bluuebunny/crossref_metadata_2025 huggingface dataset:
Automatic segmentation of esophageal cancer, metastatic lymph nodes and their adjacent structures in CTA images based on the UperNet Swin network
Authors: Wang Runyuan , Chen Xingcai , Zhang Xiaoqin , He Ping , Ma Jinfeng , Cui Huilin , Cao Ximei , Nian Yongjian , Xu Ximing , Wu Wei , Wu Yi
Published: September 2024

Objective

To create a deep‐learning automatic segmentation model for esophageal cancer (EC), metastatic lymph nodes (MLNs) and their adjacent structures using the UperNet Swin network and computed tomography angiography (CTA) images and to improve the effectiveness and precision of EC automatic segmentation and TN stage diagnosis.

Methods

Attention U‐Net, UperNet Swin, UNet++ and UNet were used to train the EC segmentation model to automatically segment the EC, esophagus, pericardium, aorta and MLN from CTA images of 182 patients with postoperative pathologically proven EC. The Dice similarity coefficient (DSC), sensitivity, and positive predictive value (PPV) were used to assess their segmentation effectiveness. The volume of EC was calculated using the segmentation results, and the outcomes and times of automatic and human segmentation were compared. All statistical analyses were completed using SPSS 25.0 software.

Results

Among the four EC autosegmentation models, the UperNet Swin had the best autosegmentation results with a DSC of 0.7820 and the highest values of EC sensitivity and PPV. The esophagus, pericardium, aorta and MLN had DSCs of 0.7298, 0.9664, 0.9496 and 0.5091. The DSCs of the UperNet Swin were 0.6164, 0.7842, 0.8190, and 0.7259 for T1‐4 EC. The volume of EC and its adjacent structures between the ground truth and UperNet Swin model were not significantly different.

Conclusions

The UperNet Swin showed excellent efficiency in autosegmentation and volume measurement of EC, MLN and its adjacent structures in different T stage, which can help to T and N stage diagnose EC and will save clinicians time and energy.
Frontline evaluation: Atezolizumab–bevacizumab versus lenvatinib for BCLC stage B hepatocellular carcinoma exceeding the up‐to‐seven criteria
Authors: Kimura Masamichi , Nishikawa Koji , Imamura Jun , Kimura Kiminori
Published: September 2024

Introduction

This study aimed to evaluate the efficacy and safety of atezolizumab combined with bevacizumab (Atez/Bev) compared to lenvatinib (LEN) as first‐line systemic therapy for patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) exceeding the up‐to‐seven criteria threshold, who are typically unsuitable for transarterial chemoembolization (TACE).

Methods

A retrospective analysis was conducted on 49 consecutive patients with HCC treated at Tokyo Metropolitan Komagome Hospital between May 2018 and October 2023. The patients were divided into two groups: the Atez/Bev group (21 patients) and the LEN group (28 patients). Eligibility criteria included Child‐Pugh A classification, no prior systemic therapy, and ineligibility for resection, ablation, or transplantation. Treatment outcomes were assessed through periodic imaging and laboratory tests, evaluating OS, PFS, ORR, and disease control rate (DCR).

Results

Both groups demonstrated comparable baseline characteristics, with a median follow‐up of 15.4 months. No significant difference was observed in OS between the Atez/Bev and LEN groups (median OS: 19.80 vs. 22.20 months, p = 0.763). The median PFS was 10.23 months for Atez/Bev and 7.20 months for LEN (p = 0.343). There were no statistically significant differences in ORR or DCR between the two groups. Common adverse events included elevated AST and ALT levels, with no significant difference in the overall rate of adverse events between the groups.

Conclusions

Atez/Bev and LEN demonstrated comparable efficacy and safety as first‐line systemic treatments for patients with BCLC stage B HCC exceeding the up‐to‐seven criteria. Both therapeutic options are viable for this population, though further large‐scale prospective studies are required to confirm these findings.
Extracellular matrix production and oxygen diffusion regulate chemotherapeutic response in osteosarcoma spheroids
Authors: Sagheb Isabel S. , Coonan Thomas P. , Randall R. Lor , Griffin Katherine H. , Leach J. Kent
Published: September 2024

Background

Osteosarcoma (OS) survival rates and outcome have not improved in 50 years since the advent of modern chemotherapeutics. Thus, there is a critical need for an improved understanding of the tumor microenvironment to identify better therapies. Extracellular matrix (ECM) deposition and hypoxia are known to abrogate the efficacy of various chemical and cell‐based therapeutics. Here, we aim to mechanistically investigate the combinatorial effects of hypoxia and matrix deposition with the use of OS spheroids.

Methods

We use two murine OS cell lines with differential metastatic potential to form spheroids. We form spheroids of two sizes, use ascorbate‐2‐phosphate supplementation to enhance ECM deposition, and study cell response under standard (21% O2) and physiologic (5% O2) oxygen tensions. Finally, we examine chemotherapeutic responses to doxorubicin treatment.

Results

ECM production and oxygen tension are key determinants of spheroid size through cell organization based on nutrient and oxygen distribution. Interestingly, highly metastatic OS is more susceptible to chemotherapeutics compared to less metastatic OS when matrix production increases. Together, these data suggest that dynamic interactions between ECM production and oxygen diffusion may result in distinct chemotherapeutic responses despite inherent tumor aggressiveness.

Conclusion

This work establishes OS spheroids as a valuable tool for early OS tumor formation investigation and holds potential for novel therapeutic target and prognostic indicator discovery.
Targeting the cancer cells and cancer‐associated fibroblasts with next‐generation FGFR inhibitors in prostate cancer co‐culture models
Authors: Afshan Syeda , Kim Yu Gang , Mattsson Jesse , Åkerfelt Malin , Härkönen Pirkko , Baumgartner Martin , Nees Matthias
Published: September 2024

Background

Inhibition of androgen receptor (AR) signaling is the main treatment strategy in advanced prostate cancer (PCa). A subset of castration resistant prostate cancer (CRPC) bypasses the AR blockade by increased fibroblast growth factor receptor (FGFR) signaling. The first‐ and second‐generation, non‐covalent FGFR inhibitors (FGFRis) have largely failed in the clinical trials against PCa. Purpose: In this study, we tested the drug sensitivity of LNCaP, VCaP, and CWR‐R1PCa cell lines to second‐generation, covalent FGFRis (FIIN1, FIIN2) and a novel FGFR downstream molecule inhibitor (FRS2αi).

Methods

2D and 3D mono‐ and co‐cultures of cancer cells, and cancer‐associated fibroblasts (CAFs) were used to mimic tumor‐stroma interactions in the extracellular matrix (ECM). The treatment responses of the FGFR signaling molecules, the viability and proliferation of cancer cells, and CAFs were determined through immunoblotting, migration assay, cell viability assay, and real‐time imaging. Immunofluorescent and confocal microscopy images of control and treated cultures of cancer cells and CAFs, and their morphometric data were deduced.

Results

The FGFRis were more effective in mono‐cultures of the cancer cells compared with co‐cultures with CAFs. The FRS2αi was specifically effective in co‐cultures with CAFs but was not cytotoxic to CAF mono‐cultures as in the case of FIIN1 and FIIN2. At the molecular level, FRS2αi decreased p‐FRS2α, p‐ERK1/2, and activated apoptosis as monitored by cleaved caspase‐3 activity in a concentration‐dependent manner in the co‐cultures. We observed no synergistic drug efficacy in the combination treatment of the FGFRi with ARi, enzalutamide, and darolutamide. The FRS2αi treatment led to a decrease in proliferation of cancer cell clusters in co‐cultures as indicated by their reduced size and Ki67 expression.

Conclusions

CAFs exert a protective effect on cancer cells and should be included in the in vitro models to make them physiologically more relevant in screening and testing of FGFRis. The FRS2αi was the most potent agent in reducing the viability and proliferation of the 3D organotypic co‐cultures, mainly by disrupting the contact between CAFs and cancer cell clusters. The next‐generation FGFRi, FRS2αi, may be a better alternative treatment option for overcoming ARi treatment resistance in advanced PCa.
What a Difference an Electron Makes: Structural Response of Saddle‐Shaped Tetraphenylene to One and Two Electron Uptake
Authors: Zhu Yikun , Zhou Zheng , Wei Zheng , Tsybizova Alexandra , Gershoni‐Poranne Renana , Petrukhina Marina A.
Published: September 2024

Cyclooctatetraene (COT) and COT2− dianion are well‐known as archetypical non‐aromatic and aromatic systems, respectively. However, despite a wealth of studies the effect of one electron addition to the eight‐membered ring remains equivocal. Herein, we report the first stepwise electron addition to tetrabenzo[a,c,e,g]cyclooctatetraene (TBCOT or tetraphenylene), accompanied by isolation and structural characterization of the mono‐ and doubly‐reduced anions. The X‐ray crystallographic study reveals only a small asymmetric distortion of the saddle‐shaped core upon one electron uptake. In contrast, the doubly‐reduced product exhibits a severely twisted conformation, with a new C−C bond separating the COT ring into two fused 5‐membered rings. The reversibility of the two‐fold reduction and bond rearrangement is demonstrated by NMR spectroscopy. In agreement with experimental results, computational analysis confirms that the reduction‐induced core rearrangement requires the addition of the second electron.
Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein
Authors: Wang Huihui , Wang Zhaoliang , Hu Linghao , Yang Bingjie , Zong Liangyi , Xu Dounan , Yu Bo , Kong Xiangqian , Wang Mingliang
Published: September 2024

DNA methyltransferase 1 (DNMT1) is an attractive therapeutic target for acute myelocytic leukemia (AML) and other malignancies. It has been reported that the genetic depletion of DNMT1 inhibited AML cell proliferation through reversing DNA methylation abnormalities. However, no DNMT1‐targeted PROTAC degraders have been reported yet. Herein, a series of proteolysis‐targeting chimera (PROTAC) degrader of DNMT1 based on dicyanopyridine scaffold and VHL E3 ubiquitin ligase ligand was developed. Among them, KW0113 (DC50=643/899 nM in MV4–11/MOLM‐13 cells) exhibited optimal DNMT1 degradation. KW0113 induced DNMT1‐selective degradation in a dose‐ and time‐dependent manner through VHL engagement. Moreover, KW0113 inhibited AML cell growth by reversing promoter DNA hypermethylation and tumor‐suppressor genes silencing. In conclusion, these findings proved the capability of PROTAC strategy for inducing DNMT1 degradation, demonstrated the therapeutic potential of DNMT1‐targeted PROTACs. This work also provided a convenient chemical knockdown tool for DNMT1‐related studies.
Management practices alter endophytic diazotrophic communities in CitraBlue St. Augustinegrass
Authors: Arevalo Alvarenga A. Fernanda , Barbosa Maximiliano , Sierra Augustinus I. Alejandra , Stingl Ulrich , Schiavon Marco
Published: September 2024

Turfgrass research based on inoculations with commercial products containing nitrogen‐fixing endophytes as an alternative to synthetic nitrogen (N) fertilizers has yielded inconclusive results, indicating a lack of understanding of the colonization and stability of diazotrophic endophytes in turfgrasses. Potential factors influencing these results are turfgrass traditional management practices. In this study, we identified and compared endophytic diazotrophic communities and their associated soil counterparts using amplicon sequencing of the nitrogenase iron protein (nifH) of 36 surfaced sterilized CitraBlue St. Augustinegrass cultivar [Stenotaphrum secundatum (Walter) Kuntze] sprigs and 12 aggregated soil samples. Samples were collected from a CitraBlue cultivar mowed either at 5 or 10 cm, with and without thatch removal, and fertilized at 98, 195, or 293 kg N ha−1 year−1. The different communities of endophytic diazotrophs were correlated to turfgrass quality related parameters such as normalized difference vegetation index (NDVI), normalized difference red edge index (NDRE), N leaf content, and visual quality as affected by management practices. CitraBlue endophytic and soil diazotrophic communities were significantly different for alpha diversity (p < 0.0001) and beta diversity (p < 0.001). Both mowing height (p < 0.001) and N fertilization rate (p < 0.05) had a significant effect on the diversity of endophytic diazotrophs. According to the redundancy analysis, turfgrass quality related parameters explained 14.3% of the variance in the endophytic diazotrophic communities. Findings from this research demonstrate that the evaluated management practices alter the endophytic diazotrophic communities of CitraBlue.
Quantifying the Abundance of Alkane Moieties in Lignins with FTIR Spectroscopy and PLS Regression; Estimating Grafting Degree of Esterification
Authors: Heen Blindheim Fredrik , Ruwoldt Jost
Published: September 2024

As society is rapidly converting from fossil‐based materials to greener alternatives, the valorization of lignin through chemical modification has been given considerable attention. Characterizing this highly heterogeneous biopolymer is a constant challenge, and an emerging strategy for dealing with variations in material characteristics is combining traditional analytical techniques with chemometrics, such as Fourier‐transform infrared (FTIR) spectroscopy with partial least squares regression (PLSR). Here, a calibration data set was built based on FTIR spectra and the total carbon‐hydrogen bond (CHB) content of mixtures of technical lignins and alkanes, meant to emulate esterified samples. From this data, a PLSR model was built which predicted the CHB content of esterified lignin reaction products with an RMSECV=5.685 mmol/g and RMSEPred=5.827 mmol/g, and from which the weight percentage of ester‐to‐lignin was determined. When compared to wet‐chemical analysis, good agreement between the techniques was found with an obtained RMSEPred=8.3 % and a R2Train=0.9752 for the degree of esterification. This indicates high model predictability and goodness of fit, and that the calibration data set successfully emulated esterified lignin samples.
An Improved Magnetic Coupling Resonant Wireless Power Transfer System Based on Ferrite‐Nanocrystalline Hybrid Shielding Method
Authors: Hu Yanwen , Heng Tingzhen , Zhang Tingrong , Zhou Wenying , Chen Qingyang
Published: September 2024

Low‐power magnetic coupling resonant wireless power transfer (MCRWPT) systems are less efficient at long transmission distances due to magnetic leakage and losses. For this reason, combining ferrite‐nanocrystalline hybrid shielding and a relay coil, an improved MCRWPT system based on the LCC‐LCC compensation network is designed in this paper. Firstly, the transmission performance of the MCRWPT systems with S‐S and LCC‐LCC compensation networks are compared and analyzed. Secondly, the transfer efficiencies of the MCRWPT system are analyzed when the relay coil is added at different locations, and the transfer efficiencies of the system with single material shielding are compared. Finally, the transmission performance of the MCRWPT system with ferrite‐nanocrystalline hybrid shieling is analyzed using simulation and experiment. Experimental results show that the transfer efficiency of the low‐power MCRWPT system using relay coil and hybrid shielding increases from 40.38% to 69.17% when the input voltage is 40 V and the transmission distance is 250 mm. Compared with the MCRWPT system based on ferrite full shielding, the weight of the MCRWPT system has been reduced by 63.11%. The hybrid shielding method not only improves the transfer efficiency of the MCRWPT system and reduces its spatial magnetic leakage but also has certain cost advantages.
Globally suitable areas for Lycorma delicatula based on an optimized Maxent model
Authors: Zhao Zhengxue , Yang Lin , Chen Xiangsheng
Published: September 2024

Lycorma delicatula, a globally invasive pest, has caused considerable economic losses in many countries. Determining the potential distribution range of L. delicatula is crucial for its effective management and control; however, our understanding of this species remains limited. In this study, Maxent model with occurrence records and environmental variables were fit first and then optimized by selecting the best combination of feature classes and regularization multipliers using the lowest score of corrected Akaike information criterion. Subsequently, we predicted global suitable areas for L. delicatula both currently and in the future (2041–2060, 2061–2080, and 2081–2100). The results indicated that the mean temperature of the driest quarter is the most important environmental variable limiting L. delicatula distribution. Currently, the suitable areas are concentrated in East Asia (mainly in China, South Korea, and Japan), central and eastern United States, and southern Europe. Compared with current environmental conditions, in all future climate scenarios, the number of suitable areas for L. delicatula increased. In addition, we revealed that suitable areas are likely to expand northward in the future. Our study results suggest that policymakers and governments should prioritize the development of pest management measures in suitable areas for L. delicatula, especially in high suitable areas, to control this invasive pest and minimize global economic losses.
Behavioral and economic traits reflect distinct resource acquisition strategies in tendril vines and stem twining vines
Authors: Bai Hua , Ji Yingzheng , Wang Xueqing , Liu Zhi , Zhou Zhe , Yue Ming , Guo Yaoxin
Published: September 2024

Climbing plants are important components of tropical and many temperate forest ecosystems. Current studies regard climbing plants as a single ecological plant type and ignore the ecological differences resulting from their climbing mechanisms, which may lead to a misrepresentation of the role of climbing plants in forest dynamics. Based on behavioral traits and economic traits of climbing plants, we test the hypothesis that tendril climbers and stem twiners are characterized by different resource acquisition strategies. We quantified and compared 4 behavioral traits and 7 economic traits of four stem twining vines and four tendril vines in a temperate oak forest and further tested their differences in resource acquisition strategy. Our study found that tendril vines were scattered in a group distinct from stem twining vines along the first axes of the principal component analysis using four behavioral traits and seven economic traits, being located at the more acquisitive end with more hosts, a larger distance to length ratio of stem, higher leaf and root nitrogen concentrations, and lower leaf carbon content, while stem twining vines showed the opposite trends. These results indicate that tendril vines have a more acquisitive strategy than stem twining vines. The findings suggest a functional variability among the different climbing mechanisms, and which should be accounted for in future studies.
Modeling the distribution of pine wilt disease in China using the ensemble models MaxEnt and CLIMEX
Authors: Chen Lin , Lu Wenxiong , Lamont Byron B. , Liu Yu , Wei Pujie , Xue Weixing , Xiong Zixuan , Tang Li , Wang Yongjian , Wang Pengcheng , Yan Zhaogui
Published: September 2024

Pine wilt disease (PWD) is a devastating plant disease caused by the pinewood nematode (PWN, Bursaphelenchus xylophilus) that is transmitted by several beetle species in the genus, Monochamus. Once present, the disease is difficult to control. Prevention rather than control is regarded as an effective strategy for PWD management. Central to this prevention strategy is the ability to predict the potential distribution of the disease. Here, we employed an integrated MaxEnt and CLIMEX approach to model the potential distribution of PWD under various climate‐change scenarios. Our results indicate that rising temperatures and lower humidity under climate change will render some of the northern regions of China more suitable for the nematode and these beetles, causing the gradual northward movement of PWD. Furthermore, suitable habitats for three pine species, Pinus massoniana, P. taiwanensis and P. shurbergia, overlap with PWN and Monochamus, suggesting that these three species are potentially at high risk of PWD. Thus, PWD management should target the northern regions of China and the three pine species that are most susceptible to PWD.
Imperfections in transparency and mimicry do not increase predation risk for clearwing butterflies with educated predators
Authors: Yeager Justin , Robison Abigail , Wade Cordon D. , Barnett James B.
Published: September 2024

Transparency is an intuitive form of concealment and, in certain butterflies, transparent patches on the wings can contribute to several distinct forms of camouflage. However, perhaps paradoxically, the largely transparent wings of many clearwing butterflies (Ithomiini, Nymphalidae) also feature opaque, and often colorful, elements which may reduce crypsis. In many instances, these elements may facilitate aposematic signaling, but little is known of how transparency and aposematism may interact. Here, we used field predation trials to ask two main questions regarding camouflage and signaling in Ithomiini clearwings. In Experiment 1, we focused on camouflage to ask where being transparent may have an advantage over being opaque. We predicted that, as a single opaque pattern can only match a limited range of backgrounds, transparent wings would offer more effective concealment, and experience lower predation risk, over a wider range of backgrounds colors (i.e., green vs. brown substrates) and behaviors (i.e., perched vs. flying) than opaque wings. In Experiment 2, we focused on the effect conspicuous opaque colors may have on clearwing survival. We predicted that although salient signals may increase detectability, those commonly associated with toxic Ithomiini clearwings would not increase predation risk. Both experiments were conducted among educated predators within the natural range of Ithomiini clearwings and we found predation rates to be very low. In Experiment 1, we found some marginal evidence to suggest that opaque, but not transparent, butterflies may suffer increased predation during flight, whereas in Experiment 2, we found equal survival across all model prey types regardless of coloration. Taken together we suggest that any loss of camouflage due to conspicuous coloration may be compensated by aversive signaling, and that educated predators may broadly generalize across a wide range of known and novel clearwing phenotypes.
Benefit of implantable cardioverter defibrillator use in Japanese patients based on modified MADIT‐ICD benefit score
Authors: Chiba Toshinori , Kondo Yusuke , Shiko Yuki , Nakano Masahiro , Takatsugu Kajiyama , Nakano Miyo , Ito Ryo , Sugawara Masafumi , Yoshino Yutaka , Ryuzaki Satoko , Takanashi Yukiko , Komai Yuya , Kobayashi Yoshio
Published: September 2024

Aims

The MADIT‐ICD benefit score is used to stratify the risk of life‐threatening arrhythmia and non‐arrhythmic mortality. We sought to develop an implantable cardioverter defibrillator (ICD) benefit‐prediction score for Japanese patients with ICDs.

Methods

Patients who underwent ICD implantation as primary prophylaxis were retrospectively enrolled. Based on their MADIT‐ICD benefit scores, we developed a modified MADIT‐ICD benefit score adapted to the Japanese population. The primary endpoints were appropriate ICD therapy and all‐cause death without appropriate ICD therapy (non‐arrhythmic death). We used the Fine and Gray multivariate model and Cox proportional hazard regression to identify factors for adjusting the MADIT‐ICD benefit–risk score specifically for the Japanese population. The scoring points for the original MADIT‐ICD benefit score were adjusted to optimal points based on the multivariate analysis results in the population.

Results

The study enrolled 167 patients [age, 61.9 ± 12.3 years; male individuals, 138 (82.6%); cardiac resynchronization therapy, 73 (43.7%); ischaemic cardiomyopathy, 53 (31.7%)]. Fourteen patients received anti‐tachycardia pacing (ATP) therapy, and 23 received shock therapy as the initial appropriate ICD therapy. Non‐arrhythmic deaths occurred in 37 patients. The original MADIT‐ICD benefit score could not stratify non‐arrhythmic mortality in the Japanese population. The patients were reclassified into three groups according to the modified MADIT‐ICD benefit score. The modified MADIT‐ICD benefit score could effectively stratify the incidence of appropriate ICD therapy and non‐arrhythmic mortality. In the highest‐benefit group, the 10 year cumulative rates of appropriate ICD therapy and non‐arrhythmic mortality were 56.8% and 12.9%, respectively (P < 0.01). In the intermediate‐benefit group, these rates were 20.2% and 40.2% (P = 0.01). In the lowest‐benefit group, the incidence of non‐arrhythmic deaths was 68.1%, and no patient received appropriate ICD therapy.

Conclusions

The modified MADIT‐ICD benefit score may be useful for stratifying ICD candidates in the Japanese population.
In‐hospital course of patients with heart failure with improved ejection fraction in the DELIVER trial
Authors: Pabon Maria A. , Vaduganathan Muthiah , Claggett Brian L. , Chatur Safia , Siqueira Sara , Marti‐Castellote Pablo , de Boer Rudolf A. , Hernandez Adrian F. , Inzucchi Silvio E. , Kosiborod Mikhail N. , Lam Carolyn S.P. , Martinez Felipe , Shah Sanjiv J. , Desai Akshay S. , Jhund Pardeep S. , McMurray John J.V. , Solomon Scott D. , Vardeny Orly
Published: September 2024

Aims

Patients with heart failure (HF) with improved ejection fraction (HFimpEF) may face residual risks of clinical events that are comparable to those experienced by patients with HF whose left ventricular ejection fraction (LVEF) has consistently been above 40%. However, little is known about the clinical course of patients with HFimpEF during hospitalization for HF.

Methods and results

DELIVER randomized patients with HF and LVEF >40% to dapagliflozin or placebo, including HFimpEF (LVEF previously ≤40%). We evaluated all HF hospitalizations adjudicated by the clinical endpoints committee with available data for determination of in‐hospital course. Complicated hospitalization was defined as any hospitalization requiring intensive care unit stay, intravenous vasopressors/inotropes/vasodilators, invasive or non‐invasive ventilation, mechanical fluid removal, ultrafiltration, or mechanical circulatory support. LVEF changes were extracted using a validated GPT‐3.5, a large language model, via a secure private endpoint. Of the 6263 patients enrolled in DELIVER, 1151 (18%) had HFimpEF. During a median follow‐up of 2.3 years, there were 224 total HF hospitalizations in 144 patients with HFimpEF and 985 in 603 patients with LVEF consistently >40%. Patients with HFimpEF experienced higher rates of complicated HF hospitalization as compared with patients with LVEF consistently >40% (39% vs. 27%; p < 0.001). Among those who experienced a first HF hospitalization, there was no significant difference in length of stay or in‐hospital mortality between patients with HFimpEF versus LVEF consistently >40%. In a subset of participants who had at least one LVEF measurement available during HF hospitalization, 66% of those with HFimpEF and 29% of patients with LVEF consistently >40% experienced a reduction in their LVEF to ≤40% from the time of enrolment (p < 0.001). In the entire DELIVER cohort, dapagliflozin reduced total uncomplicated and complicated HF hospitalizations, irrespective of HFimpEF status (pinteraction ≥0.30).

Conclusions

Among patients hospitalized for HF in DELIVER, those with HFimpEF experienced a more adverse in‐hospital clinical course, necessitating higher resource utilization beyond standard diuretic therapy compared with patients with HF and LVEF consistently >40%, but had similar in‐hospital mortality. Treatment benefits of dapagliflozin were not modified by hospitalization type.
Efficient Synthesis of the Pyoverdine Chromophore: Expanding the Toolbox for the Preparation of Pyoverdine Conjugates
Authors: Zhang Tianzhu , Bolhuis Albert , Eggleston Ian M.
Published: September 2024

The pyoverdine chromophore is an important component of a family of siderophores which are secreted by the human pathogen Pseudomonas aeruginosa for iron absorption. In this study, an efficient and improved synthetic route to the chromophore structure is reported, beginning from readily available starting materials, D‐glutamic acid and L–DOPA. This strategy has not only delivered the first synthesis of the free pyoverdine D chromophore, but also offers potential access to a wide range of other pyoverdine chromophore species.
Group dynamics and therapy outcome of multimodal pain therapies: A prospective observational trial
Authors: Mihatsch Lorenz Leopold , Luchting Benjamin , Baumann Nannette , Kiesewetter Isabel , Richter Hans Peter
Published: September 2024

Background

For the treatment of chronic pain, interdisciplinary treatment programs are recommended. Despite continuous adaptation and optimization of this cost‐ and time‐intensive and comprehensive form of therapy, it is not successful in some patients. As personality disorders have an important influence on social interaction and behaviour, the aim of our study was to identify the possible impact of patients with personality disorders on group dynamics and to analyse the influence of group dynamics on individual therapy outcomes.

Methods

We conducted a prospective observational study in patients with chronic pain (N = 104) who participated in a 5‐week interdisciplinary treatment program. The main outcome parameters were psychological state and pain intensity before and after the program.

Results

In contrast to our clinical assumption, we found that neither the type nor the number of patients with personality accentuation or personality disorders had a clinically relevant influence on group dynamics and that even a negative group dynamic did not negatively influence the individual therapy outcome.

Discussion

This trial analysed the connection between group dynamics and therapy outcome of multimodal pain therapies in chronic pain patients considering the factor of personality disorders. Our data demonstrated that neither the type nor the number of patients with personality disorders had a clinically relevant influence on group dynamics and that even a negative group dynamic did not negatively influence the individual therapy outcome. Hence, clinicians should not be afraid to include patients with personality disorders in their treatment programs.

Significance Statement

The study emphasizes that clinicians may include patients with personality disorders in multimodal pain treatment programs and groups, provided that the maintenance of a close therapeutic bond with the patient and within the interdisciplinary team is given.
Whole‐body volume of oxygen consumption while walking: Agreement between measured and estimated values
Authors: Clavero‐Jimeno Antonio , Marmol‐Perez Andres , Dote‐Montero Manuel , Ruiz Jonatan R. , Alcantara Juan M. A.
Published: September 2024

Predictive equations are widely employed for estimating the volume of oxygen consumption (VO2) while walking, which is ultimately employed to determine energy expenditure and tailor exercise prescription. This study aimed to test the agreement between the measured VO2 and estimated VO2 during a walking protocol on a treadmill at 3.5, 4.5, 5.5, and 6.5 km/h. Thirty‐eight young adults (50% women) participated in this cross‐sectional study. The Omnical (Maastricht Instruments, Maastricht, The Netherlands) and K5 (Cosmed, Rome, Italy) metabolic systems were used to measure VO2. To determine the predictive equations, a comprehensive literature search was conducted using the MEDLINE database from May 2022 to July 2023. Seven predictive equations were found and included for estimating VO2 values. We calculated the mean bias (mean difference between measured VO2 and estimated VO2) obtained at each speed using one‐sample t‐tests. We compared the VO2 measured and estimated values using repeated measures analysis of variance and the Bland–Altman method. One‐sample t‐tests showed that all score errors were different from zero (ranging from 1.1 to 5.4 mL/kg/min). Thus, no predictive equation estimated similar VO2 values in comparison with the Omnical and K5 metabolic systems at all intensities. However, the Weyand equation showed the lowest bias across all intensities (score error of 1.1 mL/kg/min). This study showed a lack of agreement between the Omnical and K5 systems compared to diverse predictive equations specially designed to estimate VO2 during walking. Nevertheless, based on our results, the Weyand equation should be the preferred option.
Novel peptides with calcium‐binding capacity from antler bone hydrolysate, its bioactivity on MC3T3‐E1 cells, and the possible chelating mode
Authors: Wang Zhaoguo , Zhai Xiaorui , Xiao Xingyu , Xia Peijun , Chen Xi , Li Yi , Hao Linlin , Zhang Yining
Published: September 2024

In this study, peptide‐calcium chelate was screened from antler bone hydrolysate, and its bioactivity on MC3T3‐E1 cells and its chelating mechanism were investigated. In vitro experiments showed that peptide‐calcium chelate promoted the differentiation and mineralization of MC3T3‐E1 cells. Subsequently, three novel calcium‐chelating peptides were obtained from antler bone hydrolysate using hydroxyapatite chromatography (HAC), Sephadex G‐25 gel filtration chromatography, and reversed‐phase high‐performance liquid chromatography (RP‐HPLC). Meanwhile, this work determined peptides' amino acid sequences as TKLGTQLQL, LETVILGLLKT, and KMVFLMDLLK based on LC–MS/MS. Then the present work prepared the three peptides, with the corresponding calcium‐chelating rates being verified as 87.68 ± 2.86%, 80.72 ± 0.93%, and 67.96 ± 0.98%, respectively. Fourier transform infrared (FTIR) spectroscopy, ultraviolet–visible absorption (UV–vis) spectroscopy, X‐ray diffraction (XRD), circular dichroism (CD), zeta potential, and molecular dynamics (MD) simulations were adopted to investigate the chelating mode of peptides with calcium ions. As a result, oxygen in the carboxyl group and the nitrogen in the amino group were related to calcium binding. In addition, the chelation site preferred the negatively charged carboxylate groups of Leu or Thr. The present work revealed that antler bone might be the new calcium‐chelating peptide source and elucidated their positive role in osteogenesis.
Red beet betalains extraction process: A comprehensive review of methods, applications, and physicochemical properties
Authors: Eyshi Saba , Ghareaghajlou Nazila , Afshar Mogaddam Mohammad Reza , Ghasempour Zahra
Published: September 2024

Red beet extract is rich in bioactive compounds and possesses health‐promoting properties. Moreover, the stability of red beet extract over a broad acidic pH range has given them great potential in developing new functional foods and drinks. The choice of extraction solvent and methodology significantly influences the efficiency of betalain extraction from plant vacuoles. Although the conventional solvent extraction method has been widely employed for betalain extraction, recent innovations have introduced alternative methods that offer advantages, such as reduced solvent consumption, energy efficiency, and minimized exposure to high temperatures. This paper aims to summarize the current knowledge about conventional and novel extraction methods, applications, biological activities, and purification of red beet betalains. Furthermore, the physicochemical properties of betalain‐rich extract of red beet and associated safety considerations have been investigated.
In Situ Driven Formation of Anatase/Brookite/Rutile Heterojunction N/TiO2 Nanocrystals as Sustainable Visible‐Light Catalysts
Authors: Assayehegn Elias , Solaiappan Ananthakumar , Gidey Abraha Tadese , Gebreegziabher Gebremedhin Gebremariam , Gebretsadik Tesfamariam Teklu , Chebude Yonas , Alemayehu Esayas
Published: September 2024

Visible‐light active anatase/brookite/rutile (A/B/R) ternary N‐doped titania (N/TiO2) crystals are successfully prepared by a facile sol‐gel method using titanium butoxide and benign N‐dopant source, guanidinium chloride. Systematically varying the aging time (1, 4, 8, and 12 d), its influence on physicochemical properties of as‐obtained spherical heterojunction nanomaterials is studied. Detailed characterizations confirm that a substantial amount of anatase (88% to 50%) is transformed to rutile (2% to 38%) via intermediate brookite phase (9% to 25%) as the function of aging time; not only the A/B/R phase content of the samples is tuned by sol‐gel aging time of the precursors solution but also their optical‐response and methylene blue photocatalytic properties are profoundly dictated. Notably under visible‐light irradiation, the photostable rutile rich mesoporous A/B/R triphasic N/TiO2 (50% A, 12% B, 38% R) aged for 12 d demonstrates higher degradation activity (97%) with a faster degradation rate (0.033 min−1) than both lesser aged N/TiO2 and undoped titania. This enhancement is attributed to the synergistic effect of interstitial‐N‐doping and optimal A/B/R interfacial charge transfer that leads to higher light absorption, lower bandgap energy and well‐separated charge carriers. The current work provides a new perspective for designing highly active visible‐light heterostructure nanomaterials with controllable phase composition.
A comprehensive method for error separation in hydrological modelling
Authors: Zhao Yilian , Li Hongyan , Zhao Lixin , Li Changhai , Chen Songliang , Su Xiaosi
Published: September 2024

Evaluation metrics play a pivotal role in the calibration process of hydrological models, serving as objective functions that directly influence the final values of model parameters and significantly affect users' perceptions of model performance. However, the choice and interpretation of evaluation metrics are subjective; therefore, this study provides a more objective framework for assessing model performance. This paper initially explored the applicability of various commonly used evaluation metrics, providing an overview of their limitations. Following this, we decomposed errors by analysing their physical significance and geometric representation in scatter plots, categorizing them into systematic and unsystematic errors. Through the decomposition and derivation of the Nash–Sutcliffe efficiency (NSE) formula, we established the quantitative relationship among various evaluation metrics. The soil and water assessment tool (SWAT) model was utilized to simulate monthly runoff in the Baishan basin (China), for the period 1994–2017, with NSE serving as the objective function for calibration. Our findings are consistent with previous studies, indicating that the model tends to slightly underestimate high flows while significantly overestimating low flows. Further analysis through error decomposition and the examination of relationships among various evaluation metrics revealed that unsystematic errors were dominant during the spring snowmelt runoff period, while systematic errors prevailed in the dry season. By evaluating the runoff series based on the magnitude of runoff or by categorizing it according to seasons and months, a more stringent assessment of the model's performance was achieved. These findings not only highlight the necessity for careful selection of evaluation metrics but also underscore the significance of our methodological advancements in enhancing hydrological model precision and reliability.
Evaluating input data sources for isotope‐enabled rainfall‐runoff models
Authors: Watson Andrew , Birkel Christian , Arciniega‐Esparza Saul , de Waal Jan , Miller Jodie , Vystavna Yuliya , van Rooyen Jared , Welham Angela , Bong Hayoung , Yoshimura Kei , Helmschrot Jörg , Künne Annika , Kralisch Sven
Published: September 2024

Isotope‐enabled models provide a means to generate robust hydrological simulations. However, daily isotope‐enabled rainfall‐runoff models applied to larger spatial scales (>100 km2) require more input data than conventional non‐isotope models in the form of precipitation isotope time series, which are difficult to generate even with point station measurements. Spatially distributed isotope data can be circumvented by isotope‐enabled climate models. Here, we evaluate the hydrological simulations of the J2000‐isotope enabled hydrological model driven with data from corrected and un‐corrected isotope‐enabled global and regional climate models (isotope‐enabled global spectral model [IsoGSM] and isotope‐enabled regional spectral model [IsoRSM], respectively) compared with 1 year of measured reference station and a yearly average precipitation isotope input for a pilot site, the data‐scarce sub‐humid Eerste River catchment in South Africa. The models driven by all input products performed well for upstream and downstream discharge gauges with Nash Sutcliffe efficiency (NSE) from 0.58 to 0.85 and LogNSE of 0.66 to 0.93. The simulated δ2H stream isotopes using the reference J2000‐iso and J2000‐isoRSM were good for the main river with a stream Kling Gupta efficiency (KGE) of between 0.4–0.9 and the top 100 Monte Carlo simulations varying by around 5‰ for δ2H. For smaller tributaries the model was unable to capture the measured stream isotopes due to biased precipitation isotope inputs. Adjusting the J2000‐iso with a bias corrected IsoRSM improved the stream and groundwater isotope simulation and outperformed the model driven by an average yearly precipitation isotope input. Differences in simulated hydrological processes were only evident between the models when evaluating percolation with unrealistic simulations for the standard J2000 model. While the regional climate model is computationally more intensive than its global counterpart, it provided better stream isotope simulations and improvements to simulated percolation. Our results indicate that isotope‐enabled climate models can provide useful input data in data scarce regions for hydrological models, where improved water management to address climate change impacts is needed.
Mechanisms of Sigma‐2/TMEM97 Involvement in Cholesterol Metabolism
Authors: Parente Martina , Tonini Claudia , Caputo Sara , Fiocchetti Marco , Pallottini Valentina
Published: September 2024

Extensive research has focused on cellular cholesterol and its regulation, primarily due to its crucial physiological roles and its association with numerous diseases resulting from dysregulated homeostasis. Consequently, investigating cholesterol metabolism and the network of regulating proteins remains an ongoing challenge for biomedical research seeking new molecular targets to manage aberrant cholesterol levels in pathologic conditions. There is evidence that Sigma‐2/TMEM97 receptor regulates cholesterol metabolism. However, the mechanisms remain incompletely understood to date. Therefore, this study aimed to employ a pharmacological approach based on selective Sigma‐2/TMEM97 agonists, rimcazole and siramesine, to uncover the contribution of this receptor to cholesterol homeostasis. Our results indicate that Sigma‐2/TMEM97 activation modulates cholesterol uptake by altering key proteins involved in, leading to free cholesterol and neutral lipids accumulation. This sheds light on potential mechanisms implied, contributing a new piece to the intricate puzzle of cholesterol metabolism homeostasis.
Repurposing Non‐Nucleosidic Reverse Transcriptase Inhibitors (NNRTIs) to Overcome EGFR T790M‐Mediated Acquired Resistance in Non‐Small Cell Lung Cancer
Authors: Ahmad Iqrar , Patel Harun M.
Published: September 2024

This study investigates the repurposing potential of non‐nucleosidic reverse transcriptase inhibitors (NNRTIs), specifically Rilpivirine and Etravirine, as L858R/T790M tyrosine kinase inhibitors for addressing acquired resistance in non‐small cell lung cancer (NSCLC). Using in silico molecular docking, Rilpivirine demonstrated a docking score of −7.534 kcal/mol, comparable to established epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) like Osimertinib and WZ4002. Molecular dynamics (MD) simulations over 200 ns revealed the stability of the Rilpivirine–EGFR complex, with RMSD values ranging from 2.5 to 3.5 Å. The in vitro antiproliferative assays showed that Rilpivirine had an IC50 value of 2.3 µM against H1975 cells, while WZ4002 had an IC50 of 0.291 µM, indicating moderate efficacy. Enzymatic assays revealed that Rilpivirine inhibited the double mutant epidermal growth factor receptor tyrosine kinase (EGFR TK) with an IC50 value of 54.22 nM and spared the wild‐type EGFR TK with an IC50 of 22.52 nM. These findings suggest Rilpivirine's potential as a therapeutic agent for NSCLC with EGFR L858R/T790M mutations
Novel variant related to SATB2‐associated syndrome
Authors: Benyahya Nada , Amllal Nada , Elalaoui Siham Chafai , El Alloussi Mustapha , Sefiani Abdelaziz , Lyahyai Jaber
Published: September 2024

Background

SATB2‐associated syndrome (SAS) also known as Glass syndrome is characterized by/intellectual disability and/or developmental delay coupled with absent or limited speech development. Other abnormalities can be noticed including craniofacial anomalies such as palatal and dental anomalies, behavioural problems and dysmorphic features. It is associated with pathogenic monoallelic variants of the SATB2 gene known to play a key role in brain, dental and jaw development. As phenotype could be unspecific and progressive, clinical diagnostic is difficult. Therefore, genetic testing is mandatory to confirm the disease. Herein, we report clinical and molecular data of a 13‐year‐old girl with psychomotor developmental delay and behavioural problems.

Methods and results

Next‐generation sequencing detected the novel monoallelic frameshift variant SATB2(NM_001172509.2): c.1135del(p.Gln379Lysfs*34). Currently, this variant is classified as likely pathogenic according to the American College of Medical Genetics. Sanger sequencing was used to validate the presence of the detected variant in the patient and confirm de novo character of this latter.

Conclusion

Through this work, we emphasize the value of next‐generation sequencing for a precise molecular diagnosis, an adapted clinical management of patients and an adequate genetic counselling of their families.
Multi‐response kinetic study of Maillard reaction hazards in the glucose‐lysine model system
Authors: Liu Kaihua , Liu Zhijie , Miao Junjian , Huang Yiqun , Lai Keqiang
Published: September 2024

BACKGROUND

Nε‐carboxymethyllysine (CML), Nε‐carboxyethyllysine (CEL) and α‐aminoadipic acid (AAA) are important foodborne hazards and their intake can cause a variety of diseases in humans. It is extremely important to investigate the formation mechanism of CML, CEL and AAA, as well as their association with each other when aiming to control their production.

RESULTS

A multi‐response kinetic model was developed within the glucose‐lysine Maillard reaction model system. The concentrations of glucose, lysine, glyoxal (GO), methylglyoxal (MGO), CML, CEL and AAA were quantified at different temperature (100–160 °C) and at different intervals (0–60 min). The experimental data were fitted to the proposed model to calculate kinetic parameters for the corresponding steps. The results indicated that the production of CML was primarily relied on the direct oxidative cleavage of the Amadori product, rather than the reaction between GO and Lys, whereas CEL and AAA were generated through the reaction of MGO with Lys. Significantly, the reaction between α‐dicarbonyl compounds and Lys preferentially generated CML and CEL, resulting in the lower concentrations of AAA compared to CML and CEL.

CONCLUSION

The multi‐response kinetic model developed in the present study can be applied well to the Maillard reaction. The relationship between the formation mechanisms of CML, CEL and AAA is also explained. © 2024 Society of Chemical Industry.