bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design Principles for Balancing Lipophilicity and Permeability in beyond Rule of 5 Space
Authors: Möbitz Henrik 
Published: November 2023

AbstractAn ab initio conformational analysis of oral beyond Rule of 5 (bRo5) drugs was complemented with measured permeability and logP(octanol) to derive design principles conferring oral bioavailability. 3D polar surface area (PSA) thresholds for oral bRo5 drugs coincided with those reported for Ro5 space. The majority of oral bRo5 drugs exceeded the Ro5 logP threshold of 5, reflecting a bias for permeability. Above 500 Da molecular weight (MW), oral drugs and highly permeable Novartis compounds occupy a narrow polarity range (topological or TPSA/MW) of 0.1‐0.3 Å2/Da, whose upper half coincides with the lower 90 percentiles of the Novartis logP set. This TPSA/MW range and 3D PSA below 100 Å2 define the “Rule of ~1/₅” for balancing lipophilicity and permeability. Neutral TPSA, defined as TPSA minus 3D PSA occurs independent of conformation, intramolecular hydrogen bonds (IMHB) and MW, suggesting it is an intrinsic molecular property. Neutral TPSA increased in the lead optimization (LO) campaigns of three first in class de novo designed bRo5 drugs and may be a useful design parameter in bRo5 space.
Safety and efficacy of ibrutinib in combination with rituximab and lenalidomide in previously untreated follicular and marginal zone lymphoma: An open label, phase 2 study
Authors: Gordon Max J. , Feng Lei , Strati Paolo , Lee Hun Ju , Hagemeister Fredrick B. , Westin Jason R. , Samaniego Felipe , Marques‐Piubelli Mario L. , Vega Vazquez Francisco , Parra Cuentas Edwin R. , Solis‐Soto Luisa M. , Ma Wencai , Wang Jing , Claret Linda , Averill Barbara , Ibanez Karina , Fayad Luis E. , Flowers Christopher R. , Green Michael R. , Davis R. Eric , Neelapu Sattva S. , Fowler Nathan H. , Nastoupil Loretta J. 
Published: November 2023

AbstractBackgroundFollicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent non‐Hodgkin lymphomas (iNHL). Median survival for iNHL is approximately 20 years. Because standard treatments are not curative, patients often receive multiple lines of therapy with associated toxicity—rationally designed, combination therapies with curative potential are needed. The immunomodulatory drug lenalidomide was evaluated in combination with rituximab for the frontline treatment of FL in the phase 3 RELEVANCE study. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, is active in NHL and was evaluated in combination with lenalidomide, rituximab, and ibrutinib (IRR) in a phase 1 study.MethodsThe authors conducted an open‐label, phase 2 clinical trial of IRR for previously untreated FL and MZL. The primary end point was progression‐free survival (PFS) at 24 months.ResultsThis study included 48 participants with previously untreated FL grade 1–3a (N = 38), or MZL (N = 10). Participants received 12, 28‐day cycles of lenalidomide (15 mg, days 1–21 cycle 1; 20 mg, cycles 2–12), rituximab (375 mg/m2 weekly in cycle 1; day 1 cycles 2‐12), and ibrutinib 560 mg daily. With a median follow‐up of 65.3 months, the estimated PFS at 24 months was 78.8% (95% confidence interval [CI], 68.0%–91.4%) and 60‐month PFS was 59.7% (95% CI, 46.6%–76.4%). One death occurred unrelated to disease progression. Grade 3–4 adverse events were observed in 64.6%, including 50% with grade 3–4 rash.ConclusionsIRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3–4 toxicity, particularly rash. The study was registered with ClinicalTrials.gov (NCT02532257).
Infinite order phase transition in the slow bond TASEP
Authors: Sarkar Sourav , Sly Allan , Zhang Lingfu 
Published: November 2023

AbstractIn the slow bond problem the rate of a single edge in the Totally Asymmetric Simple Exclusion Process (TASEP) is reduced from 1 to for some small . Janowsky and Lebowitz posed the well‐known question of whether such very small perturbations could affect the macroscopic current. Different groups of physicists, using a range of heuristics and numerical simulations reached opposing conclusions on whether the critical value of is 0. This was ultimately resolved rigorously in Basu‐Sidoravicius‐Sly which established that .Here we study the effect of the current as tends to 0 and in doing so explain why it was so challenging to predict on the basis of numerical simulations. In particular we show that the current has an infinite order phase transition at 0, with the effect of the perturbation tending to 0 faster than any polynomial. Our proof focuses on the Last Passage Percolation formulation of TASEP where a slow bond corresponds to reinforcing the diagonal. We give a multiscale analysis to show that when is small the effect of reinforcement remains small compared to the difference between optimal and near optimal geodesics. Since geodesics can be perturbed on many different scales, we inductively bound the tails of the effect of reinforcement by controlling the number of near optimal geodesics and giving new tail estimates for the local time of (near) geodesics along the diagonal.
Bioequivalence and Pharmacokinetics Study of Two Zidovudine/Lamivudine Tablets in Chinese Healthy Volunteers
Authors: Huang Xiaomei , Wang Gongzhu , Huang Jian , Liang Wu , Guan Huiyu , Liu Haisha , Deng Yuan , You Yu , Zhang Bikui 
Published: November 2023

AbstractZidovudine/lamivudine tablets are nucleoside reverse transcriptase inhibitors that are used to treat human immunodeficiency virus. The objective of this study was to investigate the bioequivalence and pharmacokinetics (PKs) of test and reference preparations of zidovudine/lamivudine tablets in healthy Chinese subjects. We designed a randomized, open, single‐center, single‐dose, 2‐crossover experiment with a 7‐day washout period involving 20 healthy subjects. The subjects were given a single dose of the test or reference preparation after fasting overnight for 10 hours. Blood samples were subsequently collected at scheduled time points from 0 hour (preadministration) up to 24 hours postadministration. The plasma concentrations of zidovudine and lamivudine were determined by a validated ultra‐performance liquid chromatography‐tandem mass spectrometry method. Analysis of variance (ANOVA) was used to compare differences in the mean values of key PK parameters between the 2 preparations. Bioequivalence was evaluated by 2 one‐sided t‐tests and 90% confidence intervals (CIs) of the geometric mean ratio (GMR). In total, 19 of the 20 subjects completed the trial. Based on the analysis of PK parameters, the relative bioavailability of zidovudine and lamivudine was 101.1% ± 2.0% and 100.3% ± 1.5%, respectively. ANOVA found no significant difference in primary PK parameters when compared between the 2 formulations, and the 90% CIs of the GMR of the 2 formulations were within the bioequivalence margins of 80%–125%. No serious adverse events occurred. Thus, we confirmed that the 2 preparations were bioequivalent in healthy Chinese volunteers. Our analysis demonstrated that both products showed good tolerance in all subjects.
Bioequivalence of 200 mg Amisulpride Tablets in Healthy Chinese Volunteers under Fasting and Fed Conditions
Authors: Cao Yi , Su Jianfen 
Published: November 2023

AbstractIn this study, we compared the pharmacokinetics and safety of a new generic product and a branded reference product of amisulpride tablets. Additionally, we assessed the bioequivalence of the 2 products in healthy Chinese volunteers to acquire sufficient evidence for the marketing approval of the generic drug. Thirty volunteers under fasting and fed conditions were randomly administered a single dose of the test or reference drug orally, followed by a 7‐day washout period. The pharmacokinetic parameters were obtained by the concentration‐time profiles, including the area under the plasma concentration‐time curve (AUC) over the dosing interval, AUC from time zero to infinity, maximum plasma concentration, time to achieve maximum plasma concentration, and elimination half‐life. AUC from time zero to infinity of amisulpride in the postprandial group was reduced by approximately 25%, suggesting that a high‐fat diet can affect this parameter. In the aspect of safety, no serious adverse events occurred. This study demonstrated that generic and reference products of amisulpride tablets were bioequivalent in healthy Chinese volunteers under fasting and fed conditions.
Implementation and evaluation of two parallel computational models for the simulation of a long‐haul DWDM system limited by FWM
Authors: Sánchez‐Lara Rafael , López‐Martínez José L. , Trejo‐Sánchez Joel A. , Offerhaus Herman L. , Álvarez‐Chávez José A. 
Published: November 2023

AbstractFour‐Wave Mixing (FWM) is one of the non‐linear phenomena affecting long‐reach communication systems and high bandwidth. Research communities use simulation tools for parameter optimization. Unfortunately, such a simulation is time‐consuming and requires more time as the number of channels increases. This paper proposes two fast implementations of Dense Wavelength Division Multiplexing (DWDM) system, limited by FWM and the intrinsic Amplified Spontaneous Emission (ASE) noise of optical amplifiers employed in each segment. Additionally, this work compares the efficiency and speed improvement of the proposed parallelization model versus an earlier sequential model. We present the computational complexity analysis of sequential and parallel models. The paper considers two different parallel implementations: a multicore processor using Open MultiProcessing (OpenMP) and Compute Unified Device Architecture (CUDA), which is based on the use of a Graphics Processing Unit (GPU). Results show that parallelism using CUDA improves by up to 70 times the simulation performance compared to the sequential model. Parallelism with CUDA is up to 15 times compared to OpenMP using 12 logical processors. It is possible to simulate an increased number of channels within our parallel execution, which was impractical in the sequential simulation.
Overview of Determination of Biopharmaceutical Properties for Development Candidate Selection
Authors: Yazdanian Mehran 
Published: November 2023

AbstractThe physicochemical and biopharmaceutical properties of putative drug molecules impact their performance in both in vitro and in vivo studies. The design and selection of molecules with drug‐like properties assist in the selection of drug candidates with a higher probability of success in the development process. Described in this overview are commonly used approaches for measuring compound solubility, permeability, and partitioning in drug discovery and development. The utility of these methods in the drug discovery process and product development is discussed. The evaluation of crystallinity and physicochemical stability in relation to biopharmaceutical properties and in assessing the potential for successful development is also discussed. © 2023 Wiley Periodicals LLC.
Genotyping Protocols for Genetically Engineered Mice
Authors: Limaye Advait , Cho Kyoungin , Hall Bradford , Khillan Jaspal S. , Kulkarni Ashok B. 
Published: November 2023

AbstractHistorically, the laboratory mouse has been the mammalian species of choice for studying gene function and for modeling diseases in humans. This was mainly due to their availability from mouse fanciers. In addition, their short generation time, small size, and minimal food consumption compared to that of larger mammals were definite advantages. This led to the establishment of large hubs for the development of genetically modified mouse models, such as the Jackson Laboratory. Initial research into inbred mouse strains in the early 1900s revolved around coat color genetics and cancer studies, but gene targeting in embryonic stem cells and the introduction of transgenes through pronuclear injection of a mouse zygote, along with current clustered regularly interspaced short palindromic repeat (CRISPR) RNA gene editing, have allowed easy manipulation of the mouse genome. Originally, to distribute a mouse model to other facilities, standard methods had to be developed to ensure that each modified mouse trait could be consistently identified no matter which laboratory requested it. The task of establishing uniform protocols became easier with the development of the polymerase chain reaction (PCR). This chapter will provide guidelines for identifying genetically modified mouse models, mainly using endpoint PCR. In addition, we will discuss strategies to identify genetically modified mouse models that have been established using newer gene‐editing technology such as CRISPR. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.Basic Protocol 1: Digestion with proteinase K followed by purification of genomic DNA using phenol/chloroformAlternate Protocol: Digestion with proteinase K followed by crude isopropanol extraction of genomic DNA for tail biopsy and ear punch samplesBasic Protocol 2: Purification of genomic DNA using a semi‐automated systemBasic Protocol 3: Purification of genomic DNA from semen, blood, or buccal swabsBasic Protocol 4: Purification of genomic DNA from mouse blastocysts to assess CRISPR gene editingBasic Protocol 5: Routine endpoint‐PCR‐based genotyping using DNA polymerase and thermal cyclerBasic Protocol 6: T7E1/Surveyor assays to detect insertion or deletions following CRISPR editingBasic Protocol 7: Detecting off‐target mutations following CRISPR editingBasic Protocol 8: Detecting genomic sequence deletion after CRISPR editing using a pair of guide RNAsBasic Protocol 9: Detecting gene knock‐in events following CRISPR editingBasic Protocol 10: Screening of conditional knockout floxed mice
Aniline Derivatives from Lignin under Mild Conditions Enabled by Electrochemistry
Authors: Castillo‐Garcia Antonio A. , Kappe Christian Oliver , Cantillo David , Barta Katalin 
Published: November 2023

AbstractThe development of environmentally friendly methods for the valorization of important phenolic platform chemicals originating directly from lignin‐first depolymerization into value‐added N‐chemicals, such as aniline derivatives, is of high industrial interest. In this work, we tackle this challenging transformation by the judicious combination of electrochemical conversion and chemical functionalization steps. In the first step, lignin‐derived para‐substituted guaiacols and syringols undergo an atom‐efficient, room‐temperature anodic oxidation using methanol both as solvent and reagent towards the formation of the corresponding cyclohexadienone derivatives, which are subsequently converted to synthetically challenging ortho‐methoxy substituted anilines by reaction with ethyl glycinate hydrochloride under mild conditions. The developed method was applied to crude lignin depolymerization bio‐oils, derived from reductive catalytic fractionation (RCF) mediated either by copper‐doped porous metal oxide (Cu20PMO) or Ru/C, allowing the selective production of 4‐propanol‐2‐methoxyaniline (1Gb) and 4‐propyl‐2‐methoxyaniline (2Gb), respectively, from pine lignocellulose. Finally, the application of 2Gb was further studied in the synthesis of carbazole 2Gc, a lignin‐derived analogue of biologically active alkaloid murrayafoline A.
The potential clinical impact of cell type‐specific genetic regulation: Crohn's disease
Authors: Tyebally Rika , Xue Angli , Powell Joseph E. 
Published: November 2023

AbstractComplex diseases are heterogenous due to variation in their genetic and environmental underpinnings, leading to varied treatment responses. Genome‐wide association studies (GWAS) integrated with single‐cell expression quantitative trait loci analyses (eQTL) can pinpoint cell‐type specific candidate disease‐relevant genes and pathways. This knowledge can be applied to patient stratification and novel therapeutic target identification. Here, we describe the translational potential of cell‐type specific genetic regulation, using Crohn's disease as an example.
Anti‐allodynic and anti‐hyperalgesic activity of (±)‐licarin A in neuropathic rats via NO‐cyclic‐GMP‐ATP‐sensitive K+ channel pathway
Authors: Hernández‐Vázquez Liliana , Colín‐Martínez Brian , Lara‐Ruíz María Guadalupe , Cordova‐Alonso Beatriz , González‐Morales Estefanía , Godínez‐Chaparro Beatriz 
Published: November 2023

AbstractThe study aimed to examine the effect of intraperitoneal and intrathecal (±)‐licarin A in neuropathic pain induced by L5 and L6 spinal nerve ligation (SNL) in male Wistar rats and the possible involvement of the NO‐cGMP‐ATP‐sensitive K+ channel pathway. Neuropathic pain signs (allodynia and hyperalgesia) were evaluated on postoperative Day 14 using von Frey filaments. Single intraperitoneal (0.01, 0.1, 1, and 10 mg/kg) and intrathecal (0.01, 0.1, 1, and 10 µg/rat) administration of (±)‐licarin A improved allodynia and hyperalgesia. The (±)‐licarin A‐induced anti‐allodynic and anti‐hyperalgesic activity was prevented by the intrathecal injection of
l‐NAME (100 µg/rat; nonselective nitric oxide synthase inhibitor), ODQ (10 µg/rat; guanylate cyclase inhibitor), and glibenclamide (50 µg/rat; adenosine triphosphate (ATP)‐sensitive K+ channel blocker). The data suggest that (±)‐licarin A exerts its anti‐allodynic and anti‐hyperalgesic activity by activating the NO‐cGMP‐ATP‐sensitive K+ channel pathway.
The Circular Economy in European Union Policy: Explaining an idea's success through policy learning
Authors: Pinyol Alberich Josep , Hartley Sarah 
Published: November 2023

AbstractThe circular economy (CE) was adopted in 2015 by the European Union (EU). Since its emergence, the CE has proved to be a remarkably powerful idea that has shifted the understanding of the economy, and consequently, it has shaped the EU's economic and environmental policies. The public policy literature theorises such shifts in collective understanding through the concept of policy learning, a process through which ideas are understood and adopted. Yet this literature lacks clarity on the factors that can explain policy learning within a policy community. We use the case of the EU's adoption of the CE to address this gap, exploring the factors that account for the EU's adoption of the CE from the policy‐learning perspective. We show how actors in the policy community have constructed, championed, supported and pioneered the CE and argue that these four factors have mutually reinforced each other, leading to policy learning and the wide acceptance of this idea within EU policy‐making. Revealing these factors helps advance policy learning theory and contributes to the CE literature and environmental policy and governance literature more generally by furthering our understanding of how and why certain policy ideas are adopted.
Transjugular tricuspid valve‐in‐ring replacement using the novel system under three‐dimensional printing guidance
Authors: Wang Yiwei , Liu Yang , Yang Jian 
Published: November 2023

AbstractRecurrent tricuspid regurgitation after failed ring annuloplasty is associated with high mortality rates and unfavourable clinical outcomes. Transcatheter tricuspid valve‐in‐ring (TVIR) replacement offers an alternative to high‐risk surgical reoperation, but challenges remain. We present a case of a 67‐year‐old male who underwent tricuspid annuloplasty 3 years ago and developed severe recurrent tricuspid regurgitation (regurgitation volume = 36 mL) 6 months ago. To avoid a high‐risk thoracotomy, we finally performed TVIR replacement using the novel device, LuX‐Valve Plus system, via the transjugular approach. Cardiovascular three‐dimensional printing technology was utilized to investigate the distinct advantages offered by the new device in this specific intervention, as well as to simulate the procedure. Successful TVIR replacement resulted in significant symptomatic improvement. TVIR replacement with the LuX‐Valve Plus system is feasible for failed annuloplasty ring cases. Patient‐specific three‐dimensional printed models enable personalized procedural planning, enhancing safety and precision.
Bioinspired Photoredox Oxidation of Alcohols with Copper‐Containing Galactose Oxidase Analog
Authors: Chiang Chien‐Wei , Chou Yi‐Hsien , Chou Chih‐Hui , Chen Hung‐Chi , Chen Jeng‐Lung , Hsu Liang‐Ching , Huang Wei‐Hsiang , Li Hung‐Li , Liu Yu‐Hao 
Published: November 2023

AbstractEnzyme mimic studies are driven by a variety of factors, including understanding the function of the active site, replicating enzyme activity, and constructing bio‐inspired catalysts. In this study, we present a ferrocene‐conjugated copper complex (FcTrpCOO)Cu(bpy) that not only serves as a structural analog of Galactose oxidase (GOase) but also demonstrates impressive catalytic efficiency for alcohol oxidation via a photoredox process. Mechanistic investigations of the reaction were carried out using a range of spectroscopic techniques, including UV‐Vis, IR, CV, LC‐MS, XAS, and EPR. These findings offer valuable insights into the mechanism of alcohol oxidation in biological systems and provide a promising approach for developing efficient and eco‐friendly catalysts for chemical synthesis.
Electrochemically Driven Tandem Cyclization Reaction of Unsaturated Sulfoximines with Diselenides
Authors: Yang Jie , Gao Wenchao , Teng Yong , Yu Lintao , Huang Kexin , Li Qiyang , Xie Huanping , Li Ting 
Published: November 2023

AbstractAn electrochemically enabled tandem cyclization reaction of unsaturated sulfoximines with diselenides has been well developed, affording metal‐ and external oxidant‐free access to sulfoximidoyl‐based heterocycles containing selenium in moderate to good yields. With nBu4NBr as the role of catalyst and electrolyte, this methodology shows broad substrate scope and functional group tolerance under mild conditions.
Divergent Synthesis of (Benzo[b][1,4]diazepin‐2‐yl)phosphonates and (Quinoxalin‐2‐yl)methylphosphonates from Phosphoryl‐Substituted Conjugated Ynones
Authors: Mitrofanov Alexander Yu. , Gontcharenko Victoria E. , Beletskaya Irina P. 
Published: November 2023

AbstractIt is shown that the reaction of conjugated ynones containing a phosphoryl group with o‐phenylenediamines can, depending on the conditions, lead to the selective formation of phosphorylated 1,5‐benzodiazepines and quinoxalines. Phosphorylated quinoxalines can be used for synthesis of substituted vinyl quinoxalines.
Evans’ Chiral Auxiliary‐Based Asymmetric Synthetic Methodology and Its Modern Extensions
Authors: Chen Ling‐Yan , Huang Pei‐Qiang 
Published: November 2023

AbstractAlthough the asymmetric catalysis has made a spurt of progress, the use of chiral auxiliaries remains crucial in asymmetric synthesis due to both the reliability and versatility of the methods, and the predictability of stereochemistry of the reactions. Up to date, Evans’ chiral non‐racemic oxazolidinone‐based asymmetric synthetic methodology is still widely used in asymmetric synthesis. More importantly, the Evans asymmetric synthetic methodology turned out to be a fruitful source of inspiration for the development of related asymmetric synthetic methodologies. However, although reviews on the application of Evans’ asymmetric synthetic methodology in both organic synthesis and medicinal chemistry continually to appear in the literature, a comprehensive review dedicating to the extensions of Evans’ chiral non‐racemic oxazolidinone‐based asymmetric methodology remains elusive. In this review, we summarize the extensions of the Evans asymmetric methodology, which cover: (1) the modification of the chiral oxazolidinone auxiliaries; (2) the extension of the Evans’ asymmetric aldol reaction from Evans’ syn‐aldol to other diastereomeric aldol adducts; (3) the extension of the asymmetric reaction types; (4) the extension of chiral imide‐type substrates to N‐alkenyl, N‐allenenyl and N‐alkynyl oxazolidinones; (5) the achiral oxazolidinone‐based asymmetric catalysis; (6) the catalytic transformation of Evans’ products; and (7) the straightforward transformations of Evans’ chiral products to other classes of compounds than the chiral carboxylic acids, esters, alcohols, and Weinreb amides.