bluuebunny/crossref_metadata_2025 huggingface dataset:
Construction of Ternary PtRuPd Alloy Supported on Carbon Nanotubes for Concentrated Methanol Oxidation
Authors: Zhang Quan , Xie Yuhua , Zhang Xia , Zhao Mengxiao , Chen Qian , Wu Yiman , Yu Jiangfeng , Pan Qiyun , Yang Fangqi , Lin Huihui
Published: April 2023

Due to the complex reaction process involving six‐electron transfer, high overpotential and slow kinetic rate of methanol oxidation, the development process of direct methanol fuel cells (DMFC) has been hampered. Herein, a simple one‐step solvent reduction approach was employed to simultaneously reduce metal ions supported on carbon nanotubes and prepared ternary metal alloy nanoparticles supported on carbon nanotubes electrocatalyst (PtRuPd@CNT). Compared with PtRu@CNT binary metal catalyst, the as‐prepared PtRuPd@CNT ternary metal catalyst displayed more outstanding methanol oxidation reaction (MOR) catalytic performance and good CO anti‐poisoning ability. In the case of using 8 M methanol, the MOR performance of PtRuPd@CNT was 1.8 times better than the PtRu@CNT electrocatalyst. The addition of the Pd atom regulates the surface electronic structure of PtRu alloy, and the strong electronic interaction enhances the MOR activity of the PtRu@CNT catalyst. Furthermore, the addition of the Pd atom in the PtRuPd@CNT electrocatalyst also diminishes adsorption of CO intermediate species on the Pt surface, boosting the CO anti‐poisoning ability of the catalyst and improving the stability. Therefore, the PtRuPd@CNT electrocatalyst incorporating the Pd atoms could actualize the practical application prospect as an efficient concentrated DMFC anode catalyst.
Multi‐object optimization study on the performance of gas cyclones based on heterogeneous condensation and turbulent agglomeration
Authors: Wang Jiarui , Peng Xiaocheng , Song Chen , Wen Jian , Wang Simin
Published: April 2023

Improving the separation efficiency of fine particles becomes more and more critical as environmental pollution aggravates. This study aims to investigate the effects of four key parameters on the performance of gas cyclones, including cyclone body height, particle concentration, initial supersaturation degree, and inlet temperature. Then, the two‐way coupling numerical model, in which is the process of heterogeneous condensation and agglomeration for insoluble fine particles, was achieved by user defined function. On this basis, the response surface analysis method and multi‐objective genetic algorithm were adopted to optimize the cyclone. The results show that when the particle concentration is less than 1000 mg/m3, the separation efficiency can reach above 95%. The initial supersaturation degree has the greatest effect on the separation efficiency and vapour consumption rate, while the cyclone body height is the most critical factor on the pressure drop. As the particle concentration increases, the separation efficiency decreases at first and then keeps almost stable. With the increase of inlet temperature, the separation efficiency is enhanced, and the pressure drop reduces. These research results can provide important guidance for the optimization and engineering application of this technology.
Psychosocial outcomes in long‐term Dutch adult survivors of childhood cancer: The DCCSS‐LATER 2 psycho‐oncology study
Authors: Maas Anne , Maurice‐Stam Heleen , Kremer Leontien C. M. , van der Aa‐van Delden Alied , van Dulmen‐den Broeder Eline , Tissing Wim J. E. , Loonen Jacqueline J. , van der Pal Helena J. H. , de Vries Andrica C. H. , van den Heuvel‐Eibrink Marry M. , Ronckers Cécile , Neggers Sebastian , Bresters Dorine , Louwerens Marloes , van der Heiden‐van der Loo Margriet , van Gorp Marloes , Grootenhuis Martha ,   Dutch LATER study group
Published: April 2023

Background

This study compares a comprehensive range of psychosocial outcomes of adult childhood cancer survivors (CCS) to general population‐based references and identifies sociodemographic and medical risk factors.

Methods

CCS from the Dutch Childhood Cancer Survivor Study (DCCSS)‐LATER cohort (diagnosed 1963–2001) part 2 (attained age ≥18 years, diagnosed <18 years, ≥5 years since diagnosis) completed the Rosenberg Self‐Esteem Scale, Hospital Anxiety and Depression Scale, Distress Thermometer, Self‐Rating Scale for Post‐Traumatic Stress Disorder, and the Short Form‐36 (Health Related Quality of Life). CCS’ scores were compared with references using analysis of variances and logistic regression analysis, controlling for age and sex (p < .05). Risk factors for worse psychosocial outcomes were assessed with regression analyses (p < .05).

Results

CCS, N = 1797, mean age 35.4 years, 49.0% female, all ≥15 years since diagnosis, participated. Three percent reported posttraumatic stress disorder because of childhood cancer and 36.6% experienced clinical distress. CCS did not differ from references on self‐esteem and anxiety but were less depressed (d = −.25), and scored poorer on all health‐related quality of life scales, except for bodily pain (.01 ≤ d  ≥  −.36). Female sex, lower educational attainment, not being in a relationship, and being unemployed were negatively associated with almost all psychosocial outcomes. Except for a central nervous system tumor diagnosis, few medical characteristics were associated with psychosocial outcomes.

Conclusion

CCS appear resilient regarding mental health but have slightly poorer health‐related quality of life than references. Sociodemographic characteristics and central nervous system tumors were related to most psychosocial outcomes, but no clear pattern was observed for other medical factors. Future studies should address additional factors in explaining CCS’ psychosocial functioning, such as coping, social support, and physical late effects.
Dual‐networks Enhanced Hollow ZIF‐8 Particles for Water Treatment
Authors: Xia Lingling , Li Yucen , Cui Jiwei , Hu Ming
Published: April 2023

Hollow ZIF‐8 particles are promising materials for water treatment because of the high porosity and catalytic activities under photon irradiation. However, hollow ZIF‐8 particles can easily degrade under harsh conditions due to the weak stability. Here, we synthesize hollow ZIF‐8 particles with polyphenol and polyethylene glycol networks embedded. The multiple interactions among the ZIF‐8 frameworks and the networks increase the mechanical and chemical stability of the hollow ZIF‐8 particles as suggested by a series of spectra. Uptake of methylene blue about 128 mg/g by the hollow particles is realized. Furthermore, hydroxyl or superoxide radicals for degradation of the adsorbed methylene blue are effectively generated through irradiation of the hollow ZIF‐8 particles. In a water treatment test, the model pollute with a concentration of 50 mg/L is completely removed within half an hour. The performance of the recycled hollow ZIF‐8 particles is proved to be significant, indicating the practical potential of the material.
The relationship among psychological distress, well‐being and excessive social media use during the outbreak of Covid‐19: A longitudinal investigation
Authors: Brailovskaia Julia , Margraf Juergen , Ceccatelli Sara , Cosci Fiammetta
Published: April 2023

Introduction

The corona pandemic has been a life event causing negative consequences on mental health. Mental health consists of positive and negative dimensions. The present longitudinal study investigated how positive and negative dimensions changed over 15 months after the Covid‐19 outbreak. Potential changes of excessive social media use (SMU) and its relationship with mental health were also investigated.

Method

Data (N = 189) on distress (measured overall and as depression, anxiety, and stress), well‐being and excessive SMU were collected at three time points (baseline, BL; 3‐month follow‐up, FU1; 15‐month follow‐up, FU2) via online surveys in Italy. Repeated analyses of variance were used to test differences among the three measurement time points. Mediational models were applied.

Results

Distress did not change over time, well‐being decreased and excessive SMU increased significantly. The relationship between distress at BL and excessive SMU at FU2 was significant (total effect, c: p < .001). The relationship between distress at BL and well‐being at FU1 (a: p < .001), and between well‐being at FU1and excessive SMU at FU2 (b: p = .004) was significant. Including FU1 well‐being in the model, the relationship between distress at BL and excessive SMU at FU2 was not significant (direct effect, c′: p = .078). The indirect effect (ab) was significant.

Conclusion

Well‐being mediated the relationship between baseline stress and excessive SMU. Enhanced stress may reduce well‐being which, in turn, increases the risk of excessive SMU. This emphasizes the urgency of programmes that foster well‐being, especially during stressful events such as a pandemic.
A new single ended primary inductor converter with high voltage gain, low voltage stress and continuous input current
Authors: Jahangiri Alireza , Abdolalizadeh Ali , Shamim Ahmad Ghaderi
Published: April 2023

This paper proposes a single‐ended primary‐inductor converter (SEPIC)‐based DC‐DC converter with higher voltage gain, continuous input current, and lower voltage stress. Suggested converter uses three‐winding coupled inductors and voltage multiplier for boosting function. The proposed structure stores lower amount of energy due to lower current magnitudes of used inductors. Moreover, using voltage multiplier reduces the voltage stress of the elements connected to the output terminals of the proposed converter. By reducing the voltage stress, in addition to reducing the rating of output elements and costs, the overall efficiency will also be increased. Also, a clamping circuit is used to diminish the voltage stresses on power switch. In order to represent the advantages of the proposed converter over some other converters in the viewpoints of the number of the used elements, continuity of input current, voltage gain, the voltage stress on power switch, and output diode, a comparison study is provided. To validate the practicability of the proposed converter, a 200‐W prototype is implemented and the experimental results are provided.
Whose job is diversity?
Authors: Arnett Autumn A.
Published: April 2023

I've been having conversations with some really smart people lately — Mensa members, actually. The conversation started because one gentleman in California came across a 2019 article I wrote about racial disparities in gifted education. His first message to me said, “Autumn, is this true? This is horrible. We've got to do something!”
A multiplex qPCR assay for transgenes detection: A novel approach for gene doping control in horseracing using conventional laboratory setup
Authors: Wong Kin‐Sing , Cheung Hiu Wing , Szeto Cherry W. L. , Tsang Candice Y. N. , Wan Terence S. M. , Ho Emmie N. M.
Published: April 2023

Illicit administration of transgene into horses is a form of gene doping that has been a key concern in equine sports. The large number of potential performance‐enhancing transgenes has demanded a cost‐effective and reliable detection method. Multiplex qPCR is a relevant technique, but the cross‐talking between fluorophores and high background noise limits the method sensitivity and specificity. This study reports a simpler multiplexing approach by using the same fluorophore for four hydrolysis probes each targeting one of the four transgenes: human growth hormone, insulin‐like growth factor 1, equine erythropoietin and interleukin‐10. Any positive findings from this multiplex qPCR assay can then be confirmed by individual qPCR assays to identify potential transgene(s). This has effectively eliminated the cross‐talking issue and allowed an improved signal‐to‐noise than conventional multiplex qPCR assay. It has also removed the limitation imposed by the available choice of fluorophores and optical channels of qPCR instruments on the number of transgenes that can be analysed in a multiplex qPCR assay. This novel multiplex qPCR has been successfully validated. The estimated limits of detection were ~1500–2500 copies/mL of blood, thus demonstrating comparable sensitivity with the corresponding duplex qPCR assays. Concurring results were obtained by analysing hundreds of official blood samples provided by racehorses with this multiplex qPCR assay and the accredited individual duplex qPCR assays. This novel multiplex qPCR assay for detecting multiple transgenes is a cost‐effective screening method using a conventional laboratory setup and has opened up the potential to include the testing of additional transgenes in a single assay.
Phosphodiesterase‐5 inhibitors for left ventricular assist device implantation complicated by right ventricular failure
Authors: Papathanasiou Maria , Jakstaite Aiste‐Monika , Mincu Raluca , Wernhart Simon , Ruhparwar Arjang , Rassaf Tienush , Luedike Peter
Published: April 2023

Aims

Phosphodiesterase‐5 inhibitors (PDE5I) are frequently implemented after left ventricular assist device (LVAD) implantation to improve haemodynamics in patients with early postoperative right ventricular (RV) failure. It is unknown if long‐term PED5I therapy beyond the early post‐operative period provides any clinical benefit in stable outpatients, who have recovered from post‐operative RV failure under univentricular device support. This study aimed to investigate the impact of PDE5I discontinuation on RV function and cardiopulmonary exercise capacity in patients on durable LVAD support.

Methods and results

We enrolled 31 clinically stable LVAD recipients on long‐term oral PDE5I therapy. The mean age was 53 years, and 90% were male. Patients discontinued PDE5I and underwent cardiopulmonary exercise testing, echocardiography, LVAD interrogation, and biomarker analysis at baseline and 4 weeks after PDE5I withdrawal. At 4 weeks, no significant changes were observed in echocardiographic indices of RV morphology and function but an increase in peak tricuspid regurgitation velocity (2.1 vs. 2.4 m/s, P = 0.01). Peak oxygen consumption (11.4 vs. 11.8 mL/min/kg, P = 0.52), minute ventilation/carbon dioxide production slope (33 vs. 35, P = 0.56), N‐terminal pro‐brain natriuretic peptide (1455 vs. 1399 pg/mL, P = 0.55), flow and power readings of the device, and quality of life (Kansas City Cardiomyopathy Questionnaire score 78.3% vs. 77.5%, P = 0.62) exhibited no significant changes. We observed an increase in 6‐min walking distance (346 vs. 364 m, P = 0.03). Two patients were hospitalized for non‐cardiac reasons (subtherapeutic INR, driveline infection). No patient was hospitalized for cardiac decompensation.

Conclusions

In LVAD patients with a history of early post‐operative RV failure, discontinuation of long‐term PDE5I therapy was not associated with deterioration of RV function, exercise capacity, and quality of life. PDE5I should be critically evaluated until more evidence regarding the net clinical benefit of this pharmacologic intervention becomes available.
TLR4 phosphorylation at tyrosine 672 activates the ERK/c‐FOS signaling module for LPS‐induced cytokine responses in macrophages
Authors: Curson James E.B. , Liu Liping , Luo Lin , Muusse Timothy W. , Lucas Richard M. , Gunther Kimberley S. , Vajjhala Parimala R. , Abrol Rishika , Jones Alun , Kapetanovic Ronan , Stacey Katryn J. , Stow Jennifer L. , Sweet Matthew J.
Published: April 2023

TLRs engage numerous adaptor proteins and signaling molecules, enabling a complex series of post‐translational modifications (PTMs) to mount inflammatory responses. TLRs themselves are post‐translationally modified following ligand‐induced activation, with this being required to relay the full spectrum of proinflammatory signaling responses. Here, we reveal indispensable roles for TLR4 Y672 and Y749 phosphorylation in mounting optimal LPS‐inducible inflammatory responses in primary mouse macrophages. LPS promotes phosphorylation at both tyrosine residues, with Y749 phosphorylation being required for maintenance of total TLR4 protein levels and Y672 phosphorylation exerting its pro‐inflammatory effects more selectively by initiating ERK1/2 and c‐FOS phosphorylation. Our data also support a role for the TLR4‐interacting membrane proteins SCIMP and the SYK kinase axis in mediating TLR4 Y672 phosphorylation to permit downstream inflammatory responses in murine macrophages. The corresponding residue in human TLR4 (Y674) is also required for optimal LPS signaling responses. Our study, thus, reveals how a single PTM on one of the most widely studied innate immune receptors orchestrates downstream inflammatory responses.
Synthesis of Cytotoxic Iron‐Containing Macrocycles Through Unexpected C(sp2)−C(sp2) Bonds Formation
Authors: Torres‐Gutiérrez Carolina , Estrada‐Montaño Aldo S. , Orvain Christophe , Mellitzer Georg , Gaiddon Christian , Le Lagadec Ronan
Published: April 2023

In previous reports, it has been demonstrated that cyclometalated iron(II/III) complexes can be prepared by reacting iron(0) precursors and mercurated or brominated derivatives. However, in this report, the reaction between [Fe3(CO)12] and mercurated 6‐phenyl‐2,2′‐bipyridine or brominated 2,6‐diphenyl‐pyridine pincer derivatives led to compounds in which C(sp2)−C(sp2) bonds have been formed between two ligands. A 16‐electron iron(II) complex (1Cl) bearing a tetradentate ligand originating from the dimerization of 6‐phenyl‐2,2′‐bipyridine was isolated, while a protonated 14‐membered macrocycle with [FeBr4]− as counterion (2) was obtained from 2,6‐diphenyl‐pyridine. Studies by X‐ray diffraction crystallography, NMR, UV‐vis and cyclic voltammetry confirmed the structures. Additionally, the cytotoxicity of the new compounds toward gastric cancer cell lines was evaluated, and it was established that the presence of the iron(II) center was crucial for an elevated activity.
Amperometric detection of indapamide on glassy carbon electrode
Authors: Oliveira Thawan G. , Santos Berlane G. , Gonçalves Josué M. , Angnes Lucio
Published: April 2023

This work describes the development of a fast, precise and reliable voltammetric method for the quantification of indapamide, an orally active diuretic sulfonamide used for hypertensive treatment. This compound acts inhibiting sodium reabsorption and increasing the elimination of water. This characteristic was responsible for its banishment by the International Olympic Committee since 1999. The study begins by finding an adequate potential range (−0.20 to 0.30 V) to avoid poisoning the working glassy carbon electrode (GCE) in phosphate buffer 0.10 mol L−1(pH=12.0). Utilizing flow injection analysis, linear responses between 2.0 × 10−6 mol L−1to 2.5 × 10−5 mol L−1of indapamide (R2=0.995), and detection limit (LOD) 3.0 × 10−7 mol L−1were obtained. This method was applied for the quantification of indapamide in tablets and in synthetic urine. The same flow system was used for the analysis of commercial drugs and the response obtained corresponded to 98 % of the concentration indicated on the drug label. These tablets were also analyzed by high performance liquid chromatography (HPLC), obtaining a recovery of 103 % and LOD 4.0 × 10−7 mol L−1. The velocity of analysis using flow methods compares advantageously to the classical chromatographic methods. For synthetic urine, linear responses were obtained in samples spiked in the region from 5.0 × 10−6 mol L−1to 30 × 10−6 mol L−1(R2=0.991) and LOD 3.0 × 10−7 mol L−1.
Effect of detonation nanodiamonds on the electrocatalytic activity of asymmetric cobalt phthalocyanine: Covalent versus non‐covalent linking
Authors: Ncwane Lunathi , Mpeta Lekhetho S. , Nyokong Tebello
Published: April 2023

We report on the effect of detonation nanodiamonds (DNDs) on electrocatalytic properties of an asymmetrically substituted cobalt phthalocyanine (CoPc). The incorporation of DNDs onto cobalt phthalocyanine enhances its electrochemical behaviour. An asymmetrical CoPc alone, when π‐π stacked (CoPc‐DNDs(ππ)) or covalently linked (CoPc@DNDs) to DNDs is used to modify a glassy carbon electrode (GCE) for the electrocatalytic detection of hydrazine. In addition, the GCE was modified by sequentially adding CoPc and DNDs onto its surface, represented as GCE/CoPc‐DNDs(seq) when CoPc is placed before DNDs on the electrode and GCE/DNDs‐CoPc(seq) when DNDs are placed before CoPc, where seq represents sequential. The obtained catalytic rate for the detection of hydrazine on GCE/CoPc@DNDs was 9.3×104 M−1.s−1 with a limit of detection as 0.33 μM. GCE/CoPc@DNDs gave better electrocatalytic activities when compared to its counterparts.
Synthesis of semiconductor ZnO nanostructures using Arctostaphylos pungens extract applicated in the photodegradation of water pollutions
Authors: Quevedo‐Robles Reina Vianey , Vilchis‐Nestor Alfredo Rafael , Luque Priscy
Published: April 2023

The presence of dyes in water can have severe health and environmental implications; consequently, effective technologies are required to remove them. In this research, ZnO nanoparticles (NPs) have been synthesized by eco‐friendly methods, using Arctostaphylos pungens extract, for use in water treatment via photocatalysis. The extract concentration strongly influenced the properties of ZnO NPs, the bandgap values revealed a direct dependence as the extract concentration increased, obtaining 2.81, 2.88, and 2.92 eV for 1%, 2%, and 4% w/v (weight/volume), respectively. In contrast, the NPs presented quasi‐spherical morphologies with a decrease in size from 24, 20, and 17 nm in response to extract concentration variations. The ZnO formation was confirmed by Fourier transform infrared, energy‐dispersive x‐ray, and x‐ray diffraction. ZnO NPs showed high photocatalytic activity with the dyes methylene blue (MB) and methyl orange (MO) under UV light, achieving 96% photodegradation of MB in just 60 min. Meanwhile, MO showed 93% of degradation at 180 min. Additionally, under solar radiation, significant photocatalytic activity was also observed, obtaining 92% and 81% photodegradation for MB and MO, respectively. The results indicate that ZnO NPs green synthesized using A. pungens extract can be used in water treatment as a friendly and efficient catalyst for the photodegradation of dyes.
Effective multi‐step ahead container throughput forecasting under the complex context
Authors: Xiao Yi , Xie Minghu , Hu Yi , Yi Ming
Published: April 2023

Accurate and effective container throughput forecasting plays an essential role in economic dispatch and port operations, especially in the complex and uncertain context of the global Covid‐19 pandemic. In light of this, this research proposes an effective multi‐step ahead forecasting model called EWT‐TCN‐KMSE. Specifically, we initially use the empirical wavelet transform (EWT) to decompose the original container throughput series into multiple components with varying frequencies. Subsequently, the state‐of‐the‐art temporal convolutional network is utilized to predict the decomposed components individually, during which an improved loss function that combines mean square error (MSE) and kernel trick is employed. Eventually, the deduced prediction results can be obtained by integrating the predicted values of each component. In particular, this research introduces the MIMO (multi‐input and multi‐output) strategy to conduct multi‐step ahead container throughput forecasting. Based on the experiments in Shanghai port and Ningbo‐Zhoushan port, it can be found that the proposed model shows its superiority over benchmark models in terms of accuracy, stability, and significance in container throughput forecasting. Therefore, our proposed model can assist port operators in their daily management and decision making.
TAF15::NR4A3 gene fusion identifies a morphologically distinct subset of extraskeletal myxoid chondrosarcoma mimicking myoepithelial tumors
Authors: Warmke Laura M. , Wang Wei‐Lien , Baumhoer Daniel , Andrei Vanghelita , Ameline Baptiste , Baker Michael L. , Kerr Darcy A.
Published: April 2023

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain differentiation predominantly arising in deep soft tissue. Its conventional morphologic appearance manifests as a relatively well‐circumscribed, multilobular tumor composed of uniform short spindle‐to‐ovoid primitive mesenchymal cells with deeply eosinophilic cytoplasm arranged in anastomosing cords within abundant myxoid matrix. The genetic hallmark of EMC has long been considered to be pathognomonic gene rearrangements involving NR4A3, which when fused to TAF15, often have high‐grade morphology with increased cellularity, moderate to severe cytologic atypia, and rhabdoid cytomorphology. Herein, we describe two cases of EMC with TAF15::NR4A3 fusion that appear morphologically distinct from both conventional and high‐grade EMC. Both cases had an unusual biphasic appearance and showed diffuse positivity for p63, mimicking myoepithelial tumors. DNA methylation profiling demonstrated that both cases clearly cluster with EMC, indicating that they most likely represent morphologically distinct variants of EMC. The clinical significance and prognostic impact of this morphologic variance remains to be determined. Molecular testing, including DNA methylation profiling, can help to confirm the diagnosis and avoid confusion with mimics; it adds another layer of data to support expanding the morphologic spectrum of EMC.
The devastating earthquake that struck Turkey and Syria: Post‐traumatic stress disorder and mental health issues among the victims
Authors: Iqbal Amna , Sheikh Ayesha
Published: April 2023

Natural catastrophes like earthquakes have the potential to be fatal by claiming lives and harming infrastructure, the environment, and mental health. Victims may experience symptoms such as anxiety, despondency, and post‐traumatic stress disorder. Recent earthquakes in Turkey and Syria caused enormous destruction and a high number of fatalities, which is growing by the day. The past examples of earthquakes in China, South Asia, and Turkey imply that there is a possibility that the victims may feel isolated and under psychological stress. Our article outlines the high strategies to minimise the risk of mental health problems among victims of Turkey and Syria.
Pooled Population Pharmacokinetic Analyses of Venetoclax in Patients Across Indications and Healthy Subjects from Phase 1, 2, and 3 Clinical Trials
Authors: Gong Jingqi Q. X. , Suleiman Ahmed A. , Menon Rajeev , Deng Rong , Mensing Sven , Salem Ahmed Hamed
Published: April 2023

Following the decade‐long clinical investigation, venetoclax has accrued pharmacokinetic (PK) data across multiple populations and widely ranging demographics, intrinsic, and extrinsic factors. We leveraged these rich data to systematically characterize venetoclax PK and assess covariate effects with population PK modeling. Plasma concentration–time data were pooled from 3016 subjects enrolled in 41 phase 1, 2, and 3 clinical studies, including patients from 9 indications and healthy volunteers. A nonlinear mixed‐effect model was developed. Covariates were evaluated with full covariate modeling approach. A 2‐compartment model with 3 transit absorption compartments described the data well. The impact of moderate and strong cytochrome P450 (CYP) 3A inhibition on apparent clearance (CL/F), female sex on apparent volume of distribution, food effect on relative bioavailability, and dose nonlinearity was confirmed. Newly identified covariate effects include 48% lower CL/F in subjects with severe hepatic impairment, 61% higher bioavailability in Asian subjects. When multiple CYP3A inhibitors are taken simultaneously, a 49% decrease in CL/F was estimated with multiple moderate inhibitors, more substantial than the 22% decrease of a single moderate inhibitor. An 85% decrease in CL/F was indicated when at least 1 strong CYP3A inhibitor was taken in combination, comparable to that of a single strong inhibitor. A venetoclax cross‐indication population PK model with improved absorption‐phase characterization was developed. Covariate analyses suggested lower CL/F for subjects with severe hepatic impairment and higher bioavailability in Asian subjects. Further decrease in CL/F was indicated when multiple moderate CYP3A inhibitors are present, compared to a single moderate inhibitor.
A Phase 1 study for safety and pharmacokinetics of BIO101 (20‐hydroxyecdysone) in healthy young and older adults
Authors: Dioh Waly , Tourette Cendrine , Del Signore Susanna , Daudigny Louiza , Dupont Philippe , Balducci Christine , Dilda Pierre J. , Lafont René , Veillet Stanislas
Published: April 2023

Background

Sarcopenia is an age‐related skeletal muscle disorder characterized by loss of muscle mass and strength leading to mobility disability. 20‐Hydroxyecdysone (20E) is a polyhydroxylated plant steroid that demonstrates pharmacological effects in many disease animal models including ageing/sarcopenia. BIO101 is a 20E purified investigational drug (≥97%) that previously demonstrated good toxicology profiles in rat and dog. BIO101 is evaluated in healthy young and older adults in a Phase 1 study.

Methods

This study is a Single Ascending Dose (SAD) followed by a 14‐day Multiple Ascending Dose (MAD). In SAD, BIO101 was administered orally to 16 young adults at doses from 100 to 1400 mg and to 8 older adults (age ≥65 years) at 1400 mg. In MAD, doses of 350 mg once daily (qd), 350 mg twice daily (bid) and 450 mg bid were administered to 10 older adults. The primary objective was to evaluate safety and pharmacokinetics (PK), including dosing of circulating metabolites. Pharmacodynamic effects were investigated with regard to myostatin, procollagen‐III‐amino‐terminal propeptide (PIIINP), myoglobin, creatine‐kinase Muscle Brain (CKMB), renin and aldosterone plasma/serum levels.

Results

BIO101 showed a good safety profile with only mild to moderate adverse events and a satisfactory pharmacokinetic profile. In SAD, at 100 mg to 1400 mg, mean Cmax and areas under the curve increased less than dose‐proportionally. Mean half‐life was short (2.4–4.9 h), and mean renal clearance was comparable in all doses (4.05–5.05 L/h). Mean plasma exposure was slightly lower in older adults (22% lower for Cmax and 13%–15% lower for AUCs) compared with young subjects. In MAD, 350 and 450 mg bid led to a slight accumulation over 14 days (mean ratio of accumulation [Rac] of 1.31 in both cohorts). Reduction of biomarkers (myoglobin, CK‐MB) mean serum levels (vs. baseline) was observed at 450 mg bid. Two major metabolites of 20E (14‐deoxy‐20‐hydroxyecdysone and 14‐deoxypoststerone) were identified and quantified.

Conclusions

BIO101 shows a good safety and pharmacokinetic profile that led to the selection of doses for the subsequent interventional clinical trials of Phase 2 in age‐related sarcopenia (SARA‐INT) and Phase 3 in Covid‐19 (COVA).
Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle
Authors: Zhao Wanni , Zhang Yansong , Lin Siyuan , Li Yajuan , Zhu Alan Jian , Shi Hanping , Liu Min
Published: April 2023

Background

Malnutrition is implicated in human metabolic disorders, including hepatic steatosis and myosteatosis. The corresponding nutrient signals and sensors as well as signalling pathways have not yet been well studied. This study aimed to unravel the nutrient‐sensing mechanisms in the pathogenesis of steatosis.

Methods

Plin2, a lipid droplet (LD) protein‐inhibiting lipolysis, is associated with steatosis in liver and muscle. Taking advantage of the Gal4‐UAS system, we used the Drosophila melanogaster wing imaginal disc as an in vivo model to study the regulation of Plin2 proteostasis and LD homeostasis. Drosophila Schneider 2 (S2) cells were used for western blotting, immunoprecipitation assays, amino acid‐binding assays and ubiquitination assays to further investigate the regulatory mechanisms of Plin2 in response to nutrient signals. Mouse AML12 hepatocytes, human JHH‐7 and SNU‐475 hepatoma cells were used for immunofluorescence, western blotting and immunoprecipitation to demonstrate that the mode of Plin2 regulation is evolutionarily conserved. In addition, we purified proteins from HEK293 cells and reconstituted in vitro cell‐free systems in amino acid‐binding assays, pulldown assays and ubiquitination assays to directly demonstrate the molecular mechanism by which Ubr1 senses amino acids to regulate Plin2 proteostasis.

Results

As a lipolysis inhibitor, Plin2 was significantly elevated in liver (P < 0.05) and muscle (P < 0.05) in patients with steatosis. Consistently, we found that the ubiquitin moiety can be conjugated to any Lys residue in Plin2, ensuring robust clearance of Plin2 by protein degradation. We further demonstrated that the E3 ubiquitin ligase Ubr1 targets Plin2 for degradation in an amino acid‐dependent manner. Ubr1 uses two canonical substrate‐binding pockets, independent of each other, to bind basic and bulky hydrophobic amino acids, respectively. Mechanistically, amino acid binding allosterically activates Ubr1 by alleviating Ubr1's auto‐inhibition. In the absence of amino acids, or when the amino acid‐binding capacity of Ubr1 is diminished, Ubr1‐mediated Plin2 degradation is inactivated, leading to steatosis.

Conclusions

We identified Ubr1 as an amino acid sensor regulating Plin2 proteostasis, bridging the knowledge gap between steatosis and nutrient sensing. Our work may provide new strategies for the prevention and treatment of steatosis.
Prognostic significance of sarcopenia and severe vitamin D deficiency in patients with cirrhosis
Authors: Saeki Chisato , Kanai Tomoya , Ueda Kaoru , Nakano Masanori , Oikawa Tsunekazu , Torisu Yuichi , Saruta Masayuki , Tsubota Akihito
Published: April 2023

Background and Aim

Sarcopenia and severe vitamin D deficiency are associated with malnutrition and poor prognosis. We investigated the impact of the comorbidity of Child–Pugh (CP) class B/C cirrhosis and the aforementioned complications on the prognosis of patients with cirrhosis.

Methods

We retrospectively evaluated 104 patients with cirrhosis. The cumulative survival rates were compared between patients with and without both or either of these disease conditions: CP class B/C and complications (sarcopenia or severe vitamin D deficiency). Sarcopenia was diagnosed according to the Japan Society of Hepatology criteria. Severe vitamin D deficiency was defined as levels of 25‐hydroxyvitamin D <10 ng/mL in serum.

Results

The prevalence of CP class B/C, sarcopenia, and severe vitamin D deficiency was 26.9%, 38.5%, and 24.0%, respectively. Patients with both CP class B/C and sarcopenia had significantly lower survival rates than those without both (hazard ratio [HR] = 6.101; P < 0.001) and with either condition (HR = 6.137; P = 0.001). Similarly, patients with both CP class B/C and severe vitamin D deficiency or with either condition had significantly lower survival rates than those without both conditions (HR = 8.135 or 3.189; P < 0.001 or =0.025, respectively). CP class B/C (HR = 3.354; P = 0.006) and severe vitamin D deficiency (HR = 2.445; P = 0.044) were independent prognostic factors.

Conclusions

The coexistence of CP class B/C and sarcopenia or severe vitamin D deficiency worsened the prognosis of patients with cirrhosis. Nutritional assessments such as sarcopenia and vitamin D status should be considered to better evaluate disease conditions and patient prognosis.
Synthesis of BI 894416 and BI 1342561, two potent and selective spleen tyrosine kinase inhibitors, labeled with carbon 14 and with deuterium
Authors: Latli Bachir , Hrapchak Matt J. , Samankumara Lalith P. , Fandrick Daniel R. , Pennino Scott , Lee Heewon , Song Jinhua J.
Published: April 2023

(R)‐4‐((R)‐1‐((6‐(1‐[tert‐butyl]‐1H‐pyrazol‐4‐yl)‐2‐methyl‐2H‐pyrazolo[3,4‐d]pyridin‐4‐yl)oxy)ethyl)pyrrolidin‐2‐one (BI 894416, 1) and (R)‐4‐((R)‐1‐((6‐(1‐[tert‐butyl]‐1H‐pyrazol‐4‐yl)‐2,3‐dimethyl‐2H‐indazol‐4‐yl)oxy)ethyl)pyrrolidin‐2‐one (BI 1342561, 2) are two new potent and selective spleen tyrosine kinase inhibitors developed to treat severe asthma. Both compounds have similar structures and they differ only in the bicyclic moiety 2‐methyl‐2H‐pyrazolo[4,3‐c]pyridine in 1 versus 2,3‐dimethyl‐2H‐indazole in 2. In the carbon 14 synthesis, 1‐(1‐[tert‐butyl]‐1H‐pyrazol‐4‐yl)ethan‐1‐one‐1‐14C ([14C]‐8) was prepared from the cyanation of 4‐bromopyrazole using zinc [14C]cyanide followed by methyl lithium addition on the nitrile group. The enolate of [14C]‐8 was then used to access these two bicyclic moieties via pyrano‐pyrazoles [14C]‐11 and [14C]‐12, which were further transformed in few more steps to [14C]‐(1) and [14C]‐2. Both inhibitors contain a tert‐butyl group. Introducing tert‐butyl‐d9 will not only provide internal standards for bioanalytical studies, but it is also expected to slow down the metabolism of these two compounds. Most of the metabolites of compound 1, for example, are the result of tert‐butyl oxidation, like alcohol 3, acid 4, and the further N‐demethylation of 4 to 5. The detailed preparation of these deuterium‐labeled metabolites is also described.
HSV‐1 infection‐induced herpetic neuralgia involves a CCL5/CCR5‐mediated inflammation mechanism
Authors: Wu Songbin , Yang Shaomin , Li Rongzhen , Ba Xiyuan , Jiang Changyu , Xiong Donglin , Xiao Lizu , Sun Wuping
Published: April 2023

Herpetic‐related neuralgia (HN) caused by varicella‐zoster virus (VZV) infection is one of the most typical and common neuropathic pain in the clinic. However, the potential mechanisms and therapeutic approaches for the prevention and treatment of HN are still unclear. This study aims to provide a comprehensive understanding of the molecular mechanisms and potential therapeutic targets of HN. We used an HSV‐1 infection‐induced HN mouse model and screened the differentially expressed genes (DEGs) in the DRG and spinal cord using an RNAseq technique. Moreover, bioinformatics methods were used to figure out the signaling pathways and expression regulation patterns of the DEGs enriched. In addition, quantitative real‐time RT‐PCR and western blot were carried out to further confirm the expression of DEGs. HSV‐1 inoculation in mice resulted in mechanical allodynia, thermal hyperalgesia, and cold allodynia, following the infection of HSV‐1 in both DRG and spinal cord. Besides, HSV‐1 inoculation induced an up‐regulation of ATF3, CGRP, and GAL in DRG and activation of astrocytes and microglia in the spinal cord. Moreover, 639 genes were upregulated, 249 genes were downregulated in DRG, whereas 534 genes were upregulated and 12 genes were downregulated in the spinal cord of mice 7 days after HSV‐1 inoculation. GO and KEGG enrichment analysis suggested that immune responses and cytokine‐cytokine receptor interaction are involved in DRG and spinal cord neurons in mice after HSV‐1 infection. In addition, CCL5 and its receptor CCR5 were significantly upregulated in DRG and spinal cord upon HSV‐1 infection in mice. And blockade of CCR5 exhibited a significant analgesic effect and suppressed the upregulation of inflammatory cytokines in DRG and spinal cord induced by HSV‐1 infection in mice. HSV‐1 infection‐induced allodynia and hyperalgesia in mice through dysregulation of immune response and cytokine‐cytokine receptor interaction mechanism. Blockade of CCR5 alleviated allodynia and hyperalgesia probably through the suppression of inflammatory cytokines. Therefore, CCR5 could be a therapeutic target for the alleviation of HSV‐1 infection‐induced HN.
Dynamic immunogenicity after primary and booster inactivated SARS‐CoV‐2 vaccination in people living with HIV: A longitudinal observational study
Authors: Lu Ting , Chen Zhiwei , Cao Yu , Ao Ling , Li Zisheng , Gu Xiaoyi , Ren Xingqian , Wang Yixuan , Zhang Gaoli , Xiang Dejuan , Chen Min , Cai Dachuan , Hu Peng , Zhang Dazhi , Peng Mingli , Shi Xiaofeng , Ren Hong
Published: April 2023

People living with HIV (PLWH) have poor outcomes from severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2); vaccination reduces the associated mortality. The humoral immune response dynamics after booster inactivated vaccinations in PLWH remain unclear. In this longitudinal observational study, 100 PLWH after primary inactivated SARS‐CoV‐2 vaccination were consecutively recruited and followed up. After booster vaccination (BV), neutralizing antibodies (NAbs) were detected at 1 month from all the PLWH, and the titer increased sixfold compared to that associated with the primary vaccination (PV), similar to that in healthy controls after BV. The NAbs titer declined over time after BV, but remained higher at 6 months than after PV. The NAbs response was elevated after BV with CD4 count <200 cells/μL, it was the poorest among the different CD4 cell count subgroups. Similar results were observed for anti‐RBD‐IgG responses. Moreover, RBD‐specific MBCs were significantly elevated after BV in PLWH. No serious AEs were observed after BV in PLWH. In conclusion, booster inactivated SARS‐CoV‐2 vaccination is well tolerated and can elicit robust and durable humoral responses in PLWH. PLWH may benefit from a third dose of the inactivated vaccine.
Urine‐based detection of HPV for cervical cancer screening: Time for standardized tests
Authors: Li Guorong , Lamsisi Maryame , Chenafi Sara , Moniod Louise , Benlghazi Abdelhamid , Ennaji Moulay Mustapha , Chauleur Céline , Bourlet Thomas
Published: April 2023

Cervical cancer is preventable because it has an established etiology, mainly attributed to a detectable pathogen, human papillomavirus (HPV). In 2018, the world health organization issued an unprecedented call for global action to eliminate cervical cancer by 2030. The adaptation of regular screening programs is fundamental to achieve the goal of cervical cancer elimination. However, it is still difficult to achieve satisfactory coverage rates of screening in developing countries as well as in developed countries because many women are reluctant to participate in gynecologic examination. HPV detection in urine is a convenient, widely acceptable by women and relatively affordable without the necessity for clinical visits to improve the coverage rates of cervical cancer screening. Unfortunately, the clinical implementation of urine‐based tests for HPV detection has been hindered by the lack of standardized tests. Further optimization of protocols and standardization of urinary HPV detection are expected to be realized. With the advantages of urine sampling to overcome cost, personal, and cultural barriers, time has come for the standardized tests to facilitate a wide clinical implementation of urinary HPV detection that will significantly contribute to the WHO's goal, that is, to eliminate the cervical cancer globally.
Biocontrol of Trichoderma gamsii induces soil suppressive and growth‐promoting impacts and rot disease‐protecting activities
Authors: Valan Arasu Mariadhas , Vijayaraghavan Ponnuswamy , Al‐Dhabi Naif Abdullah , Choi Ki Choon , Moovendhan Meivelu
Published: April 2023

Plant growth‐promoting rhizosphere of associated fungi is often used to improve productivity and crop health. Some biocontrol fungi showed less disease protection efficiency due to environmental factors. Hence, the analysis of biocontrol fungi strains in the field is valuable to analyze their performance in the natural environment. The main objective of this study is to isolate the growth‐promoting, rot disease‐protecting activities of Trichoderma gamsii RH4 obtained from the rhizosphere of black gram (Vigna mungo). In this study, we evaluated the protective role of 13 fungal strains, including T. gamsii against Fusarium oxysporum in the laboratory experiment (antagonistic assay), greenhouse. The growth‐promoting activity of the isolated 13 fungal strains was initially screened and the lytic property was assayed. The T. gamsii showed excellent growth‐promoting and lytic properties. Lytic enzyme assays revealed a significant difference in the enzyme yield than other isolates (p < 0.05). The influence of selected plant‐growth‐promoting fungal strains on the suppression of F. oxysporum rot and wilt black gram was analyzed. Results revealed that these fungal isolates improved black gram growth in greenhouse and significantly reduced wilt and rot disease. The improved growth and yield registered in this study proved growth‐promoting and biocontrol properties. The potent T. gamsii was applied in the open field and its effect on green gram was observed. The field trial experiment revealed several growth‐promoting effects such as the weight and length of the root and shoot system. The isolated native T. gamsii has the potential to improve the biocontrol properties against rot disease.
Effects of probiotics in rats with experimental metabolic syndrome and periodontitis: An investigation of the intestine–adipose tissue axis
Authors: Moreira André L. G. , Silva Pedro H. F. , Salvador Sérgio L. , Ishikawa Karin H. , Ferreira Graziele C. , Tanus‐Santos José E. , Mayer Marcia P. A. , de Souza Sérgio L. S. , Furlaneto Flávia A. C. , Messora Michel R.
Published: April 2023

Background

This study evaluated the systemic (intestine and adipose tissue) and local (periodontal tissues) impact of probiotic therapy in rats with metabolic syndrome (MS) associated or not with periodontitis (PE).

Methods

Forty‐eight rats received a high‐fat diet for induction of MS for 16 weeks. They were subdivided into groups with (+) and without (−) PE, receiving (*) or not (**) receiving probiotics (PROB): MS (−**), MSP (−*), MSPE (+**), and MSPEP (+*). PROB administration (Bifidobacterium animalis subsp. lactis HN019) started on the 8th week of the study and PE was induced on the 14th week by placing ligature on the animals’ lower first molars. Euthanasia occurred in the 16th week. Biomolecular, immunoenzymatic assays, and histomorphometric analyses were performed. The data obtained were statistically analyzed (ANOVA, Tukey, p < 0.05).

Results

The MSPEP group exhibited reduced alveolar bone loss when compared with the MSPE group, as well as lower levels of hepatic steatosis and proteinuria (p < 0.05). In the intestinal environment, the MSPE group exhibited significantly lower villus height and crypt depth, as well as a greater increase in Bacillota when compared with the MSPEP group (p < 0.05). The MSPEP group showed lower adipokine gene expression (LEPR, NAMPT, and FABP4) in adipose tissue than the MSPE group (p < 0.05).

Conclusion

The probiotic B. lactis HN019 reduced the severity of experimental periodontitis and modulated the expression of lipogenic genes and intestinal morphological and microbiological parameters in rats with MS.
Rheology on novel viscoelastic trimeric octadecyl zwitterionic surfactant micelle solutions
Authors: Xu Wenting , Han Xiaoyang , Fang Bo , He Jinlan , Wu Huinan , Xin Hui
Published: April 2023

In this work, a novel trimeric octadecyl zwitterionic surfactant (TOCC) was successfully synthesized. TOCC was compounded with sodium salicylate (NaSal) for an optimized formulation to form viscoelastic micelles. The effects of NaSal concentration, pH, and temperature on the rheological properties of TOCC and TOCC/NaSal micelle solutions were investigated. The flow curves for both TOCC and TOCC/NaSal micelle solutions can be fitted with the Carreau–Yasuda model. Zero shear viscosity of TOCC/NaSal micelle solution increased and then decreased with increasing NaSal concentration, and the same trend was observed for viscoelasticity. Some micelle solutions exhibited significant thixotropy with stress overshoot. The optimal composition of the TOCC/NaSal micelle solution obtained was 5.0/0.5 wt%. Frequency sweep in the form of Cole–Cole plots indicated that the viscoelastic modulus of the TOCC/NaSal micelle solution fitted the Maxwell model at low and medium frequencies. With increasing pH, 5.0 wt% TOCC micelle solution had the maximum zero shear viscosity at pH = 6.9. The steady‐state viscosities of different concentrations of TOCC micelle solutions reached their maximum at neutral conditions (pH = 6.5 ~ 7.0). Viscoelastic modulus of 5.0 wt% TOCC and TOCC/NaSal (5.0/0.5 wt%) micelle solutions decreased with increasing temperature, and thermal thixotropy was observed in both micelle solutions. The novel TOCC and TOCC/NaSal micelle solutions enrich the variety of trimeric surfactants and viscoelastic micelle solutions. This study provides a rheological reference for the applications of viscoelastic trimeric surfactants in smart materials and oil fields.