bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical Synthesis with Gaseous Molecular Ions: Harvesting [B12Br11N2]− from a Mass Spectrometer
Authors: Rohdenburg Markus , Warneke Ziyan , Knorke Harald , Icker Maik , Warneke Jonas
Published: August 2023

Mass spectrometry frequently reveals the existence of transient gas phase ions that have not been synthesized in solution or in bulk. These elusive ions are, therefore, often considered to be primarily of analytical value in fundamental gas phase studies. Here, we provide proof‐of‐concept that the products of ion‐molecule reactions in mass spectrometers may be collected on surfaces to generate condensed matter and thus serve as building blocks to synthesize new compounds. The highly reactive fragment anion [B12Br11]− was generated in a mass spectrometer and converted to [B12Br11N2]− in the presence of molecular nitrogen followed by its mass‐selection and soft‐landing on surfaces. The molecular structure of [B12Br11N2]−, which has not been synthetically obtained before, was confirmed by conventional methods of molecular analysis, including nuclear magnetic resonance and infrared spectroscopy. The [B12Br11N2]− ion is stable on surfaces and in solution at room temperature, but thermal annealing induces elimination of N2 and provides access to the highly reactive intermediate [B12Br11]− in the condensed phase, which can be further used as a reagent, for example, for electrophilic aromatic substitutions. Thus, isolation of [B12Br11N2]− expands the repertoire of the available diazo ions that can be employed as versatile intermediates in various chemical transformations.
Perspectives on lung visualization: Three‐dimensional anatomical modeling of computed and micro‐computed tomographic data in comparative evolutionary morphology and medicine with applications for COVID‐19
Authors: Schachner Emma R. , Lawson Adam B. , Martinez Aracely , Grand Pre Clinton A. , Sabottke Carl , Abou‐Issa Farid , Echols Scott , Diaz Raul E. , Moore Andrew J. , Grenier John‐Paul , Hedrick Brandon P. , Spieler Bradley
Published: August 2023

The vertebrate respiratory system is challenging to study. The complex relationship between the lungs and adjacent tissues, the vast structural diversity of the respiratory system both within individuals and between taxa, its mobility (or immobility) and distensibility, and the difficulty of quantifying and visualizing functionally important internal negative spaces have all impeded descriptive, functional, and comparative research. As a result, there is a relative paucity of three‐dimensional anatomical information on this organ system in all vertebrate groups (including humans) relative to other regions of the body. We present some of the challenges associated with evaluating and visualizing the vertebrate respiratory system using computed and micro‐computed tomography and its subsequent digital segmentation. We discuss common mistakes to avoid when imaging deceased and live specimens and various methods for merging manual and threshold‐based segmentation approaches to visualize pulmonary tissues across a broad range of vertebrate taxa, with a particular focus on sauropsids (reptiles and birds). We also address some of the recent work in comparative evolutionary morphology and medicine that have used these techniques to visualize respiratory tissues. Finally, we provide a clinical study on COVID‐19 in humans in which we apply modeling methods to visualize and quantify pulmonary infection in the lungs of human patients.
May the force be with you: Nuclear condensates function beyond transcription control
Authors: Negri Maria Luce , D'Annunzio Sarah , Vitali Giulia , Zippo Alessio
Published: August 2023

Over the past decade, research has revealed biomolecular condensates' relevance in diverse cellular functions. Through a phase separation process, they concentrate macromolecules in subcompartments shaping the cellular organization and physiology. In the nucleus, biomolecular condensates assemble relevant biomolecules that orchestrate gene expression. We here hypothesize that chromatin condensates can also modulate the nongenetic functions of the genome, including the nuclear mechanical properties. The importance of chromatin condensates is supported by the genetic evidence indicating that mutations in their members are causative of a group of rare Mendelian diseases named chromatinopathies (CPs). Despite a broad spectrum of clinical features and the perturbations of the epigenetic machinery characterizing the CPs, recent findings highlighted negligible changes in gene expression. These data argue in favor of possible noncanonical functions of chromatin condensates in regulating the genome's spatial organization and, consequently, the nuclear mechanics. In this review, we discuss how condensates may impact nuclear mechanical properties, thus affecting the cellular response to mechanical cues and, eventually, cell fate and identity.

Chromatin condensates organize macromolecules in the nucleus orchestrating the transcription regulation and mutations in their members are responsible for rare diseases named chromatinopathies. We argue that chromatin condensates, in concert with the nuclear lamina, may also govern the nuclear mechanical properties affecting the cellular response to external cues.
Hantzsch Ester Modified Asymmetric BODIPY Probe with Ultra‐high Sensitivity for Ultra‐fast Detection of Endogenous Hypochlorite in Living Cells
Authors: Zhu Tianli , Zhao Mengting , Wang Rongcheng , Dong Chenjun , Dong Xuemei , Sun Jie , Sun Lixin , Zhao Chunchang
Published: August 2023

Comprehensive Summary

Hypochlorite (ClO–) is an important reactive oxygen species produced by the immune system to fight off invading pathogens, but its over‐expression can interfere with normal physiological process and induce serious diseases. Although a variety of molecular probes have been reported for detecting ClO–, the development of advanced fluorescent tools with faster response and higher sensitivity to precisely monitor ClO– remains a challenge. In this work, two Hantzsch ester (a derivative of 1,4‐dihydropyridine) derived fluorescent probes MeDHP‐BCl and MeDHP‐PhBCl were constructed based on asymmetric BODIPY‐matrix. These probes exhibit significant fluorescence turn‐on in the ultra‐sensitive (detection limit < 1 nmol/L) and ultra‐fast response (≤ 5 s) to ClO–. The reaction has been determined to be a highly selective N‐chlorination of Hantzsch ester which cannot be activated by various common bioactive species, including nitric oxide (NO) that could oxidize Hantzsch ester under aerobic physiological conditions in most reports. MeDHP‐PhBCl possessed a relatively longer fluorescence emission wavelength and higher quantum yield after activation, while more notably, MeDHP‐BCl displayed lower cytotoxicity and more remarkable fluorescence increment in the response to ClO–, enabling selective and precise visualization of endogenous ClO– over‐expression in living RAW264.7 cells.
Outcome of rare primary malignant bone sarcoma treated with multimodal therapy: Results from the EUROpean Bone Over 40 Sarcoma Study (EURO‐B.O.S.S.)
Authors: Palmerini Emanuela , Reichardt Peter , Hall Kirsten Sundby , Bertulli Rossella , Bielack Stefan S. , Comandone Alessandro , Egerer Gerlinde , Hansmeier Anna , Kevric Matthias , Carretta Elisa , Hansson Lina , Jebsen Nina , Eriksson Mikael , Bruland Øyvind S. , Donati Davide Maria , Ibrahim Toni , Smeland Sigbjørn , Ferrari Stefano
Published: August 2023

Background

Rare primary malignant bone sarcomas (RPMBS) account for 5%–10% of primary high‐grade bone tumors and represent a major treatment challenge. The outcome of patients with RPMBS enrolled in the EUROpean Bone Over 40 Sarcoma Study (EURO‐B.O.S.S) is presented.

Methods

Inclusion criteria were as follows: age from 41 to 65 years and a diagnosis of high‐grade spindle cell, pleomorphic, or vascular RPMBS. The chemotherapy regimen included doxorubicin 60 mg/m2, ifosfamide 9 g/m2, and cisplatin 90 mg/m2; postoperative methotrexate 8 g/m2 was added in case of a poor histologic response. Version 2.0 of the Common Terminology Criteria for Adverse Events, Kaplan–Meier curves, log‐rank tests, and univariate Cox regression models were used.

Results

In total, 113 patients were evaluable for analysis. The median patient age was 52 years (range, 40–66 years), and 67 patients were men. Eighty‐eight tumors were categorized as undifferentiated pleomorphic sarcomas (UPS), 20 were categorized as leiomyosarcomas, three were categorized as fibrosarcomas, and two were categorized as angiosarcomas. Eighty‐three of 113 tumors were located in the extremities. Ninety‐five of 113 patients presented with no evidence of metastases. After a median follow‐up of 6.8 years (interquartile range [IQR], 3.5–9.8 years), the 5‐year overall survival rate for patients with localized disease was 68.4% (IQR, 56.9%–77.5%), and it was 71.7% (IQR, 58.1%–81.6%) for patients with UPS and 54.9% (IQR, 29.5%–74.5%) for patients with leiomyosarcoma. Grade III–IV hematologic toxicity was reported in 81% patients; 23% had grade II–III neurotoxicity, and 37.5% had grade I–II nephrotoxicity. Five‐year overall survival was significantly better for patients with localized disease, for patients who obtained surgical complete remission, and when the primary tumor was located in the extremities.

Conclusions

The survival of patients who had RPMBS in the current series was similar to that of age‐matched patients who had high‐grade osteosarcoma treated according to the same protocol. An osteosarcoma‐like chemotherapy may be proposed in patients who have RPMBS.
Multi‐Functionalization of Single crystals Mediated by Gel‐Incorporation: A Bioinspired Strategy
Authors: Yao Yuqing , Ren Jie , Li Hanying
Published: August 2023

Biominerals are inherently organic‐inorganic crystal composites. Drawing inspiration from this biomineral structure, functionalized single crystals can be synthesized using the gel‐grown method, resulting in the incorporation of gel‐networks into the host crystals. By incorporating gel‐networks, diverse guest materials, such as nanoparticles and dye molecules, can be uniformly and isotropically distributed within the crystals, thereby imparting non‐intrinsic optical or magnetic properties to the host crystals. Additionally, gel‐incorporation enhances the toughness and stability of the crystals as the incorporated gel‐fibers and accompanying guest materials act as bridges to prevent crack propagation. Furthermore, gel‐incorporation enables protein crystals to exhibit self‐healing properties, which can be attributed to the dynamic bonding interaction between gel‐networks and crystals. Notably, recent research has demonstrated that the incorporation of zwitterionic gel‐networks enhances the charge effects on crystal morphology evolution as the charged groups become bound to the developing crystal surfaces, and their detachment is impeded by the interconnected gel‐networks. Therefore, preparing single crystals with gel‐incorporation is a remarkable strategy for synthesizing functionalized crystal materials.
Impact of CYP2C:TG Haplotype on CYP2C19 Substrates Clearance In Vivo, Protein Content, and In Vitro Activity
Authors: Zubiaur Pablo , Soria‐Chacartegui Paula , Boone Erin C. , Prasad Bhagwat , Dinh Jean , Wang Wendy Y. , Zugbi Santiago , Rodríguez‐Lopez Andrea , González‐Iglesias Eva , Leeder J. Steven , Abad‐Santos Francisco , Gaedigk Andrea
Published: August 2023

A novel haplotype composed of two non‐coding variants, CYP2C18 NM_000772.3:c.*31T (rs2860840) and NM_000772.2:c.819+2182G (rs11188059), referred to as “CYP2C:TG,” was recently associated with ultrarapid metabolism of various CYP2C19 substrates. As the underlying mechanism and clinical relevance of this effect remain uncertain, we analyzed existing in vivo and in vitro data to determine the magnitude of the CYP2C:TG haplotype effect. We assessed variability in pharmacokinetics of CYP2C19 substrates, including citalopram, sertraline, voriconazole, omeprazole, pantoprazole, and rabeprazole in 222 healthy volunteers receiving one of these six drugs. We also determined its impact on CYP2C8, CYP2C9, CYP2C18, and CYP2C19 protein abundance in 135 human liver tissue samples, and on CYP2C18/CYP2C19 activity in vitro using N‐desmethyl atomoxetine formation. No effects were observed according to CYP2C:TG haplotype or to CYP2C19*1+TG alleles (i.e., CYP2C19 alleles containing the CYP2C:TG haplotype). In contrast, CYP2C19 intermediate (e.g., CYP2C19*1/*2) and poor metabolizers (e.g., CYP2C19*2/*2) showed significantly higher exposure in vivo, lower CYP2C19 protein abundance in human liver microsomes, and lower activity in vitro compared with normal, rapid (i.e., CYP2C19*1/*17), and ultrarapid metabolizers (i.e., CYP2C19*17/*17). Moreover, a tendency toward lower exposure was observed in ultrarapid metabolizers compared with rapid metabolizers and normal metabolizers. Furthermore, when the CYP2C19*17 allele was present, CYP2C18 protein abundance was increased suggesting that genetic variation in CYP2C19 may be relevant to the overall metabolism of certain drugs by regulating not only its expression levels, but also those of CYP2C18. Considering all available data, we conclude that there is insufficient evidence supporting clinical CYP2C:TG testing to inform drug therapy.
Comparative Study of Polarization‐Dependent Conversion Efficiency of GaAs and Si Solar Cells at Oblique Incident Angles Using Surface DLAR Coating of MgF2/ZnSe
Authors: Mercy P. Arockia Michael , Wilson K. S. Joseph
Published: August 2023

The aim of this work is to minimize reflection losses in order to increase the efficiency of solar cells by using anti‐reflection coatings (ARCs). Despite extensive research on improving solar cell conversion efficiency at normal incidence, development at angle of incidence has received little attention. Thus, the reflectivity of single‐layer ARC (SLARC) MgF2 and ZnSe, double‐layer ARC (DLARC), MgF2/ZnSe on Si, and GaAs substrates at transverse electric (TE) and transverse magnetic (TM) modes of polarization in the visible and near‐IR regions for different angles of incidence is analyzed. The optical and electrical properties of Si and GaAs solar cells are analyzed by using the reflectance spectra of SLARC and DLARC at various angles of incidence for the TM and TE modes of polarization under the solar power spectrum (AM1.5). The achieved results due to the effect of DLARC are compared for Si and GaAs solar cells. From these analyses, it is concluded that MgF2/ZnSe is an appropriate DLARC for the range of wavelengths 400–800 nm at 10°–30° angles of incidence in TM mode for tuning the optical and electrical properties of Si and GaAs substrates for terrestrial applications.
Transcription factor OsDOF1 enhances cold‐stress tolerance potentially through interactions with OsICE1 and its target genes in rice (Oryza sativa L.)
Authors: Liu Jia , Meng Qinglin , Xiang Hongtao , Shi Fengmei , Ma Ligong , Li Yichu , Yu Liangbin , Liu Chunlai , Liu Yu , Su Baohua
Published: August 2023

Rice plants are generally sensitive to cold temperatures, which adversely affect their yield. Japonica rice, a major subspecies of Oryza sativa L. (Asian cultivated rice), exhibits cold tolerance. Recently, we identified that the plant‐specific transcription factor DNA binding with one finger 1 (Dof1) was associated with the cold resistance of Japonica rice. The purpose of this study was to delineate the role of the OsDof1 gene in cold‐stress tolerance and its potential molecular pathways. Two japonica rice varieties, including the cold‐resistant line LD5 and the cold‐sensitive line LJ11, were used. The protein–protein interactions were determined by yeast two‐hybrid (Y2H), tag‐based pull‐down, and bimolecular fluorescence complementation (BiFC) assays. Truncated DsDOF1 protein was identified in LJ11 as a consequence of a point mutation, and OsDOF1‐T failed to be transported into the nucleus. Furthermore, OsDREB1B, OsDREB2A, OsNF‐YC, OsLEA3, OsRAB16A, OsLIP9, OsNCED3, OsABI2, OsMYBS3, and OsBS3R‐2 were differentially expressed in OsDof1‐overexpressing transgenic versus wild‐type rice lines. Notably, OsICE1 was found to be the target protein of OsDOF1, and subsequent Y2H, BiFC, and tag‐based pull‐down assays showed a direct interaction between the two proteins. In conclusion, OsDOF1 exerts a critical role in cold tolerance potentially through direct interactions with OsICE1 and its target genes in rice. These findings may help to better understand the molecular basis of rice adaptation to cold stress, and OsDof1 could be a target gene in the molecular breeding of rice for better adaptation to a cold‐climate environment, which might eventually improve the yield of rice.
flowSim: Near duplicate detection for flow cytometry data
Authors: Montante Sebastiano , Chen Yixuan , Brinkman Ryan R.
Published: August 2023

The analysis of large amounts of data is important for the development of machine learning (ML) models. flowSim is the first algorithm designed to visualize, detect and remove highly redundant information in flow cytometry (FCM) training sets to decrease the computational time for training and increase the performance of ML algorithms by reducing overfitting. flowSim performs near duplicate image detection by combining community detection algorithms with the density analysis of the marker expression values. flowSim clustering compared to consensus manual clustering on a dataset composed of 160 images of bivariate FCM data had a mean Adjusted Rand Index of 0.90, demonstrating its efficiency in identifying similar patterns. flowSim selectively discarded near duplicate files in datasets constructed with known redundancy, and removed 92.6% of FCM images in a dataset of over 500,000 drawn from public repositories.
Embedding communication concepts in forecasting training increases students' understanding of ecological uncertainty
Authors: Woelmer Whitney M. , Moore Tadhg N. , Lofton Mary E. , Thomas R. Quinn , Carey Cayelan C.
Published: August 2023

Communicating and interpreting uncertainty in ecological model predictions is notoriously challenging, motivating the need for new educational tools, which introduce ecology students to core concepts in uncertainty communication. Ecological forecasting, an emerging approach to estimate future states of ecological systems with uncertainty, provides a relevant and engaging framework for introducing uncertainty communication to undergraduate students, as forecasts can be used as decision support tools for addressing real‐world ecological problems and are inherently uncertain. To provide critical training on uncertainty communication and introduce undergraduate students to the use of ecological forecasts for guiding decision‐making, we developed a hands‐on teaching module within the Macrosystems Environmental Data‐Driven Inquiry and Exploration (EDDIE; MacrosystemsEDDIE.org) educational program. Our module used an active learning approach by embedding forecasting activities in an R Shiny application to engage ecology students in introductory data science, ecological modeling, and forecasting concepts without needing advanced computational or programming skills. Pre‐ and post‐module assessment data from more than 250 undergraduate students enrolled in ecology, freshwater ecology, and zoology courses indicate that the module significantly increased students' ability to interpret forecast visualizations with uncertainty, identify different ways to communicate forecast uncertainty for diverse users, and correctly define ecological forecasting terms. Specifically, students were more likely to describe visual, numeric, and probabilistic methods of uncertainty communication following module completion. Students were also able to identify more benefits of ecological forecasting following module completion, with the key benefits of using forecasts for prediction and decision‐making most commonly described. These results show promise for introducing ecological model uncertainty, data visualizations, and forecasting into undergraduate ecology curricula via software‐based learning, which can increase students' ability to engage and understand complex ecological concepts.
A Dibismuthane with Olefin Functional Groups: Towards Tridentate Hybrid Chalcogen/Olefin Ligands
Authors: Geist Felix , Martínez Sebastián , Ramler Jacqueline , Oberdorf Kai , Brändler Lisa , Reith Sascha , Lichtenberg Crispin
Published: August 2023

Bis[dibenzobismepine], a dibismuthane composed of two bismepine units (R2Bi−BiR2), was synthesized and fully characterized (R2=(C6H4CH)2). Reactions of this dibismuthane with diphenyl dichalcogenides, dibenzoylperoxide, and elemental chalcogens have been investigated. All products of these reactions have been isolated and fully characterized, including a series of compounds R2Bi−E−BiR2 (E=O−Te). These species contain two olefin units of the bismepine moieties and a chalcogen atom as potential coordination sites. The potential of these species to act as hybrid tridentate chalcogen/olefin ligands with bismuth atoms as structure‐determining elements in the backbone has been investigated by theoretical approaches, aiming at the complexation of CoI, RhI, IrI and Ni0, Pd0, Pt0. The analytical techniques applied in this work include heteronuclear and 2D NMR spectroscopy, elemental analysis, single‐crystal X‐ray diffraction analysis, and DFT calculations.
Quality of Experience (QoE)‐based joint admission control and power allocation with guaranteed data rate
Authors: Zabetian Negar , Khalaj Babak Hossein
Published: August 2023

Service providers use objective models to map system quality of service (QoS) conditions to an estimated mean opinion score (MOS) in order to assess users' quality of experience (QoE). In contrast with earlier studies, we propose a hybrid model for call services that models the MOS in terms of the received signal strength indicator (RSSI) using a machine learning approach. Unlike most existing studies, which focus on maximizing the sum‐MOS of all users, we aim to maximize the average number of satisfied users in order to allocate optimal power to each user while ensuring the minimum data rate for each of them. Simulation results show that the proposed hybrid model outperforms the conventional objective model in terms of MOS per user and the probability of user satisfaction. Furthermore, when compared to conventional sum‐MOS and sum‐rate maximization problems, users are more satisfied with the proposed problem. In addition, we will present a joint power allocation and admission control problem due to the limited power available to meet the needs of all users. The findings show a trade‐off between the number of admitted users and their level of satisfaction, giving operators valuable insight into how to better utilize their network resources.
Lasting scars: The impact of depression in early adulthood on subsequent labor market outcomes
Authors: Wang Buyi , Frank Richard , Glied Sherry
Published: August 2023

A growing body of evidence indicates that poor health early in life can leave lasting scars on adult health and economic outcomes. While much of this literature focuses on childhood experiences, mechanisms generating these lasting effects—recurrence of illness and interruption of human capital accumulation—are not limited to childhood. In this study, we examine how an episode of depression experienced in early adulthood affects subsequent labor market outcomes. We find that, at age 50, people who had met diagnostic criteria for depression when surveyed at ages 27–35 earn 10% lower hourly wages (conditional on occupation), work 120–180 fewer hours annually, and earn 24% lower annual wage incomes. A portion of this income penalty (21%–39%) occurs because depression is often a chronic condition, recurring later in life. But a substantial share (25%–55%) occurs because depression in early adulthood disrupts human capital accumulation, by reducing work experience and by influencing selection into occupations with skill distributions that offer lower potential for wage growth. These lingering effects of early depression reinforce the importance of early and multifaceted intervention to address depression and its follow‐on effects in the workplace.
Incorporating the benefits of vegetative filter strips into risk assessment and risk management of pesticides
Authors: Chen Huajin , Carley Danesha Seth , Muñoz-Carpena Rafael , Ferruzzi Giulio , Yuan Yongping , Henry Eric , Blankinship Amy , Veith Tamie L. , Breckels Ross , Fox Garey , Luo Yuzhou , Osmond Deanna , Preisendanz Heather E. , Tang Zhenxu , Armbrust Kevin , Costello Kevin , McConnell Laura L. , Rice Patricia , Westgate Johnny , Whiteside Mélanie
Published: August 2023

The pesticide registration process in North America, including the USA and Canada, involves conducting a risk assessment based on relatively conservative modeling to predict pesticide concentrations in receiving waterbodies. The modeling framework does not consider some commonly adopted best management practices that can reduce the amount of pesticide that may reach a waterbody, such as vegetative filter strips (VFS). Currently, VFS are being used by growers as an effective way to reduce off-site movement of pesticides, and they are being required or recommended on pesticide labels as a mitigation measure. Given the regulatory need, a pair of multistakeholder workshops were held in Raleigh, North Carolina, to discuss how to incorporate VFS into pesticide risk assessment and risk management procedures within the North American regulatory framework. Because the risk assessment process depends heavily on modeling, one key question was how to quantitatively incorporate VFS into the existing modeling approach. Key outcomes from the workshops include the following: VFS have proven effective in reducing pesticide runoff to surface waterbodies when properly located, designed, implemented, and maintained; Vegetative Filter Strip Modeling System (VFSMOD), a science-based and widely validated mechanistic model, is suitable for further vetting as a quantitative simulation approach to pesticide mitigation with VFS in current regulatory settings; and VFSMOD parametrization rules need to be developed for the North American aquatic exposure assessment. Integr Environ Assess Manag 2024;20:454–464. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).
From nature to therapy: Luteolin's potential as an immune system modulator in inflammatory disorders
Authors: Hussain Md Sadique , Gupta Gaurav , Goyal Ahsas , Thapa Riya , almalki Waleed Hassan , Kazmi Imran , Alzarea Sami I. , Fuloria Shivkanya , Meenakshi Dhanalekshmi Unnikrishnan , Jakhmola Vikas , Pandey Manisha , Singh Sachin Kumar , Dua Kamal
Published: August 2023

Inflammation is an essential immune response that helps fight infections and heal tissues. However, chronic inflammation has been linked to several diseases, including cancer, autoimmune disorders, cardiovascular diseases, and neurological disorders. This has increased interest in finding natural substances that can modulate the immune system inflammatory signaling pathways to prevent or treat these diseases. Luteolin is a flavonoid found in many fruits, vegetables, and herbs. It has been shown to have anti‐inflammatory effects by altering signaling pathways in immune cells. This review article discusses the current research on luteolin's role as a natural immune system modulator of inflammatory signaling mechanisms, such as its effects on nuclear factor‐kappa B, mitogen‐activated protein kinases, Janus kinase/signal transducer and activator of transcription, and inflammasome signaling processes. The safety profile of luteolin and its potential therapeutic uses in conditions linked to inflammation are also discussed. Overall, the data point to Luteolin's intriguing potential as a natural regulator of immune system inflammatory signaling processes. More research is needed to fully understand its mechanisms of action and possible therapeutic applications.
The importance of pulmonary pulse transit time in indicating right ventricular dysfunction and pulmonary arterial stiffness in rheumatoid arthritis
Authors: Ulutas Zeynep , Tasolar Hakan , Bayramoglu Adil , Yigit Yakup , Kuloglu Huseyın Emre , Karaca Yucel , Yolbas Servet , Hidayet Siho , Akaycan Julide
Published: August 2023

Subject

Rheumatoid arthritis patients are at risk of developing cardiovascular disease such as right heart failure and pulmonary hypertension (PH). Arterial stiffness can be used to assess pulmonary hemodynamics. Noninvasive approaches can also be used to assess pulmonary hemodynamics. Recently, there have been reports that pulmonary pulse transit time (PPTT) may also be a useful measure. This study aims to examine the effects of pulmonary hemodynamic alterations on PPTT in RA patients.

Methods

Forty RA patients and 40 healthy controls were included in the study. Sociodemographic characteristics, laboratory data, and echocardiographic examinations were performed in both groups. Conventional echocardiographic examination included left and right ventricular systolic and diastolic diameters, right ventricular myocardial performance index (RVMPI), right ventricular diastolic function, estimated pulmonary artery systolic pressure (sPAP), tricuspid annular plane systolic excursion (TAPSE), pulmonary artery stiffness (PAS), and PPTT. Right ventricular diastolic and systolic volumes, right ventricular ejection fraction (RVEF), and right ventricular fractional area change (RVFAC) were determined by four‐dimensional echocardiography (4DE).

Results

There was no difference between the sPAP values of the patients. RVMPI and PAS were increased in RA patients compared with controls. The PPTT was shortened in RA patients and correlated with RVEF, RVFAC, RVMPI, TAPSE/sPAP, disease duration, and C‐reactive protein (CRP). In univariate linear regression analysis, PPTT (p < .001) was thought to be an independent predictor of PAS. RVFAC, disease duration, and PAS were also independent predictors of PPTT.

Conclusion

In RA patients, PPTT may be the first evidence of early abnormalities in pulmonary vascular hemodynamics. PPTT and PAS are the values that may predict each other in RA patients. Due to its more practical application, PPTT can be used instead of PAS to assess pulmonary hemodynamics.
Fifty years of research on mitochondrial fatty acid oxidation disorders: The remaining challenges
Authors: Vianey‐Saban Christine , Guffon Nathalie , Fouilhoux Alain , Acquaviva Cécile
Published: August 2023

Since the identification of the first disorder of mitochondrial fatty acid oxidation defects (FAOD) in 1973, more than 20 defects have been identified. Although there are some differences, most FAOD have similar clinical signs, which are mainly due to energy depletion and toxicity of accumulated metabolites. However, some of them have an unusual clinical phenotype or specific clinical signs. This manuscript focuses on what we have learnt so far on the pathophysiology of these disorders, which present with clinical signs that are not typical of categorical FAOD. It also highlights that some disorders have not yet been identified and tries to make assumptions to explain why. It also deals with new treatments under consideration in FAOD, including triheptanoin and similar anaplerotic substrates, ketone body treatments, RNA and gene therapy approaches. Finally, it suggests challenges for the diagnosis of FAOD in the coming years, both for symptomatic patients and for those diagnosed through newborn screening. The ultimate goal would be to identify all the patients born with FAOD and ensure for them the best possible quality of life.
Gene therapy for organic acidemias: Lessons learned from methylmalonic and propionic acidemia
Authors: Chandler Randy J. , Venditti Charles P.
Published: August 2023

Organic acidemias (OA) are a group of rare autosomal recessive disorders of intermediary metabolism that result in a systemic elevation of organic acid. Despite optimal dietary and cofactor therapy, OA patients still suffer from potentially lethal metabolic instability and experience long‐term multisystemic complications. Severely affected patients can benefit from elective liver transplantation, which restores hepatic enzymatic activity, improves metabolic stability, and provides the theoretical basis for the pursuit of gene therapy as a new treatment for patients. Because of the poor outcomes reported in those with OA, especially methylmalonic and propionic acidemia, multiple gene therapy approaches have been explored in relevant animal models. Here, we review the results of gene therapy experiments performed using MMA and PA mouse models to illustrate experimental paradigms that could be applicable for all forms of OA.
Alveolar mucosal cell spheroids promote extraction socket healing and osseous defect regeneration
Authors: Tu Che‐Chang , Zheng Zhao‐Cheng , Cheng Nai‐Chen , Yu Jiashing , Tai Wei‐Chiu , Pan Yi‐Xuan , Chang Po‐Chun
Published: August 2023

Background

Alveolar mucosa could be a promising source of mesenchymal stem cells (MSCs) for regeneration therapeutics because it exhibits faster healing potential and can be easily collected with minimal periodontal disturbance. This study aimed to evaluate the potential of alveolar mucosal cell (AMC) spheroids for promoting extraction socket healing and calvarial osseous defect regeneration.

Methods

AMCs were isolated from Sprague–Dawley rats. Antigenic and MSC surface marker expressions and trilineage differentiation capability were assessed. AMCs were then osteogenically stimulated (OAs) or unstimulated (UAs), self‐aggregated to form spheroids, and encapsulated in gelatin hydrogel to fill rat extraction sockets or combined with freeze‐dried bone graft (FDBG) to fill rat calvarial osseous defects. The outcome was assessed by gross observation, micro‐CT imaging, and immunohistochemistry.

Results

AMCs highly expressed MSC surface markers, showed weak antigenicity, and were capable of trilineage differentiation at Passage 3. In the extraction sockets, wound closure, socket fill, keratinization, and proliferative activities were accelerated in those with AMC spheroids treatment. Socket fill and maturation were further promoted by OA spheroids. In the calvarial osseous defects, the mineralized tissue ratio was promoted with AMC spheroids/FDBG treatment, and bone sialoprotein expression and cell proliferation were more evident with OA spheroids/FDBG treatment.

Conclusion

AMCs exhibited MSC properties with weak antigenicity. AMC spheroids promoted extraction socket healing, AMC spheroids/FDBG promoted calvarial osseous defect regeneration, and the outcomes were further enhanced by osteogenically stimulation of AMCs.
The effect of dipeptidyl peptidase‐4 inhibitor on incidence and clinical course in bullous pemphigoid patients in a tertiary medical center
Authors: Hsu Yu‐Han Alice , Yang Ting‐Ting , Huang Shu‐Mei , Lan Cheng‐Che Eric
Published: August 2023

Several studies have reported an association between dipeptidyl peptidase 4 inhibitor (DPP4i), a commonly prescribed second‐line oral antihyperglycemic drug, and bullous pemphigoid (BP). However, the benefits of DPP4i withdrawal in patients with BP remain controversial. This study primarily aimed to evaluate the clinical severity of DPP4i‐associated BP by comparing it to those without Type 2 diabetes mellitus (DM). The secondary objective was to determine whether cessation of DPP4i is necessary for all patients with BP. This retrospective case–control study included 83 patients. The participants were divided into three groups according to their diabetic status and the status of discontinuance or continuance of DPP4i. The 12‐month follow‐up of the monthly dosage of systemic steroids per body weight (kg) and the percentage of systemic steroid off‐therapy in these participants were recorded since the diagnosis of BP. Compared to patients with BP without DM, the 1st, 3rd, and 12th systemic prednisolone doses were significantly lower in the DPP4i group (p = 0.01684, 0.02559, and 0.009336, respectively). The 12th systemic prednisolone dose was significantly lower in patients who discontinued DPP4i (p = 0.0338). Nevertheless, several spontaneous remissions with systemic steroid off‐therapy were also noted in the DPP4i‐continuance group within 12 months of follow‐up. This article supports the favorable impact of DPP4i withdrawal in patients with BP and shows that DPP4i may incite or aggravate BP, resulting in a milder disease course.
Paeoniflorin inhibits colorectal cancer cell stemness through the miR‐3194‐5p/catenin beta‐interacting protein 1 axis
Authors: Su Zhao , Hu Beier , Li Jing , Zeng Zhichun , Chen Hu , Guo Yuhang , Mao Yun , Cao Wen
Published: August 2023

Paeoniflorin (PF) is a natural plant ingredient with remarkable antitumor effects. Herein, we investigated the biological effects and mechanism of PF in colorectal cancer (CRC) cell stemness. The messenger RNA (mRNA) and protein expressions were assessed using quantitative real‐time polymerase chain reaction and western blot. The viability, proliferation, and migration and invasion of CRC cells were evaluated using cell counting kit‐8, clone‐formation, and transwell migration and invasion assays, respectively. The sphere‐formation capacity was determined using the sphere‐formation assay. A dual‐luciferase reporter gene assay was employed to analyze the interaction between miR‐3194‐5p and catenin beta‐interacting protein 1 (CTNNBIP1). The viability, migration, invasion, epithelial–mesenchymal transition, and stemness of CRC cells were repressed by PF. MiR‐3194‐5p was upregulated in CRC tissues and cells. MiR‐3194‐5p knockdown suppressed CRC cell stemness, while miR‐3194‐5p overexpression had the opposite effect. In addition, the inhibition of CRC cell stemness caused by PF was eliminated by miR‐3194‐5p overexpression. CTNNBIP1 functioned as the target of miR‐3194‐5p, whose knockdown abrogated the repression of CRC cell stemness and Wnt/β‐catenin signaling activation by PF.PF regulated the miR‐3194‐5p/CTNNBIP1/Wnt/β‐catenin axis to repress CRC cell stemness.
Mass spectrometry in ocular drug research
Authors: del Amo Eva M. , Vellonen Kati‐Sisko , Urtti Arto , Terasaki Tetsuya , Hammid Anam , Honkakoski Paavo , Auriola Seppo
Published: August 2023

Mass spectrometry (MS) has been proven as an excellent tool in ocular drug research allowing analyzes from small samples and low concentrations. This review begins with a short introduction to eye physiology and ocular pharmacokinetics and the relevance of advancing ophthalmic treatments. The second part of the review consists of an introduction to ocular proteomics, with special emphasis on targeted absolute quantitation of membrane transporters and metabolizing enzymes. The third part of the review deals with liquid chromatography–MS (LC‐MS) and MS imaging (MSI) methods used in the analysis of drugs and metabolites in ocular samples. The sensitivity and speed of LC‐MS make simultaneous quantitation of various drugs and metabolites possible in minute tissue samples, even though ocular sample preparation requires careful handling. The MSI methodology is on the verge of becoming as important as LC‐MS in ocular pharmacokinetic studies, since the spatial resolution has reached the level, where cell layers can be separated, and quantitation with isotope‐labeled standards has come more reliable. MS will remain in the foreseeable future as the main analytical method that will progress our understanding of ocular pharmacokinetics.
Correcting statistical CT number biases without access to raw detector counts: Applications to high spatial resolution photon counting CT imaging
Authors: Griner Dalton , Lei Nikou , Chen Guang‐Hong , Li Ke
Published: July 2023

Background

Due to the nonlinear nature of the logarithmic operation and the stochastic nature of photon counts (N), sinogram data of photon counting detector CT (PCD‐CT) are intrinsically biased, which leads to statistical CT number biases. When raw counts are available, nearly unbiased statistical estimators for projection data were developed recently to address the CT number bias issue. However, for most clinical PCD‐CT systems, users' access to raw detector counts is limited. Therefore, it remains a challenge for end users to address the CT number bias issue in clinical applications.

Purpose

To develop methods to correct statistical biases in PCD‐CT without requiring access to raw PCD counts.

Methods

(1) The sample variance of air‐only post‐log sinograms was used to estimate air‐only detector counts, . (2) If the post‐log sinogram data, y, is available, then N of each detector pixel was estimated using . Once N was estimated, a closed‐form analytical bias correction was applied to the sinogram. (3) If a patient's post‐log sinogram data are not archived, a forward projection of the bias‐contaminated CT image was used to perform a first‐order bias correction. Both the proposed sinogram domain‐ and image domain‐based bias correction methods were validated using experimental PCD‐CT data.

Results

Experimental results demonstrated that both sinogram domain‐ and image domain‐based bias correction methods enabled reduced‐dose PCD‐CT images to match the CT numbers of reference‐standard images within [‐5, 5] HU. In contrast, uncorrected reduced‐dose PCD‐CT images demonstrated biases ranging from ‐25 to 55 HU, depending on the material. No increase in image noise or spatial resolution degradation was observed using the proposed methods.

Conclusions

CT number bias issues can be effectively addressed using the proposed sinogram or image domain method in PCD‐CT, allowing PCD‐CT acquired at different radiation dose levels to have consistent CT numbers desired for quantitative imaging.
Nutrition considerations in the transgender and gender‐diverse patient
Authors: Gold Evelyn , Perez de Bronner Susana , Goday Praveen S.
Published: August 2023

The nutrition professional is increasingly providing care to individuals who identify as transgender. However, there are few definitive guidelines on providing medical nutrition care to this population. It is becoming better understood that this population is at elevated nutrition risk secondary to significant health disparities. More recently, the increasing prevalence of gender‐affirming medical intervention has resulted in uncertainty when providing medical nutrition assessments and therapies, as many standardized guidelines and assessment tools are sex‐specific. This review aims to provide clarity in exploring various gender‐affirming methods to providing nutrition care to the transgender and gender‐diverse population.
Past human‐induced ecological legacies as a driver of modern Amazonian resilience
Authors: McMichael Crystal N. H. , Bush Mark B. , Jiménez Juan C. , Gosling William D.
Published: August 2023

People have modified landscapes throughout the Holocene (the last c. 11,700 years) by modifying soils, burning forests, cultivating and domesticating plants, and directly and indirectly enriched and depleted plant abundances. These activities also took place in Amazonia, which is the largest contiguous piece of rainforest in the world, and for many decades was considered to have very little human impact until the modern era.

The compositional shift caused by past human disturbances can alter forest traits, creating ecological legacies that may persist through time. As the lifespan of most Amazonian tree species is more than 200 years, forests that were modified over the last centuries to millennia are likely still in a mid‐successional state.

Ecological legacies resulting from past human activity may also affect modern forest resilience to ongoing anthropogenic and climatic changes.

Current estimates of resilience assume that forests are in equilibrium, and long‐term successional trajectories are not considered.

We suggest that disturbance histories, generated through palaeoecological and archaeological surveys, should be paired with field‐based and remotely sensed estimates of forest resilience to recent drought events, to determine whether past human activities affect modern forest resilience. We have outlined how this can be accomplished in future research.

Read the free Plain Language Summary for this article on the Journal blog.
High‐speed countercurrent chromatography with offline detection by electrospray mass spectrometry and nuclear magnetic resonance detection as a tool to resolve complex mixtures: A practical approach using Coffea arabica leaf extract
Authors: de Souza Wuillda Aline Camargo Jesus , das Neves Costa Fernanda , Garrett Rafael , dos Santos de Carvalho Mauro , Borges Ricardo Moreira
Published: August 2023

Introduction

Many secondary metabolites isolated from plants have been described in the literature owing to their important biological properties and possible pharmacological applications. However, the identification of compounds present in complex plant extracts has remained a great scientific challenge, is often laborious, and requires a long research time with high financial cost.

Objectives

The aim of this study was to develop a method that allows the identification of secondary metabolites in plant extracts with a high degree of confidence in a short period of time.

Material and methods

In this study, an ethanolic extract of Coffea arabica leaves was used to validate the proposed method. Countercurrent chromatography was chosen as the initial step for extraction fractionation using gradient elution. Resulting fractions presented a variation of compounds concentrations, allowing for statistical total correlation spectroscopy (STOCSY) calculations between liquid chromatography coupled with high‐resolution tandem mass spectrometry (LC‐HRMS/MS) and NMR across fractions.

Results

The proposed method allowed the identification of 57 compounds. Of the annotated compounds, 20 were previously described in the literature for the species and 37 were reported for the first time. Among the inedited compounds, we identified flavonoids, alkaloids, phenolic acids, coumarins, and terpenes.

Conclusion

The proposed method presents itself as a valid alternative for the study of complex extracts in an effective, fast, and reliable way that can be reproduced in the study of other extracts.
Importance of accounting for timing of time‐varying exposures in association studies: Hydrochlorothiazide and non‐melanoma skin cancer
Authors: Danieli Coraline , Moura Cristiano S. , Pilote Louise , Bernatsky Sasha , Abrahamowicz Michal
Published: August 2023

Purpose

Hydrochlorothiazide (HCTZ), a widely prescribed antihypertensive drug with photosensitising properties, has been linked with non‐melanoma skin cancer (NMSC) risk. However, previous analyses did not fully explore if and how the impact of past HCTZ exposures accumulates with prolonged use and/or depends on time elapsed since exposures. Therefore, we used different models to more comprehensively assess how NMSC risk vary with HCTZ exposure, and explore how the results may depend on modeling strategies.

Methods

We used different parametric models with alternative time‐varying exposure metrics, and the flexible weighted cumulative exposure model (WCE) to estimate associations between HCTZ exposures and NMSC risk in a population‐based cohort of HCTZ users over 65 years old, in the province of Ontario, Canada.

Results

Among 3844 HCTZ users, 273 developed NMSC during up to 8 years of follow‐up. In parametric models, based on all exposures, increased duration of past HCTZ use was associated with an increase of NMSC risk but cumulative dose showed no systematic association. Yet, WCE results suggested that only exposures taken 2.5–4 years in the past were associated with the current NMSC hazard. This finding led us to re‐define the parametric models, which also confirmed that any HCTZ dose taken outside this time‐window were not systematically associated with NMSC incidence.

Conclusions

Our analyses illustrate how flexible modeling may yield new insights into complex temporal relationships between a time‐varying drug exposure and risks of adverse events. Duration and recency of antihypertensive agents exposures must be taken into account in evaluating risk and benefits.