bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quinoxaline‐based efflux pump inhibitors restore drug susceptibility in drug‐resistant nontuberculous mycobacteria
Authors: Corona Paola , Ibba Roberta , Piras Sandra , Molicotti Paola , Bua Alessandra , Carta Antonio 
Published: May 2022

AbstractNontuberculous mycobacteria (NTM) comprise several ubiquitous, environmentally localized bacteria that may be responsible for serious human diseases. NTM‐associated pulmonary infections largely affect individuals with underlying respiratory disease or chronic disease and immunosuppressed patients. Mycobacterium simiae and M. abscessus are two NTMs responsible for lung disease in immunocompetent and immunocompromised individuals. In this study, two NTM strains were isolated from two patients admitted to an Italian hospital and were identified as M. simiae and M. abscessus. The two NTMs were tested for drug susceptibility against different antibiotics. To restore drug susceptibility, a new series of 2‐aryl‐3‐phenoxymethyl‐quinoxaline derivatives (QXs) was designed, synthesized, and investigated as efflux pump inhibitors (EPIs) against two clinical isolates of the above‐cited NTMs, evaluating how EPIs can influence the drug minimal inhibitory concentration values and, therefore, the activity. The different\ resistance levels tracked in the clinical strains were reduced by EPIs, and in several cases, the susceptibility was completely restored. QXs also resulted as potential chemical probes to be used in drug susceptibility tests to identify the resistance origin when detected.
Therapeutic potential of 1,2,3‐triazole hybrids for leukemia treatment
Authors: Yang Wenchao , Xuan Bixia , Li Xiaofang , Si Haiyan , Chen Aiping 
Published: May 2022

AbstractLeukemia, a hematological malignancy originating from the bone marrow, is the principal cancer of childhood. In recent decades, improved remission rates and survival of patients with leukemia have been achieved due to significant breakthroughs in the treatment. However, chemoresistance and relapse are common, creating an urgent need for the search for novel pharmaceutical interventions. 1,2,3‐Triazole is one of the most fascinating pharmacophores in the discovery of new drugs, and several 1,2,3‐triazole derivatives have already been used in clinics or are under clinical evaluation for the treatment of cancers. In particular, 1,2,3‐triazole hybrids could suppress tumor proliferation, invasion, and metastasis by inhibiting enzymes, proteins, and receptors in cancer cells, revealing their potential as putative antileukemic agents. This review covers the recent advances regarding the 1,2,3‐triazole hybrids with potential antileukemic activity, focusing on the chemical structures, structure–activity relationship, and mechanisms of action, covering articles published from January 2017 to January 2022.
Quantitative in vitro to in vivo extrapolation for developmental toxicity potency of valproic acid analogues
Authors: Chang Xiaoqing , Palmer Jessica , Lumen Annie , Lee Un Jung , Ceger Patricia , Mansouri Kamel , Sprankle Catherine , Donley Elizabeth , Bell Shannon , Knudsen Thomas B. , Wambaugh John , Cook Bethany , Allen David , Kleinstreuer Nicole 
Published: May 2022

AbstractBackgroundThe developmental toxicity potential (dTP) concentration from the devTOX quickPredict (devTOXqP) assay, a metabolomics‐based human induced pluripotent stem cell assay, predicts a chemical's developmental toxicity potency. Here, in vitro to in vivo extrapolation (IVIVE) approaches were applied to address whether the devTOXqP assay could quantitatively predict in vivo developmental toxicity lowest effect levels (LELs) for the prototypical teratogen valproic acid (VPA) and a group of structural analogues.MethodsVPA and a series of structural analogues were tested with the devTOXqP assay to determine dTP concentration and we estimated the equivalent administered doses (EADs) that would lead to plasma concentrations equivalent to the in vitro dTP concentrations. The EADs were compared to the LELs in rat developmental toxicity studies, human clinical doses, and EADs reported using other in vitro assays. To evaluate the impact of different pharmacokinetic (PK) models on IVIVE outcomes, we compared EADs predicted using various open‐source and commercially available PK and physiologically based PK (PBPK) models. To evaluate the effect of in vitro kinetics, an equilibrium distribution model was applied to translate dTP concentrations to free medium concentrations before subsequent IVIVE analyses.ResultsThe EAD estimates for the VPA analogues based on different PK/PBPK models were quantitatively similar to in vivo data from both rats and humans, where available, and the derived rank order of the chemicals was consistent with observed in vivo developmental toxicity. Different models were identified that provided accurate predictions for rat prenatal LELs and conservative estimates of human safe exposure. The impact of in vitro kinetics on EAD estimates is chemical‐dependent. EADs from this study were within range of predicted doses from other in vitro and model organism data.ConclusionsThis study highlights the importance of pharmacokinetic considerations when using in vitro assays and demonstrates the utility of the devTOXqP human stem cell‐based platform to quantitatively assess a chemical's developmental toxicity potency.
Docosahexaenoic acid may inhibit immune evasion of colorectal cancer cells through targeting immune checkpoint and immunomodulator genes and their controlling microRNAs
Authors: Fadaee Manouchehr , Abbasi Hajar , Maralbashi Sepideh , Baradaran Behzad , Shanehbandi Dariush , Dinevari Masood Faghih , Kazemi Tohid 
Published: May 2022

AbstractColorectal cancer is one of the major concerns in both developed and developing societies. Because of the serious side effects of the current treatments, novel therapy agents have been developed that target immune checkpoint and immunomodulatory molecules in the tumor environment. Therefore, this study investigates the effect of docosahexaenoic acid (DHA) fatty acid on the expression of immune checkpoint molecule, PD‐L1, and immunomodulatory molecules, CD47 and CD39, and their controlling miRNAs in the colorectal cancer cell lines. Human colorectal cell lines HT‐29 and Caco‐2 were treated with 100 μM DHA and 50 μM LA for 24 h under the normoxic and hypoxic conditions. Total RNA was extracted and the qRT‐PCR was performed to analyze the expression of the studied genes and miRNAs. The western blotting technique was also used for validation. The qRT‐PCR results showed that DHA treatment decreased the expression of the PD‐L1, CD47, and CD39 genes, but decreases these genes controlling miRNAs, mir‐424, mir‐133a, and mir‐142, respectively. Western blotting analysis demonstrated that PD‐L1 protein expression decreased after DHA treatment. LA administration had no inhibitory effect on the studied genes. This study showed that DHA may have anti‐cancer properties by downregulation of proteins involved in the immune evasion of colorectal tumors. DHA could be used as a potential immune checkpoint inhibitor for the treatment of colorectal cancers.
Comparative histomorphological analysis of elbow ligaments and capsule
Authors: Lühmann Paul , Kremer Thomas , Siemers Frank , Rein Susanne 
Published: May 2022

AbstractThis study aimed to compare the histomorphology of the elbow capsule and its ligaments to gain a better understanding of the clinically relevant biomechanical stabilization. Eleven human elbows were dissected including the joint capsule with its anterior (AJC) and posterior (PJC) parts, the annular ligament (AL), the radial collateral ligament (RCL) and the ulnar collateral ligament with its anterior (AUCL), posterior (PUCL) and transverse (TUCL) parts. Hematoxylin–Eosin and Elastica van Gieson as conventional histology stainings were applied to determine collagenous and elastic fiber arrangements in transmission and polarization light microscopy. The radial collateral ligament and the anterior part of the ulnar collateral ligament showed significantly more densely packed parallel fiber arrangement than the anterior joint capsule, the posterior joint capsule, and the posterior part of the ulnar collateral ligament (p < 0.02, respectively). The PUCL had significantly more mixed tight and loose parallel arrangements than the PJC, the annular ligament, the RCL, the AUCL and the transverse part of the ulnar collateral ligamentp < 0.02, respectively), while the PJC showed significantly more interlaced mixed tight and loose fiber arrangement than the AL, the RCL and the AUCL (p < 0.003, respectively). The AJC had a significantly higher amount of elastic fibers as compared to the AL, the RCL, the AUCL and the TUCL in fascicular regions (p < 0.04, respectively), while the AUCL had significantly lesser elastic fibers than the AJC and the PJC (p < 0.004, respectively). The densely packed parallel fiber arrangement and few elastic fibers of the AUCL, RCL, and AL indicate a strong biomechanically stabilizing function. The fiber arrangement of the PUCL and the TUCL with few elastic fibers support the medial elbow stabilization. Crimping and elastic fibers provide the viscoelasticity of the joint capsule.
Cucurbit[7]uril Inhibits Islet Amyloid Polypeptide Aggregation by Targeting N Terminus Hot Segments and Attenuates Cytotoxicity
Authors: Maity Debabrata , Oh Yujeong , Gremer Lothar , Hoyer Wolfgang , Magzoub Mazin , Hamilton Andrew D. 
Published: May 2022

AbstractTwo “hot segments” within an islet amyloid polypeptide are responsible for its self‐assembly, which in turn is linked to the decline of β‐cells in type 2 diabetes (T2D). A readily available water‐soluble, macrocyclic host, cucurbit[7]uril (CB[7]), effectively inhibits islet amyloid polypeptide (IAPP) aggregation through ion–dipole and hydrophobic interactions with different residues of the monomeric peptide in its random‐coil conformation. A HSQC NMR study shows that CB[7] likely modulates IAPP self‐assembly by interacting with and masking major residues present in the “hot segments” at the N terminus. CB[7] also prevents the formation of toxic oligomers and inhibits seed‐catalyzed fibril proliferation. Importantly, CB[7] recovers rat insulinoma cells (RIN‐m) from IAPP‐assembly associated cytotoxicity.
2‐O‐Acetyl‐3,4,5,6‐tetra‐O‐benzyl‐d‐myo‐inosityl diphenylphosphate: A new useful intermediate to inositol phosphate and phospholipids
Authors: Sangiorgio Sara , Cambò Mattia , Semproli Riccardo , Ubiali Daniela , Speranza Giovanna , Rabuffetti Marco 
Published: May 2022

AbstractInositol phosphates and inositol phospholipids are ubiquitous in biochemistry and play a central role in cell signaling and regulation events. For this reason, their synthesis has attracted widespread interest. This paper describes the preparation of a new optically active inositol phosphate derivative, 2‐O‐acetyl‐3,4,5,6‐tetra‐O‐benzyl‐d‐myo‐inosityl diphenylphosphate (6), and its characterization by spectroscopic methods. Compound (6) represents a useful intermediate for the preparation of inositol phosphate and phospholipids, in particular of glycerophosphoinositol (GPI), a natural anti‐inflammatory agent.
Comprehensive Theoretical View of the [Cu2O2] Side‐on‐Peroxo‐/Bis‐μ‐Oxo Equilibria
Authors: Stańczak Agnieszka , Chalupský Jakub , Rulíšek Lubomír , Straka Michal 
Published: May 2022

AbstractCoupled binuclear copper (CBC) sites are employed by many metalloenzymes to catalyze a broad set of biochemical transformations. Typically, the CBC catalytic sites are activated by the O2molecule to form various [Cu2O2] reactive species. This has also inspired synthesis and development of various biomimetic inorganic complexes featuring the CBC core. From theoretical perspective, the [Cu2O2] reactivity often hinges on the side‐on‐peroxo‐dicopper(II) (P) vs. bis‐μ‐oxo‐dicopper(III) (O) isomerism ‐ an equilibrium that has become almost iconic in theoretical bioinorganic chemistry. Herein, we present a comprehensive calibration and evaluation of the performance of various composite computational protocols available in contemporary computational chemistry, involving coupled‐cluster and multireference (relativistic) wave function methods, popular density functionals and solvation models. Starting with the well‐studied reference [Cu2O2(NH3)6]2+system, we compared the performance of electronic structure methods and discussed the relativistic effects. This allowed us to select several ‘calibrated’ DFT functionals that can be conveniently employed to study ten experimentally well‐characterized [Cu2O2] inorganic systems. We mostly predicted the lowest‐energy structures (Pvs.O) of the studied systems correctly. In addition, we present calibration of the used electronic structure methods for prediction of the spectroscopic features of the [Cu2O2] core, mostly provided by the resonance Raman (rR) spectroscopy.
Next‐Generation Sequencing to Characterize Mitochondrial Genomic DNA Heteroplasmy
Authors: Yang Zeyu , Slone Jesse , Huang Taosheng 
Published: May 2022

AbstractMitochondria play a very important role in many crucial cellular functions. Each eukaryotic cell contains hundreds of mitochondria with hundreds of mitochondrial genomes. Mutant and wild‐type mitochondrial DNA (mtDNA) may co‐exist as heteroplasmy and cause human disease. The purpose of the protocols in this article is to simultaneously determine the mtDNA sequence and quantify the heteroplasmy level using parallel sequencing. The protocols include mitochondrial genomic DNA PCR amplification of two full‐length products using two distinct sets of PCR primers. The PCR products are mixed at an equimolar ratio, and the samples are then barcoded and sequenced with high‐throughput next‐generation sequencing technology. This technology is highly sensitive, specific, and accurate in determining mtDNA mutations and the degree/level of heteroplasmy. © 2022 Wiley Periodicals LLC.Basic Protocol 1: PCR amplification of mitochondrial DNABasic Protocol 2: Analysis of next‐generation sequencing of mitochondrial DNABasic Protocol 3: Mutect2 pipeline for automated sample processing and large‐scale data analysis
Extraction and Surfactant Properties of Glyoxylic Acid‐Functionalized Lignin
Authors: Bertella Stefania , Bernardes Figueirêdo Monique , De Angelis Gaia , Mourez Malcolm , Bourmaud Claire , Amstad Esther , Luterbacher Jeremy S. 
Published: May 2022

AbstractThe amphiphilic chemical structure of native lignin, composed by a hydrophobic aromatic core and hydrophilic hydroxy groups, makes it a promising alternative for the development of bio‐based surface‐active compounds. However, the severe conditions traditionally needed during biomass fractionation make lignin prone to condensation and cause it to lose hydrophilic hydroxy groups in favour of the formation of C−C bonds, ultimately decreasing lignin's abilities to lower surface tension of water/oil mixtures. Therefore, it is often necessary to further functionalize lignin in additional synthetic steps in order to obtain a surfactant with suitable properties. In this work, multifunctional aldehyde‐assisted fractionation with glyoxylic acid (GA) was used to prevent lignin condensation and simultaneously introduce a controlled amount of carboxylic acid on the lignin backbone for its further use as surfactant. After fully characterizing the extracted GA‐lignin, its surface activity was measured in several water/oil systems at different pH values. Then, the stability of water/mineral oil emulsions was evaluated at different pH and over a course of 30 days by traditional photography and microscopy imaging. Further, the use of GA‐lignin as a surfactant was investigated in the formulation of a cosmetic hand cream composed of industrially relevant ingredients. Contrary to industrial lignins such as Kraft lignin, GA‐lignin did not alter the color or smell of the formulation. Finally, the surface activity of GA‐lignin was compared with other lignin‐based and fossil‐based surfactants, showing that GA‐lignin presented similar or better surface‐active properties compared to some of the most commonly used surfactants. The overall results showed that GA‐lignin, a biopolymer that can be made exclusively from renewable carbon, can successfully be extracted in one step from lignocellulosic biomass. This lignin can be used as an effective surfactant without further modification, and as such is a promising candidate for the development of new bio‐based surface‐active products.
Research about two‐step channel with lateral narrowing structures in the flow mass transfer of proton exchange membrane fuel cell
Authors: Li J.R. , Wang H.Y. , Lin P.J , Wang G.D. , Sun J.C. , Yang D.M. 
Published: May 2022

AbstractProton exchange membrane fuel cell (PEMFC) is a new energy device with wide application prospects. The design of its flow field is one of the effective methods to improve its performance. As key parameters of the PEMFC, mass transport is directly dependent on these channels in flow fields. To enhance the mass transport in the channel, some simple two‐step structures with forced convection are proposed in previous research. But the convections formed by these simple structures are only in one direction. Compared to the complex flow behaviors of the gas in PEMFC, these one‐direction convections are not enough. Then the more comprehensive dimensional convections are made by a new kind of two‐step structure with lateral narrowing. The mathematical model of the new‐designed PEMFC is simulated by the Fluent module in the computational fluid dynamics software ANSYS. Compared with the parallel‐straight‐flow channel, the current density of the new channel proposed in this paper can be increased by 12.5%.
Relationship between dementia, COVID‐19 risk, and adherence to COVID‐19 mitigation behaviors among older adults in the United States
Authors: Wong Roger , Lovier Margaret Anne 
Published: May 2022

AbstractObjectivesTo examine how dementia is associated with COVID‐19 risk and adherence to COVID‐19 mitigation behaviors, and whether mitigation behaviors mediate the relationship between dementia and COVID‐19 risk.Methods/DesignWe analyzed 2019 and 2020 data from the National Health and Aging Trends Study, a national prospective cohort study of United States older adults age 65+. Outcomes were COVID‐19 diagnosis and adherence to COVID‐19 mitigation behaviors (handwashing, mask‐wearing, and social distancing).ResultsAmong the 3257 older adults in this study, 485 (14.9%) had dementia in 2019 and 98 (3.1%) were COVID‐19 positive in 2020. Dementia significantly increased the odds of COVID‐19 by 129% (odds ratio [OR] = 2.29, 95% confidence interval [CI] 1.32–3.97), and remained elevated after adjusting for sociodemographics and health (OR = 1.67, 95% CI 0.90–3.11). Dementia significantly decreased the odds of handwashing by 72% (OR = 0.28, 95% CI 0.17–0.44), which remained lower after adjusting for sociodemographics and health (OR = 0.53, 95% CI 0.23–1.21). Dementia was not significantly associated with mask‐wearing and social distancing. The relationship between dementia and COVID‐19 was primarily mediated by functional impairment, income, and residential setting.ConclusionsDementia was associated with an increased COVID‐19 risk and lower adherence to handwashing among U.S. older adults. Adherence to COVID‐19 mitigation behaviors did not mediate COVID‐19 risk by dementia status. For older adults with dementia, COVID‐19 risk could be decreased by prioritizing health interventions.
A data driven policy to minimise the tuberculosis testing cost among healthcare workers
Authors: Girishan Prabhu Vishnunarayan , Taaffe Kevin M. , Pirrallo Ronald G. , Shvorin Dotan 
Published: May 2022

AbstractIntroductionThe Centres for Disease Control and Prevention (CDC) mandates that healthcare employees at high‐risk exposure to Tuberculosis (TB) undergo annual testing. Currently, two methods of TB testing are used: a two‐step skin test (TST) or a whole‐blood test (IGRA). Healthcare leadership's test selection must account for not only direct costs such as procedure and resources but also indirect costs, including employee workplace absence.MethodsA mathematical model based on Upstate South Carolina's largest health system affecting over 18,000 employees on six campuses was developed to investigate the value loss perspective of these testing methods and assist in decision‐making. A process flow map identified the varied direct and indirect costs for each test for four employee types, and 6 travel‐to‐testing‐site times were calculated.ResultsThe switching point between testing procedures that minimised total system costs was most influenced by employee salary compared to travel distance. Switching from the current hospital policy to an integrated TST/IGRA testing could reduce TB compliance costs by 28%.ConclusionsThis study recommends an integrated approach as cost‐effective for large health systems with multiple campuses while considering the direct and indirect costs. When accounting for ‘inconvenience costs’ (stress, etc.) associated with visits, IGRAs are recommended irrespective of employee salary.
Physiologically Based Pharmacokinetic and Pharmacodynamic Modeling of Diazepam: Unbound Interstitial Brain Concentrations Correspond to Clinical End Points
Authors: Burkat P.M. 
Published: May 2022

AbstractBenzodiazepines induce a series of clinical effects by modulating subtypes of γ‐aminobutyric acid type A receptors in the central nervous system. The brain concentration‐time profiles of diazepam that correspond to these effects are unknown, but can be estimated with physiologically based pharmacokinetic (PBPK) modeling. In this study, a PBPK model for the 1,4‐benzodiazepines diazepam and nordiazepam was developed from plasma concentration–time courses with PK‐Sim software to predict brain concentrations. The PBPK model simulations accurately parallel plasma concentrations from both an internal model training data set and an external data set for both intravenous and peroral diazepam administrations. It was determined that the unbound interstitial brain concentration–time profiles correlated with diazepam pharmacodynamic end points. With a 30‐mg intravenous diazepam dose, the peak unbound interstitial brain concentration from this model is 160 nM at 2 minutes and 28.9 nM at 120 minutes. Peak potentiation of recombinant γ‐aminobutyric acid type A receptors composed of α1β2γ2s, α2β2γ2s, and α5β2γ2s subunit combinations that are involved in diazepam clinical endpoints is 108%, 139%, and 186%, respectively, with this intravenous dose. With 10‐mg peroral administrations of diazepam delivered every 24 hours, steady‐state peak and trough unbound interstitial brain diazepam concentrations are 22.3 ± 7.5 and 9.3 ± 3.5 nM. Nordiazepam unbound interstitial brain concentration is 36.1 nM at equilibrium with this diazepam dosing schedule. Pharmacodynamic models coupled to the diazepam unbound interstitial brain concentrations from the PBPK analysis account for electroencephalographic drug effect, change in 13‐ to 30‐Hz electroencephalographic activity, amnesia incidence, and sedation score time courses from human subjects.