Aligned, Orthogonal or In-conflict: When can we safely optimize Chain-of-Thought?
Max Kaufmann, David Lindner, Roland S. Zimmermann
et al.
Chain-of-Thought (CoT) monitoring, in which automated systems monitor the CoT of an LLM, is a promising approach for effectively overseeing AI systems. However, the extent to which a model's CoT helps us oversee the model - the monitorability of the CoT - can be affected by training, for instance by the model learning to hide important features of its reasoning. We propose and empirically validate a conceptual framework for predicting when and why this occurs. We model LLM post-training as an RL environment where the reward decomposes into two terms: one term depending on final outputs and another term depending on the CoT. Our framework allows us to classify these two terms as "aligned", "orthogonal", or "in-conflict" before training. We predict that training with in-conflict terms will reduce monitorability, orthogonal terms will not affect it, and aligned terms will improve it. To validate our framework, we use it to classify a set of RL environments, train LLMs within those environments, and evaluate how training affects CoT monitorability. We find that (1) training with "in-conflict" reward terms reduces CoT monitorability and (2) optimizing in-conflict reward terms is difficult.
Dracocephalum subcapitatum Alleviates Hyperglycemia, Dyslipidemia, Oxidative Stress, and Organ Injury in STZ-Induced Diabetic Rats: a Dose-Response Study
Zeinab Yazdiniapour, Nastaran Rashidi, Leila Safaeian*
et al.
Background and objectives: Dracocephalum subcapitatum is a plant indigenous to northeastern Iran with some traditional applications and limited pharmacological data. Since antidiabetic activities have been reported for several species of Dracocephalum genus, this study aimed to explore the effects of the hydroalcoholic extract of D. subcapitatum in an animal model of diabetes mellitus. Methods: Extraction was prepared through the maceration technique, and the total phenolics content was determined using the Folin-Ciocalteu method. Male Wistar rats were divided into five groups (n=8). Hyperglycemia was induced by a single dose of streptozotocin (60 mg/kg, i.p.). In the treatment groups, diabetic animals orally received the extract (50, 100, and 200 mg/kg) or glibenclamide (10 mg/kg) for 21 days. The glucose and insulin tolerance tests, and biochemical evaluations of fasting blood glucose, HbA1c, cholesterol, triglycerides, ALT, AST, ALP, creatinine, BUN, malondialdehyde, and total plasma antioxidant levels were performed. The rat's liver, kidneys, and pancreas were examined histologically. Results: The total phenolics content was 70.2±1.8 mg gallic acid equivalent/g of the extract. Dracocephalum subcapitatum extract, especially at higher doses, effectively lowered serum blood glucose, HbA1c, triglycerides, creatinine, and MDA levels, as well as the activities of ALT and ALP enzymes (p<0.001), without a positive effect on AST levels in diabetic rats. It also improved blood sugar regulation and insulin resistance, enhanced the total antioxidant capacity of plasma (p<0.001), and reversed tissue toxicities. Conclusions: This study suggests that D. subcapitatum has antihyperglycemic, triglyceride-lowering, antioxidant, and tissue-protective activities in diabetes caused by streptozotocin.
Pharmacy and materia medica
Machine Learning on Multiple Topological Materials Datasets
Yuqing He, Pierre-Paul De Breuck, Hongming Weng
et al.
A dataset of 35,608 materials with their topological properties is constructed by combining the density functional theory (DFT) results of Materiae and the Topological Materials Database. Thanks to this, machine-learning approaches are developed to categorize materials into five distinct topological types, with the XGBoost model achieving an impressive 85.2% classification accuracy. By conducting generalization tests on different sub-datasets, differences are identified between the original datasets in terms of topological types, chemical elements, unknown magnetic compounds, and feature space coverage. Their impact on model performance is analyzed. Turning to the simpler binary classification between trivial insulators and nontrivial topological materials, three different approaches are also tested. Key characteristics influencing material topology are identified, with the maximum packing efficiency and the fraction of $\textit{p}$ valence electrons being highlighted as critical features.
Demonstrating Narrative Pattern Discovery from Biomedical Literature
Hermann Kroll, Pascal Sackhoff, Bill Matthias Thang
et al.
Digital libraries maintain extensive collections of knowledge and need to provide effective access paths for their users. For instance, PubPharm, the specialized information service for Pharmacy in Germany, provides and develops access paths to their underlying biomedical document collection. In brief, PubPharm supports traditional keyword-based search, search for chemical structures, as well as novel graph-based discovery workflows, e.g., listing or searching for interactions between different pharmaceutical entities. This paper introduces a new search functionality, called narrative pattern mining, allowing users to explore context-relevant entities and entity interactions. We performed interviews with five domain experts to verify the usefulness of our prototype.
Treatment Patterns and Characteristics of Patients with Hereditary Angioedema Treated with Lanadelumab: A US Retrospective Chart Review
Maureen Watt, Rose Chang, Louise Huafeng Yu
et al.
Abstract Background and Objective Hereditary angioedema presents as recurrent, unpredictable, and often debilitating attacks of cutaneous/submucosal swelling. This study assessed the characteristics and treatment patterns of patients receiving long-term prophylaxis with the plasma kallikrein inhibitor lanadelumab in US clinical practice. Methods This retrospective longitudinal study, based on a physician panel-based medical chart review, included patients with a diagnosis of hereditary angioedema due to C1 esterase inhibitor deficiency/dysfunction (HAE-C1INH-Type1/2), initiating lanadelumab in/after August 2018 (index date), and with ≥ 3 months’ post-index follow-up (Part 1, N = 186) and, additionally, a dosing interval extension after initiating lanadelumab 300 mg every 2 weeks (Part 2, N = 75). Results Patients in Part 1 were predominantly aged ≥ 18 years (95.7%) with HAE-CINH-Type1 (90.3%); Part 2 included a higher proportion of patients with HAE-C1INH-Type2 (28.0% vs 9.7%). In Part 1, 115/165 (69.7%) patients with hereditary angioedema attack information experienced 371 attacks in the 3 months pre-index; these were mostly mild/moderate (60.4%) and most commonly affected the lips (38.0%) and hands (32.9%). In total, 19/155 (12.3%) patients had 39 attacks during the post-index period (mean ± standard deviation [interquartile range] attack rate: 0.1 ± 0.3 [0.0, 0.0] per month). In Part 2, a dosing interval extension was enabled by well-controlled disease (74/75, 98.7%); most patients (86.7%) transitioned from every 2 weeks to every 4 weeks dosing. Among patients with attack information, 7/72 (9.7%) experienced a hereditary angioedema attack while receiving an initial every 2 weeks dosing regimen and 4/75 (5.3%) after an extended-interval dosing regimen. Conclusions Lanadelumab dosing intervals can be individualized to maintain effective disease control. A dosing interval extension may be considered in well-controlled disease.
Therapeutics. Pharmacology, Pharmacy and materia medica
Adenosine Monophosphate as a Metabolic Adjuvant Enhances Antibiotic Efficacy against Drug-Resistant Bacterial Pathogens
Wenxuan Zhang, Zhenyi Wu, Zulifukeer Maituersong
et al.
Global bacterial infections are on the rise, and drug resistance to bacteria is gradually rendering existing antibiotics ineffective. Therefore, the discovery of new strategies is urgently needed. Cellular metabolism is a key factor in the regulation of bacterial drug resistance, which cannot be separated from the utilization of energetic substances, suggesting that energetic substances may be associated with bacterial drug resistance. In this study, we found that adenosine monophosphate (AMP) can enhance the bactericidal effect of gentamicin against gentamicin-resistant <i>Staphylococcus aureus.</i> This synergistic effect can be generalized for use with different antibiotics and Gram-positive or Gram-negative bacteria. We also validated that the mechanism of AMP reversal of antibiotic resistance involves enhancing the proton motive force via the tricarboxylic acid cycle to increase antibiotic uptake. Simultaneously, AMP increases oxidative stress-induced cell death. This study presents a strategy for adopting low-dose antibiotics to control drug-resistant bacteria, which is important for future drug development and bacterial control.
Medicine, Pharmacy and materia medica
Evaluation of the Transverse Strength and UV Spectrophotometric Analysis of the Residual Monomer Content of Autoclave Polymerized Conventional and High-Impact Heat-Cure Denture Base Resins—An In-Vitro Study
Savarimuthu Paulraj Roseline, Chalakuzhiyil Abraham Mathew, S Sakthi Gnanavel
et al.
Background and Objective:
Inspite of advancements in material properties of heat cure acrylic resin, fracture of denture base and allergic reactions due to release of residual monomer is encountered frequently. To improve strength and to reduce residual monomer, different polymerization methods need to be investigated. The objective is to evaluate and compare transverse strength and residual monomer content of two different heat cured denture base resins polymerized by conventional water bath and by autoclave.
Materials and Methods:
Samples were prepared with Acralyn-H conventional heat cure resin and Acralyn-H super hi-impact resin using metal dies. Samples undergoing water bath polymerization were polymerized in water bath at 74°C for 2 hours followed by 100°C for 1 hour and samples undergoing autoclave polymerization were cured in an autoclave at 121°C and 210 kPa for 30 minutes as holding temperature. Transverse strength specimens were processed and then tested for transverse strength in a Universal testing machine. Specimens for residual monomer content estimation were weighed and each specimen’s residual monomer was extracted in methanol using Soxhlet extractor and then read at 230nm in Ultraviolet-Visible spectrophotometer. Concentrations of residual monomer were evaluated and weight fractions were calculated.
Results:
The results of this study showed a statistically significant difference in transverse strength of Acralyn-H conventional heat cure resin polymerized by autoclave, whereas all other groups showed a non-significant result.
Conclusion:
Autoclave can be used as an alternative polymerization technique as it has shown similar results when compared with water bath polymerization and the time required for polymerization was also reduced.
Pharmacy and materia medica, Analytical chemistry
Evaluating the Surrogate Index as a Decision-Making Tool Using 200 A/B Tests at Netflix
Vickie Zhang, Michael Zhao, and Maria Dimakopoulou
et al.
Surrogate index approaches have recently become a popular method of estimating longer-term impact from shorter-term outcomes. In this paper, we leverage 1098 test arms from 200 A/B tests at Netflix to empirically investigate to what degree would decisions made using a surrogate index utilizing 14 days of data would align with those made using direct measurement of day 63 treatment effects. Focusing specifically on linear "auto-surrogate" models that utilize the shorter-term observations of the long-term outcome of interest, we find that the statistical inferences that we would draw from using the surrogate index are ~95% consistent with those from directly measuring the long-term treatment effect. Moreover, when we restrict ourselves to the set of tests that would be "launched" (i.e. positive and statistically significant) based on the 63-day directly measured treatment effects, we find that relying instead on the surrogate index achieves 79% and 65% recall.
Coexistence of multiple interfacial states at heterogeneous solid/liquid interface
Jiaojiao Liu, Hongtao Liang, Jinfu Li
et al.
The growing trend towards engineering interfacial complexion (or phase) transitions has been seen in the grain boundary and solid surface systems.Meanwhile, little attention has been paid to the chemically heterogeneous solid/liquid interfaces. In this work, novel in-plane multi-interfacial states coexist within the Cu(111)/Pb(l) interface at a temperature just above the Pb freezing point is uncovered using atomistic simulations.Four monolayer interfacial states, i.e., two CuPb alloy liquids and two pre-freezing Pb solids, are observed coexisting within two interfacial layers sandwiched between the bulk solid Cu and bulk liquid Pb. Through computing the spatial variations of various properties along the direction normal to the in-plane solid-liquid boundary lines for both interfacial layers, a rich and varied picture depicting the inhomogeneity and anisotropy in the mechanical, thermodynamical, and dynamical properties is presented. The bulk values extracted from the in-plane profiles suggest that each interfacial state examined has distinct equilibrium values from each other and significantly deviates from those of the bulk solid and liquid phases, and indicate that the complexion (or phase) diagrams for the Cu(111)/Pb(l) interface bears a resemblance to that of the eutectic binary alloy systems, instead of the monotectic phase diagram for the bulk CuPb alloy. The reported data could support the development of interfacial complexion (or phase) diagrams and interfacial phase rules and provide a new guide for regulating heterogeneous nucleation and wetting processes.
Causality assessment of adverse drug reaction reported in patients treated with arthritis in a tertiary care hospital: A prospective study
Neha K, Nasrin Nisha, Chethan Kumar G
et al.
Background: Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory condition, initially affecting smaller joints but slowly progressing to involve larger joints. Osteoarthritis (OA) is a degenerative disease affecting mainly large joints. Pain, stiffness, and loss of mobility are the cardinal features of OA. Treatment goals of RA are pain relief, slowing the progression of joint inflammation and prevention of joint disability or deformity, whereas those of OA are immediate relief of symptoms and improving joint function. Non-steroidal anti-inflammatory drugs (NSAIDS) and disease-modifying anti-rheumatic drugs (DMARDS) are used to treat above conditions. Long treatment is associated with development of ADR. The present study aimed to evaluate the prevalence of ADR patients treating for arthritis.
Aims and Objectives: The objective of the study was as follows: (i) To assess the prevalence of use of drugs and drug classes in RA and OA; (ii) to assess the prevalence of adverse events (ADE) of prescribed drugs; and (iii) causality assessment of ADE.
Materials and Methods: This study was an observational study of ADE of drug prescribed among 100 arthritis patients in a tertiary care teaching hospital, India. Patients diagnosed with RA or OA with or without comorbidities were enrolled in the study based on inclusion and exclusion criteria. Causality assessment severity was assessed from Hartwig and colleagues' criteria and preventable ADE was defined by Schumock and Thornton's criteria.
Results: Out of 100 arthritis cases, the prevalence of OA was more than RA. OA was more commonly seen in males and RA in females. Arthritis was more prevalent in the age group of 36–65 years. NSAIDs were the first-choice drug in arthritis. Among NSAIDS, diclofenac was the commonly used drug for monotherapy in OA and methotrexate was commonly used in RA. Sixty-eight ADEs were detected in 51 patients. The prevalence of ADE was 35.7%. Thirty out of 68 ADEs (44.1%) were preventable. NSAIDS and DMARDS resulted in ADEs by 23 (29.6%) and 24 (34.8%) events, respectively. Common affected organs were cutaneous manifestations, gastrointestinal tract, and eyes which accounted for 20 (29.4%), 18 (26.5%), and 8 events (11.6%), respectively. Continuation of the suspected drug was noted in 42 ADEs (61.8%), classified as severity level 1 and 2a-b, and 43 ADEs (63.2%) were completely or partially resolved during the study period.
Conclusion: ADEs are common in RA and OA patients with the prevalence of 35.7%. ADEs should be monitored properly and reported to prevent irrational use of drugs. [Natl J Physiol Pharm Pharmacol 2023; 13(11.000): 2299-2303]
Therapeutics. Pharmacology, Pharmacy and materia medica
Wound Healing Performance in a Moist Environment of Crystalline Glucose/Mannose Film as a New Dressing Material Using a Rat Model: Comparing with Medical-Grade Wound Dressing and Alginate
Celine Chia Qi Wong, Kanako Tomura, Osamu Yamamoto
Although medical wound dressings produced using hydrocolloids and alginate were effective in wound healing, adhesion at the wound site and the resulting delayed healing have been a problem. As a new wound dressing material, crystalline wound dressings produced from glucose/mannose were used in this study, which aimed to clarify the properties, adhesion reduction, and wound healing performance of a new wound dressing. Crystalline glucose/mannose films were obtained via alkali treatment using the solution casting method. The structure of the crystalline glucose/mannose films was analogous to the cellulose II polymorph, and the crystallinity decreased with time in hydrated conditions. The crystalline glucose/mannose films had adequate water absorption of 34 × 10<sup>−4</sup> g/mm<sup>3</sup> for 5 min. These allowed crystalline glucose/mannose films to remove excess wound exudates while maintaining a moist wound healing condition. This in vivo study demonstrated the healing effects of three groups, which were crystalline glucose/mannose group > alginate group > hydrocolloid group. At 1 week, the crystalline glucose/mannose group was also found to be non-adhesive to the portion of wound healing. This was evidenced by the earlier onset of the healing process, which assisted in re-epithelization and promotion of collagen formation and maturation. These results implied that crystalline glucose/mannose films were a promising candidate that could accelerate the wound healing process, compared with medical-grade wound dressing and alginate.
Medicine, Pharmacy and materia medica
Quality by Design Approach for Development and Characterization of Granisetron Hydrochloride-Loaded Orodispersible Films
Ming-Yan Li, Bing Wang, Jun-Qi Zhang
et al.
Granisetron hydrochloride can be used to prevent and treat nausea and vomiting induced by chemotherapy. Its prolonged half-life and reduced dose requirement improve patient acceptance. However, patients undergoing chemotherapy often suffer from dysphagia and drug spitting due to emesis. Hence, the development of a patient-centered formulation of granisetron hydrochloride with simple medication and high compliance is crucial. The current study employed a polymer combination of polyvinylpyrrolidone/polyvinyl alcohol (PVP/PVA) as film-forming materials and Lycoat® RS 780 as a disintegrant to formulate orodispersible films (ODFs) loaded with granisetron hydrochloride. Guided by the concept of quality by design, the quality target product profile and critical quality attributes (CQAs) for the ODF were defined. Through the quality risk assessment, essential factors that have a significant impact on CQAs were identified. The formulation was screened using the Box–Behnken statistical design with three factors and three levels. Our data suggested that all ODF formulations exhibited a disintegration time of less than 60 seconds and complete dissolution within 5 minutes. Furthermore, the formulation displayed appropriate mechanical properties, water residue, and pH values. Thus, the granisetron hydrochloride-loaded ODF is regarded as a patient-friendly formulation that enhances compliance and consequently aids in therapeutic effectiveness.
Pharmacy and materia medica
Residual surface charge mediated near-field radiative energy transfer: A topological insulator analog
Minggang Luo, Jiaqi Zhu, S. -A. Biehs
et al.
We study the modifications of near-field radiative energy transfer (NFRET) caused by residual surface charges, which are common in micro- and nano-systems like NEMS/MEMS. The host object with the residual surface charges and the inherent bulk state can be treated as an analog of the real three-dimensional topological insulator, which is inherent of also both surface states and bulk states and is promising to modulate NFRET. Through constructing such a topological insulator analog, we aim to modulate NFRET concerning only common trivial materials. Besides the well-known resonant modes (surface polariton and localized surface polariton) supported by the bulk state, the residual surface charges give rise to an additional temperature-dependent mode providing a new heat flux channel. For low temperatures we find a giant surface-charge-induced enhancement of the NFRET due to a good match between the surface-charge-induced resonance and the Planck window. However, for relative high temperatures where the Fröhlich resonance dominates the heat transfer rather the surface-charge-induced resonance, the residual charges result in a weakening of the NFRET. This work paves way for understanding and modulating the near-field radiative energy transfer for micro- and nano-systems.
Assessing long-term medical remanufacturing emissions with Life Cycle Analysis
Julia A. Meister, Jack Sharp, and Yan Wang
et al.
The unsustainable take-make-dispose linear economy prevalent in healthcare contributes 4.4% to global Greenhouse Gas emissions. A popular but not yet widely-embraced solution is to remanufacture common single-use medical devices like electrophysiology catheters, significantly extending their lifetimes by enabling a circular life cycle. To support the adoption of catheter remanufacturing, we propose a comprehensive emission framework and carry out a holistic evaluation of virgin manufactured and remanufactured carbon emissions with Life Cycle Analysis (LCA). We followed ISO modelling standards and NHS reporting guidelines to ensure industry relevance. We conclude that remanufacturing may lead to a reduction of up to 60% per turn (-1.92 kg CO2eq, burden-free) and 57% per life (-1.87 kg CO2eq, burdened). Our extensive sensitivity analysis and industry-informed buy-back scheme simulation revealed long-term emission reductions of up to 48% per remanufactured catheter life (-1.73 kg CO2eq). Our comprehensive results encourage the adoption of electrophysiology catheter remanufacturing, and highlight the importance of estimating long-term emissions in addition to traditional emission metrics.
Asymmetric Phenyl Substitution: An Effective Strategy to Enhance the Photosensitizing Potential of Curcuminoids
Guglielmo Vesco, Martino Brambati, Luca Scapinello
et al.
Curcumin has been demonstrated to exhibit photosensitized bactericidal activity. However, the full exploitation of curcumin as a photo-pharmaceutical active principle is hindered by fast deactivation of the excited state through the transfer of the enol proton to the keto oxygen. Introducing an asymmetry in the molecular structure through acting on the phenyl substituents is expected to be a valuable strategy to impair this undesired de-excitation mechanism competing with the therapeutically relevant ones. In this study, two asymmetric curcumin analogs were synthesized and characterized as to their electronic-state transition spectroscopic properties. Fluorescence decay distributions were also reconstructed. Their analysis confirmed the substantial stabilization of the fluorescent state with respect to the parent compound. Nuclear magnetic resonance experiments were performed with the aim of determining the structural features of the keto–enol ring and the strength of the keto–enol hydrogen bond. Electronic structure calculations were also undertaken to elucidate the effects of substitution on the features of the keto–enol semi-aromatic system and the proneness to proton transfer. Finally, their singlet oxygen-generation efficiency was compared to that of curcumin through the 9,10-dimethylanthracene fluorescent assay.
Medicine, Pharmacy and materia medica
Development of a Hospital Compounded, Taste-Masked, Temozolomide Oral Suspension and 5-Year Real-Life Experience in Treating Paediatric Patients
Maxime Annereau, Mélanie Hinterlang, Hugues Bienayme
et al.
The development of oral pediatric forms by pharmaceutical companies is still insufficient. In fact, many drugs used in paediatric oncology, such as temozolomide, are not labeled and adapted for paediatric use. Temozolomide (TMZ) is an alkylating agent used as the standard of care for many adult and pediatric brain tumours, such as neuroblastoma, glioblastoma and medulloblastoma. The present study was carried out to propose a suitable and palatable formulation of the oral liquid preparation of TMZ. The suspension is composed of TMZ suspended in SyrSpend SF pH 4, as well as TMZ crystallization stabilizing agents and sweetening agents. To reach this formulation, several taste-masking agents were evaluated. Here, we describe the method of preparation of the formation as well as the monocentric population treated with the formulation over a 5–year period. A 20 mg/mL TMZ suspension was developed. TMZ suspension is stable for 6 weeks, stored between 2 and 8 degrees, protected from light, and compatible with nasogastric tubes. Thirty-eight patients participated in the palatability study and choose cola flavour, and 104 patients were treated in Gustave Roussy with the developed suspension; no unexpected event was reported. To conclude, we propose here a new TMZ liquid formulation which is stable for at least 6 weeks and well-tolerated with extensive feedback.
Medicine, Pharmacy and materia medica
Experimental Evidence for Diiodohydroxyquinoline-Induced Neurotoxicity: Characterization of Age and Gender as Predisposing Factors
Ahmed S. Kamel, Ahmed F. Mohamed, Mostafa A. Rabie
et al.
Though quinoline anti-infective agents-associated neurotoxicity has been reported in the early 1970s, it only recently received regulatory recognition. In 2019, the European Medicines Agency enforced strict use for quinoline antibiotics. Thus, the current study evaluates the relation between subacute exposure to diiodohydroxyquinoline (DHQ), a commonly misused amebicide, with the development of motor and sensory abnormalities, highlighting age and gender as possible predisposing factors. Eighty rats were randomly assigned to eight groups according to their gender, age, and drug exposure; namely, four control groups received saline (adult male, adult female, young male, and young female), and the other four groups received DHQ. Young and adult rats received DHQ in doses of 176.7 and 247.4 mg/kg/day, respectively. After 4 weeks, rats were tested for sensory abnormality using analgesiometer, hot plate, and hind paw cold allodynia tests, and for motor function using open field and rotarod tests. Herein, the complex behavioral data were analyzed by principal component analysis to reduce the high number of variables to a lower number of representative factors that extracted components related to sensory, motor, and anxiety-like behavior. Behavioral outcomes were reflected in a histopathological examination of the cerebral cortex, striatum, spinal cord, and sciatic nerve, which revealed degenerative changes as well demyelination. Noteworthy, young female rats were more susceptible to DHQ’s toxicity than their counterparts. Taken together, these findings confirm previous safety concerns regarding quinoline-associated neurotoxicity and provide an impetus to review risk/benefit balance for their use.
Medicine, Pharmacy and materia medica
Synthesis, Biological Evaluation and Machine Learning Prediction Model for Fluorinated <i>Cinchona</i> Alkaloid-Based Derivatives as Cholinesterase Inhibitors
Alma Ramić, Ana Matošević, Barbara Debanić
et al.
A series of 46 <i>Cinchona</i> alkaloid derivatives that differ in positions of fluorine atom(s) in the molecule were synthesized and tested as human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. All tested compounds reversibly inhibited AChE and BChE in the nanomolar to micromolar range; for AChE, the determined enzyme-inhibitor dissociation constants (<i>K</i><sub>i</sub>) ranged from 3.9–80 µM, and 0.075–19 µM for BChE. The most potent AChE inhibitor was <i>N</i>-(<i>para</i>-fluorobenzyl)cinchoninium bromide, while <i>N</i>-(<i>meta</i>-fluorobenzyl)cinchonidinium bromide was the most potent BChE inhibitor with <i>K</i><sub>i</sub> constant in the nanomolar range. Generally, compounds were non-selective or BChE selective cholinesterase inhibitors, where <i>N</i>-(<i>meta</i>-fluorobenzyl)cinchonidinium bromide was the most selective showing 533 times higher preference for BChE. In silico study revealed that twenty-six compounds should be able to cross the blood-brain barrier by passive transport. An extensive machine learning procedure was utilized for the creation of multivariate linear regression models of AChE and BChE inhibition. The best possible models with predicted R<sup>2</sup> (CD-derivatives) of 0.9932 and R<sup>2</sup>(CN-derivatives) of 0.9879 were calculated and cross-validated. From these data, a smart guided search for new potential leads can be performed. These results pointed out that quaternary <i>Cinchona</i> alkaloids are the promising structural base for further development as selective BChE inhibitors which can be used in the central nervous system.
Medicine, Pharmacy and materia medica
Paris-CARLA-3D: A Real and Synthetic Outdoor Point Cloud Dataset for Challenging Tasks in 3D Mapping
Jean-Emmanuel Deschaud, David Duque, Jean Pierre Richa
et al.
Paris-CARLA-3D is a dataset of several dense colored point clouds of outdoor environments built by a mobile LiDAR and camera system. The data are composed of two sets with synthetic data from the open source CARLA simulator (700 million points) and real data acquired in the city of Paris (60 million points), hence the name Paris-CARLA-3D. One of the advantages of this dataset is to have simulated the same LiDAR and camera platform in the open source CARLA simulator as the one used to produce the real data. In addition, manual annotation of the classes using the semantic tags of CARLA was performed on the real data, allowing the testing of transfer methods from the synthetic to the real data. The objective of this dataset is to provide a challenging dataset to evaluate and improve methods on difficult vision tasks for the 3D mapping of outdoor environments: semantic segmentation, instance segmentation, and scene completion. For each task, we describe the evaluation protocol as well as the experiments carried out to establish a baseline.
Validated UHPLC-HRMS method for simultaneous quantification of flavonoid contents in the aerial parts of Chenopodium bonus-henricus L. (wild spinach)
Zlatina Kokanova-Nedialkova, Paraskev Nedialkov
A UHPLC-HRMS method for simultaneous quantification of flavonoid contents in the aerial parts of Chenopodium bonus-henricus L. was developed and validated. The amount of 12 detected flavonoids was calculated relative to external standard hyperoside. The calibration curve of hyperoside showed very good linear regressions and the correlation coefficient was R2 &gt; 0.9979. The limits of detection and quantitation limits were 0.39 ng/mL and 1.17 ng/mL, respectively. The UHPLC-HRMS method showed acceptable accuracy. At three different concentrations the recoveries of hyperoside ranging from 99.63% to 100.70% with RSD from 1.58% to 2.31%. The intra-day and inter-day precision were determined by analyzing the retention times and recovery of the external standard. The glycosides of spinacetin and patulenin (1) were the predominant compounds in the wild spinach which contents ranging from 1.79 to 4.41 mg g-1 D.W., calculated as hyperoside. The total amount of flavonoids was found to be 15.12 mg g-1 D.W.
Pharmacy and materia medica