated cells, there were no changes in caspase-8 activity. In addition, there were no changes in the extent of cell death in myeloid precursor cells exposed to 6BG/TMZ in the presence of neutralizing or agonistic anti-FAS antibodies, indicating that FAS-mediated signaling was not operative., Conclusions: In human myeloid precursor cells, 6BG/TMZ-initiated apoptosis occurred by intrinsic, mitochondrial-mediated and not extrinsic, FAS-mediated apoptosis. Human myeloid precursor cells represent a clinically relevant model system for gaining insight into how hematopoietic cells respond to chemotherapeutics and offer an approach for selecting effective chemotherapeutic regimens with limited hematopoietic toxicity., (©2013 AACR)

The spiroiminodihydantoins (Sp) are highly mutagenic oxidation products of guanine and 8-oxo-7,8-dihydroguanine in DNA. The Sp lesions have recently been detected in the liver and colon of mice infected with Helicobacter hepaticus that induces inflammation and the development of liver and colon cancers in murine model systems [Mangerich, A., et al. (2012) Proc. Natl. Acad. Sci. U.S.A. 109, E1820-E1829]. The impact of Sp lesions on the thermodynamic characteristics and the effects of the diastereomeric Sp-R and Sp-S lesions on the conformational features of double-stranded 11-mer oligonucleotide duplexes have been studied by a combination of microcalorimetric methods, analysis of DNA melting curves, and two-dimensional nuclear magnetic resonance methods. The nonplanar, propeller-like shapes of the Sp residues strongly diminish the extent of local base stacking interactions that destabilize the DNA duplexes characterized by unfavorable enthalpy contributions. Relative to that of an unmodified duplex, the thermally induced unfolding of the duplexes with centrally positioned Sp-R and Sp-S lesions into single strands is accompanied by a smaller release of cationic counterions (Δn(Na⁺) = 0.6 mol of Na⁺/mol of duplex) and water molecules (Δn(w) = 17 mol of H₂O/mol of duplex). The unfolding parameters are similar for the Sp-R and Sp-S lesions, although their orientations in the duplexes are different. The structural disturbances radiate one base pair beyond the flanking C:G pair, although Watson-Crick hydrogen bonding is maintained at all flanking base pairs. The observed relatively strong destabilization of B-form DNA by the physically small Sp lesions is expected to have a significant impact on the processing of these lesions in biological environments.