bluuebunny/crossref_metadata_2025 huggingface dataset:
Low Leakage in High‐k Perovskite Gate Oxide SrHfO3
Authors: Kim Juhan , Song Dowon , Yun Hwanhui , Lee Jaehyeok , Kim Jae Ha , Kim Jae Hoon , Kim Bongju , Char Kookrin
Published: April 2023

Reducing the leakage current through the gate oxide is becoming increasingly important for power consumption reduction as well as reliability in integrated circuits as the semiconducting devices continue to scale down. Here, this work reports on the high‐k dielectric SrHfO3(SHO) based devices with ultralow leakage current density via pulsed laser deposition (PLD). The ultralow current density is achieved by optimizing the growth conditions and the associated structural properties. In the optimized conditions, the dielectric properties of the 50‐nm‐thick SHO capacitors are measured: high dielectric constant (κ = 32), low leakage current density (<10−8A cm−2at 2 MV cm−1), and large breakdown field (EBD > 4 MV cm−1). The surprisingly low leakage current density of SHO is ascribed to the large bandgap (≈6 eV), the large conduction band offset (CB offset > 3 eV) with respect to the semiconductor, and the low density of defect states inside the bandgap. The optimized SHO dielectric with high dielectric constant and ultralow leakage current density is proposed for future low‐power consumption devices based on Si as well as perovskite oxide semiconductors.
Role of reduction gastrectomy in patients with gastric cancer with a single non‐curable factor: Supplementary analysis of REGATTA trial
Authors: Terashima Masanori , Fujitani Kazumasa , Yang Han‐Kwang , Mizusawa Junki , Tsujinaka Toshimasa , Nakamura Kenichi , Katayama Hiroshi , Lee Hyuk‐Joon , Lee Jun Ho , An Ji‐Yeong , Takagane Akinori , Park Young‐Kyu , Choi Seung Ho , Song Kyo Young , Ito Seiji , Park Do Joong , Jin Sung‐Ho , Boku Narikazu , Yoshikawa Takaki , Sasako Mitsuru ,   REGATTA study investigators
Published: April 2023

Background

REGATTA trial failed to demonstrate the survival benefit of reduction gastrectomy in patients with advanced gastric cancer with a single non‐curable factor. However, a significant interaction was found between the treatment effect and tumor location in the subset analysis. Additionally, the treatment effect appeared to be different between Japan and Korea. This supplementary analysis aimed to elucidate the effect of reduction surgery based on tumor location and country.

Methods

Multivariable Cox regression analyses in each subgroup were performed to estimate the hazard ratio (HRadj), including the following variables as explanatory variables: country, age, sex, incurable factor, cT, cN, primary tumor, performance status, histological type, and macroscopic type.

Results

Patients (95 in Japan and 80 in Korea) were randomized to chemotherapy alone (86 patients) or gastrectomy plus chemotherapy (89 patients). The subgroup analysis according to the country revealed a worse overall survival in gastrectomy plus chemotherapy arm in Japan (hazard ratio: 1.32, 95% confidence interval: 0.85–2.05), but not in Korea (hazard ratio: 0.85.95% confidence interval: 0.52–1.40). Overall survival was better in distal gastrectomy plus chemotherapy compared with chemotherapy alone (hazard ratio = 0.69, 95% confidence interval: 0.42–1.13), and worse in total gastrectomy plus chemotherapy compared with chemotherapy alone (hazard ratio = 1.34, 95% CI: 0.93–1.94), which was more remarkable in Korea than in Japan.

Conclusions

Primary chemotherapy is a standard of care for advanced gastric cancer; however, the survival benefits from reduction by distal gastrectomy remained controversial.
Overweight and obesity in adulthood, sociodemographic factors, lifestyle, and the early burden of noncommunicable diseases among Americans: NHANES 2007–2018
Authors: dos Santos Pereira Débora Borges , Conde Wolney Lisboa
Published: April 2023

Objectives

To evaluate the association between nutritional status in early adulthood and the burden of noncommunicable diseases (NCDs); To evaluate the influence of sociodemographic factors and lifestyle on the outcomes of BMI kg/m2 ≤24.9, ≥25.0, and ≥30.0; to estimate the population attributable fraction (PAF) to BMI elevated at 25 years old in the burden of NCDs in American adults.

Methods

We used data from 15 721 American adults participating in the National Health and Nutrition Examination Survey from 2007 to 2018. The Hazard Ratio (HR), Incidence Rate Ratio (IRR), and 95% confidence intervals (CI) were estimated in the proportional risk regression models of Cox (entire population) and Poisson (restricted to non‐patients), respectively. The proportionality of the risk between the burden of NCDs and BMI at 25 years old was drawn by the Kaplan–Meier curve, and the PAF was calculated. All analyses were adjusted taking into account the sample weights.

Results

Health disparities (sex, age, race/ethnicity, education, poverty index, and education level), and lifestyle (physical activity, smoking, and alcohol consumption) influenced the current nutritional status. Cumulative survival in overweight and obese groups decreased considerably over time (p < .0001). Being overweight and obese in adulthood may increase the risk of early NCDs (HR: 1.68, 95% CI: 1.54–1.84 and HR: 2.87, 95% CI: 2.56–3.21, respectively). About 22.72% (95% CI: 19.99–25.36, p < .001) of the burden NCDs could have been avoided if overweight at age 25 had been prevented.

Conclusions

Monitoring weight change from young adulthood can provide a sensitive and useful clinical measure for early detection of adverse trends in NCDs risk.
Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM‐associated syndromes
Authors: Lozano Chinga Michell M. , Bertuch Alison A. , Afify Zeinab , Dollerschell Kaylee , Hsu Joanne I. , John Tami D. , Rao Emily S. , Rowe Robert Grant , Sankaran Vijay G. , Shimamura Akiko , Williams David A. , Nakano Taizo A.
Published: April 2023

The MECOM gene encodes multiple protein isoforms that are essential for hematopoietic stem cell self‐renewal and maintenance. Germline MECOM variants have been associated with congenital thrombocytopenia, radioulnar synostosis and bone marrow failure; however, the phenotypic spectrum of MECOM‐associated syndromes continues to expand and novel pathogenic variants continue to be identified. We describe eight unrelated patients who add to the previously known phenotypes and genetic defects of MECOM‐associated syndromes. As each subject presented with unique MECOM variants, the series failed to demonstrate clear genotype‐to‐phenotype correlation but may suggest a role for additional modifiers that affect gene expression and subsequent phenotype. Recognition of the expanded hematologic and non‐hematologic clinical features allows for rapid molecular diagnosis, early identification of life‐threatening complications, and improved genetic counseling for families. A centralized international publicly accessible database to share annotated MECOM variants would advance their clinical interpretation and provide a foundation to perform functional MECOM studies.
KCNT2‐Related Disorders: Phenotypes, Functional, and Pharmacological Properties
Authors: Cioclu Maria Cristina , Mosca Ilaria , Ambrosino Paolo , Puzo Deborah , Bayat Allan , Wortmann Saskia B. , Koch Johannes , Strehlow Vincent , Shirai Kentaro , Matsumoto Naomichi , Sanders Stephan J. , Michaud Vincent , Legendre Marine , Riva Antonella , Striano Pasquale , Muhle Hiltrud , Pendziwiat Manuela , Lesca Gaetan , Mangano Giuseppe Donato , Nardello Rosaria ,   KCNT2‐study group, Lemke Johannes R. , Møller Rikke S. , Soldovieri Maria Virginia , Rubboli Guido , Taglialatela Maurizio
Published: April 2023

Objective

Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2‐related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants.

Methods

Twenty‐five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole‐cell electrophysiology in HEK‐293 and SH‐SY5Y cells.

Results

The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in‐frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain‐of‐function (GoF), and 6 loss‐of‐function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others.

Interpretation

We expanded the phenotypic and genotypic spectrum of KCNT2‐related disorders, highlighting novel genotype–phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332–349
Ionic Nickel Embedded in Ceria with High Specific CO2 Methanation Activity
Authors: Barreau Mathias , Salusso Davide , Li Juan , Zhang Jinming , Borfecchia Elisa , Sobczak Kamil , Braglia Luca , Gallet Jean‐Jacques , Torelli Piero , Guo Hua , Lin Sen , Zafeiratos Spyridon
Published: April 2023

CO2 hydrogenation to methane is gaining increasing interest as one of the most promising ways to store intermittent renewable energy in the form of chemical fuels. Ni particles supported on CeO2 represent a highly efficient, stable and inexpensive catalyst for this reaction. Herein, Ni‐doped CeO2 nanoparticles were tested for CO2 methanation showing an extremely high Ni mass‐specific activity and CH4 selectivity. Operando characterization reveals that this performance is tightly associated with ionic Νi and Ce3+ surface sites, while formation of metallic Ni does not seem to considerably promote the reaction. Theoretical calculations confirmed the stability of interstitial ionic Ni sites on ceria surfaces and highlighted the role of Ce‐O frustrated Lewis pair (FLP), Ni‐O classical Lewis pair (CLP) and Ni‐Ce pair sites to the activation of H2 and CO2 molecules. To a large extent, the theoretical predictions were validated by in situ spectroscopy under H2 and CO2 : H2 gaseous environments.
Copper(II)/polyimide linked covalent organic framework as a powerful catalyst for the solvent‐free microwave irradiation‐based synthesis of 2,4,5‐trisubstituted imidazoles
Authors: Sedaghat Mahnaz , Moeinpour Farid , Mohseni‐Shahri Fatemeh S.
Published: April 2023

Copper(II)/polyimide‐linked covalent organic frameworks under solvent‐free and microwave‐assisted conditions have been used in an efficient one‐pot protocol for the preparation of 2,4,5‐trisubstituted imidazoles via benzil, aromatic aldehydes and ammonium acetate. By applying solvent‐free conditions and microwave irradiation, three‐component condensation provides safe operations, low pollution, quick access to products, and an easy set‐up. As a result of its reusability, the catalyst can also be reutilized for many runs without missing any activity.
Nanoemulsions for increased penetrability and sustained release of leishmanicidal compounds
Authors: García Darlyn J. , Fernández‐Culma Maritza , Upegui Yulieth A. , Ríos‐Vásquez Luz A. , Quiñones Wiston , Ocampo‐Cardona Rogelio , Echeverri Fernando , Vélez Iván D. , Robledo Sara M.
Published: April 2023

In the last decade, the World Health Organization has driven the development of drugs for topical use in patients with cutaneous leishmaniasis (CL), the most prevalent clinical form of leishmaniasis, a neglected tropical disease. The chemicals C6I, TC1, and TC2 were reported as promising antileishmanial drugs. We aimed to develop a topical nanoformulation that enhances the advantageous effect of C6I, TC1, and TC2, guaranteeing higher stability and bioavailability of the pharmacologically active components through the topical route. Nanoemulsions were prepared by ultrasonication based on oleic acid (0.5 g). A relation of Tween®‐80/ethanol (1:3) and water was obtained; physicochemical characterization of all formulations was performed, and the preliminary stability and transdermal penetration of these nanoemulsions were also investigated. Newtonian‐type fluids with high load capacity, 147–273 nm globule size, and −15 to −18 mV zeta potential were obtained with differential permeability rates in the first pig ear skin assay, first‐order kinetics‐release model for C6I, and Weibull for TC1 and TC2. The nanoemulsion showed good stability, high encapsulation efficiency, and higher leishmanicidal activity against Leishmania braziliensis with lower cytotoxicity in U937 macrophages. In conclusion, nanoemulsions of ethanol–oleic acid/Tween®‐80 increase the activity of compounds with leishmanicidal activity by increasing their penetration and sustained release.
Use of macroalgal waste from the carrageenan industry as feedstock for the production of polyhydroxybutyrate
Authors: Romero‐Vargas Agustín , Gallé Ana , Blandino Ana , Romero‐García Luis I
Published: April 2023

The industrial waste generated in the extraction of carrageenan from red seaweed, Eucheuma spinosum, was tested in this study to produce fermentable sugars that could be used for the production of high‐value‐bioproducts with a biorefinery approach. A sequential process was used: thermochemical pretreatment with HCl and enzymatic hydrolysis. Hydrogen chloride concentrations in the range from 0 mol L−1 to 0.5 mol L−1 and pretreatment times from 15 to 100 min were assayed. The best conditions found for pretreatment were HCl 0.3 mol L−1 for 60 min, leading to reducing sugar concentrations of 21.4 g L−1 (274 mg of reducing sugars per gram of algal residue). The hydrolysates coming from the sequential process under the pretreatment conditions of HCl 0.3 mol L−1 for 60 and 80 min have been used successfully for the production of polyhydroxyalkanoates by Cupriavidus necator. The yields of polyhydroxybutyrate were 0.21–0.26 g PHB g−1 reducing sugar consumed and the accumulation of the biopolymer was of the order of 58% dry cell weight. © 2023 The Authors. Biofuels, Bioproducts and Biorefining published by Society of Industrial Chemistry and John Wiley & Sons Ltd.
The role of noncoding RNAs in pancreatic birth defects
Authors: Yang Ziyue Zoey , Parchem Ronald J.
Published: April 2023

Congenital defects in the pancreas can cause severe health issues such as pancreatic cancer and diabetes which require lifelong treatment. Regenerating healthy pancreatic cells to replace malfunctioning cells has been considered a promising cure for pancreatic diseases including birth defects. However, such therapies are currently unavailable in the clinic. The developmental gene regulatory network underlying pancreatic development must be reactivated for in vivo regeneration and recapitulated in vitro for cell replacement therapy. Thus, understanding the mechanisms driving pancreatic development will pave the way for regenerative therapies. Pancreatic progenitor cells are the precursors of all pancreatic cells which use epigenetic changes to control gene expression during differentiation to generate all of the distinct pancreatic cell types. Epigenetic changes involving DNA methylation and histone modifications can be controlled by noncoding RNAs (ncRNAs). Indeed, increasing evidence suggests that ncRNAs are indispensable for proper organogenesis. Here, we summarize recent insight into the role of ncRNAs in the epigenetic regulation of pancreatic development. We further discuss how disruptions in ncRNA biogenesis and expression lead to developmental defects and diseases. This review summarizes in vivo data from animal models and in vitro studies using stem cell differentiation as a model for pancreatic development.
Analysis of antiplatelet therapy adherence in patients with ischemic cerebral stroke
Authors: Zhong Jie , Gao Yuguang , Huang Deqing , Hu Yueqiang , He Qianchao , Diao Limei , Hu Yuying , Chen Wei
Published: April 2023

Background

The related factors affecting the adherence of ischemic cerebral stroke (ICS) patients to antiplatelet therapy have attracted much attention.

Methods

Patients with ICS (confirmed by CT or MRI) were enrolled from January 2020 to July 2021. The demographic data were retrospectively investigated and analyzed. The adherence calculation was as follows: Adherence = number of tablets taken/number of tablets needed to be taken. Adherence < 100% was defined as nonadherence. Severe nonadherence is defined as adherence ≤ 75%.

Results

A total of 229 patients with ICS were enrolled. We found no significant difference in the proportion of patients with nonadherence, while the proportion of severe nonadherence in the aspirin group was significantly higher (p < .001). Multivariable analysis indicated that medical insurance (odds ratio [OR] = 0.071, p < .001) and regular exercise (OR = 0.438, p = .015) were independent factors associated with adherence. In addition, only medical insurance (OR = 5.475, p < .001) and aspirin treatment (OR = 0.228, p < .001) were independent risk factors associated with severe nonadherence. We therefore constructed a nomogram plot and a model as follows: Adherence risk score = 3 × medical insurance + regular exercise. Patients were divided into low‐risk and high‐risk groups for adherence based on the median model score. A total of 13.3% of patients in the low‐risk group were nonadherent patients compared with 53.4% in the high‐risk group (p < .001). Similarly, 8.4% of patients in the low‐risk group had severe nonadherence compared with 19.9% in the high‐risk group (p = .022). Moreover, in low‐risk patients, no significant difference was observed. In patients with high risk, aspirin‐treated patients showed significantly decreased adherence compared with the other two groups.

Conclusion

Medical insurance and regular exercise were independent factors for antiplatelet therapy adherence. For patients with high model scores, timely intervention is necessary.
HMGB1, angel or devil, in ischemic stroke
Authors: Gao Bin , Wang Shuwen , Li Jiangfeng , Han Nannan , Ge Hanming , Zhang Gejuan , Chang Mingze
Published: April 2023

Introduction

High‐mobility group box 1 protein (HMGB1) is extensively involved in causing ischemic stroke, pathological damage of ischemic brain injury, and neural tissue repair after ischemic brain injury. However, the precise role of HMGB1 in ischemic stroke remains to be elucidated.

Methods

Comprehensive literature search and narrative review to summarize the current field of HMGB1 in cerebral ischemic based on the basic structure, structural modification, and functional roles of HMGB1 described in the literature.

Results

Studies have exhibited the crucial roles of HMGB1 in cell death, immunity and inflammation, thrombosis, and remodeling and repair. HMGB1 released after cerebral infarction is extensively involved in the pathological injury process in the early stage of cerebral infarction, whereas it is involved in the promotion of brain tissue repair and remodeling in the late stage of cerebral infarction. HMGB1 plays a neurotrophic role in acute white matter stroke, whereas it causes sustained activation of inflammation and plays a damaging role in chronic white matter ischemia.

Conclusions

HMGB1 plays a complex role in cerebral infarction, which is related to not only the modification of HMGB1 and bound receptors but also different stages and subtypes of cerebral infarction. future studies on HMGB1 should investigate the spatial and temporal dynamics of HMGB1 after cerebral infarction. Moreover, future studies on HMGB1 should attempt to integrate different stages and infarct subtypes of cerebral infarction.
Continuous and intermittent theta burst stimulation of primary visual cortex do not modulate resting state functional connectivity: A sham‐controlled multi‐echo fMRI study
Authors: Cohan Remy , Rafique Sara A. , Stoby Karlene S. , Gorbet Diana J. , Steeves Jennifer K. E
Published: April 2023

Introduction: Theta burst stimulation (TBS) is a type of rTMS protocol which has the advantage of a shorter delivery time over traditional rTMS. When applied to motor cortex, intermittent TBS (iTBS) has been shown to yield excitatory aftereffects, whereas continuous TBS (cTBS) may lead to inhibitory aftereffects, both lasting from minutes to hours. The majority of TBS research has targeted motor, frontal, and parietal regions, and to date very few studies have examined its efficacy at visual areas. We designed a sham‐controlled study to investigate the immediate poststimulation and short‐term (1 h post‐stimulation) effects of iTBS and cTBS to V1.

Methods: Using multiecho functional magnetic resonance imaging, we measured the direct and indirect effects of TBS by comparing resting state functional connectivity (FC) before and after stimulation in whole brain networks, and seeds from V1 (stimulation site) and neighboring occipital and parietal visual networks. In addition, we also measured pre‐ and post‐TBS phosphene thresholds (PTs) to examine the modulatory effects of TBS on cortical excitability.

Results: We found no changes in FC for iTBS, cTBS or sham stimulation conditions from baseline to poststimulation timepoints. Additionally, cTBS and iTBS had no effect on visual cortical excitability.

Conclusions: Our results indicate that unlike our previous low frequency rTMS to V1 study, which resulted in widespread FC changes up to at least 1 h after stimulation, TBS to V1 does not affect FC. Contrary to the studies showing comparable TBS and rTMS aftereffects in motor and frontal regions, our findings suggest that a single session of cTBS or iTBS to V1 at 80% PT using a standard protocol of 600 pulses may not be effective in targeting FC, especially in clinical settings where therapy for pathological networks is the goal.
Recognizing schizophrenia using facial expressions based on convolutional neural network
Authors: Zhang Xiaofei , Li Tongxin , Wang Conghui , Tian Tian , Pang Haizhu , Pang Jisong , Su Chen , Shi Xiaomei , Li Jiangong , Ren Lina , Wang Jing , Li Lulu , Ma Yanyan , Li Shen , Wang Lili
Published: April 2023

Objective

Facial expressions have been served as clinical symptoms to convey mental conditions in psychiatry. This paper proposes to recognize patients with schizophrenia (SCZ) using their facial images based on deep learning algorithm, and to investigate objective differences in facial expressions between SCZ patients and healthy controls using deep learning algorithm and statistical analyses.

Methods

The study consists of two parts. The first part recruited 106 SCZ patients and 101 healthy controls, and videotaped their facial expressions through a fixed experimental paradigm. The video data were randomly divided into two sets, one for training a convolutional neural network (CNN) with the classification of “healthy control” or “SCZ patient” as output and the other for evaluating the classification result of the trained CNN. In the second part, all facial images of the recruited participants were put into another CNN separately, which was priorly trained with a facial expression database and will output the most likely facial expressions of the recruited participants. Statistical analyses were performed on the obtained facial expressions to find out the objective differences in facial expressions between the two recruited groups.

Results

The trained CNN achieved an overall accuracy of 95.18% for classifying “healthy control” or “SCZ patient.” Statistical results on the obtained facial expressions demonstrated that the objective differences between the two recruited groups were statistically significant (p < .05).

Conclusions

Facial expressions hold great promise as SCZ clues with the help of deep learning algorithm. The proposed approach would be potentially applied to mobile devices for autorecognizing SCZ in the context of clinical and daily life.
Corporate Nirvana: The Buddhist way to social sustainability and business innovation
Authors: Sharma Daneshwar , Sahoo Saumyaranjan , Kumar Ashwani , Huisingh Donald , Sharma Dheeraj
Published: April 2023

Prevailing consumption‐based business models and capitalist practices place significant strain on the environment and society. Buddhism, as a practicing religion, may provide insights on practicing models as a solution to sustain society, the environment, and businesses. The present investigation adopts a structured literature review methodology to take stock of such prior studies and articulate its representation of Buddhism‐based business models, practices, ethical frameworks, and economic views. Based on the findings, it is clear that the prior studies have discussed the practitioner context of Buddhism religion in order to promote ethical and mindful business practices at the consumer, managerial, and business levels; to reduce the negative effects of identity politics in the workplace through spirituality; to introduce the idea of considering factors other than purely financial profitability; and to encourage the long‐term viability and genuine happiness of individuals, communities, and organizations. In relation to these topics, research avenues are proposed.
What was yours is (for now) mine: Prior user knowledge reduces product satisfaction but can improve experiential satisfaction in access‐based consumption
Authors: Stough Rusty Allen , Carter Erin Percival
Published: April 2023

With the rise of the sharing economy, more consumers than ever are thinking about products not in terms of ownership, but in terms of access necessary to facilitate experiences. In this paper, we build on prior literature, which distinguished product from experiential satisfaction to explore the role that knowledge of a prior user plays in shaping these two types of satisfaction in access‐based consumption experiences. Across three studies, we demonstrate that product and experiential satisfaction can be affected differently when consumers are provided with information about previous users of products. We find that information about the previous user of a product consistently negatively impacts product satisfaction. However, we find that when the previous user has positive and experientially relevant traits, experiential satisfaction is increased. When the information about the previous user is negative or experientially irrelevant, experiential satisfaction is decreased. In cases in which we find a positive effect of prior user information on experiential satisfaction, we find it is mediated by transfer of the previous user's traits and that the effectiveness of this mechanism depends on the relevance of traits and the stability of the self‐concept of the consumer.
Emodin‐Induced Necroptosis in Prostate Cancer Cells via the Mitochondrial Fission HSP90/MLKL/PGAM Pathway
Authors: Zhou Xi , Yeasmin Khusbu Farjana , Xie Yang , Yang Peng
Published: April 2023

Currently, prostate cancer is one of the major malignant tumors in males. Recurrence and metastasis are the main obstacles that prevent the effective treatment of prostate cancer. In the present study, we aimed to evaluate emodin (EG) against human prostate cancer PC3 and DU145 cells. Our study showed that EG significantly decreased the cell viability of PC3 and DU145 cells and strikingly induced non‐apoptotic cell death via necroptosis that was visualized through colony formation assay, Hoechst 33258 staining, and TEM analysis. Furthermore, RNA‐sequencing and KEGG functional enrichment analysis revealed that the necroptosis‐related pathway was activated upon EG treatment in PC3 cells. mRNA and protein expression of necroptosis markers were analyzed by qPCR and immunoblotting, which implied that EG‐induced cell necroptosis via enhancing the expression of MLKL and HSP90AA1 activating PGAM pathway which is considered as a key mediator of mitochondrial fission and leading to ROS generation in PC3 and DU145 cells. Thus, our findings suggested that EG is a new small molecule agonist that induced necroptosis in prostate cancer cells via the mitochondrial fission HSP90/MLKL/PGAM pathway.
22‐Oxocholestanes SPGP4 and SPGP8: in Silico and in Vitro Study as Activators of Plant Growth Promotion
Authors: Balbuena‐Hernández Luis , Miranda‐Arámbula Mariana , Merino‐Montiel Penélope , Carrasco‐Carballo Alan , Sandoval‐Ramírez Jesús
Published: April 2023

The 22‐oxocholestanes compounds have shown an outstanding plant growth promoting activity; they have similar bioactivity as brassinosteroids, so they are normally named as brassinosteroid analogs thinking that they also impact on the known receptor BRI1. However, in silico studies allow us to predict interactions with other receptors and thus it's possible to evaluate them, through receptors of gibberellins, auxins, jasmonates, strigolactones and the protein associated with the BRI1 gene. This article describes the bioactivity of structures SPGP4 and SPGP8 as plant growth‐promoting compounds. Both structures present coupling energies and interactions at the same level as epibrassinolide in the protein associated with BRI1 gene. Additionally, interactions through the auxin pathway and to strigolactone receptor were found using selected tests. In the rice lamina tilt, a higher effect was obtained when SPGP4 and SPGP8 were compared to epibrassinolide, although in a lesser level vis à vis to homobrassinolide. In the same way, when SPGP4 and SPGP8 were tested in the Growth Root Model an activity as strigonolactones was observed, enhancing the relationship between the main and secondary roots. However, the growth of coleptiles, when applying auxins, compounds SPGP4 and SPGP8 did not reach the same level as controls. In the tests associated to gibberellins and jasmonic acid, an increased bioactivity was observed, although this behavior was not reflected from the in silico study, possibly due to secondary signaling cascades. This work demonstrates that the 22‐oxocolestane compounds SPGP4 and SPGP8 could be used as plant growth hormones, promoting several pathways.
limpca: An R package for the linear modeling of high‐dimensional designed data based on ASCA/APCA family of methods
Authors: Thiel Michel , Benaiche Nadia , Martin Manon , Franceschini Sébastien , Van Oirbeek Robin , Govaerts Bernadette
Published: April 2023

Many modern analytical methods are used to analyze samples issued from an experimental design, for example, in medical, biological, chemical, or agronomic fields. Those methods generate most of the time, highly multivariate data like spectra or images, where the number of variables (descriptor responses) tends to be much larger than the number of experimental units. Therefore, multivariate statistical tools are necessary to identify variables that are consistently affected by experimental factors. In this context, two recent methods combining ANOVA and PCA, namely, ASCA (ANOVA‐Simultaneous Component Analysis) and APCA (ANOVA‐Principal Component Analysis), were developed. They provide powerful visualization tools for multivariate structures in the space of each effect of the statistical model linked to the experimental design. Their main limitation is that they produce biased estimators of the factor effects when the design of experiment is unbalanced. This article presents the R package limpca (for linear models with principal component effects analysis) that implements ASCA+ and APCA+, an enhanced version of ASCA and APCA methods based on several principles from the theory of general linear models (GLM). In this paper, the methodology is reviewed, the package structure and functions are presented, and a metabolomics data set is used to clearly demonstrate the potential of ASCA+ and APCA+ methods to highlight true biomarkers corresponding to effects of interest in unbalanced designs.
Electron‐Rich MoIV3‐Polyoxomolybdates Resembling the Paratungstic Archetype
Authors: Cheng Cheng , Yi Xiaofeng , Chen Weipeng , Sang Ruili , Xu Li
Published: April 2023

The first polyoxometalates (POMs) composed of MoIV, MoV2, discrete d1‐MoV and MoVI, [MoIV3MoV6MoVI4O32(μ2‐OH)(μ3‐OH)py9] (1), was prepared from the solvothermal partial oxidation of [MoIV3O2(O2CCH3)6(H2O)3]ZnCl4 in a mixture of pyridine and water. The MoV=O adduct‐free unit [H2Mo12O33py9] presents the 11e‐reduced Mo derivative of the paratungtic archetype. The use of methanol, ethanol, n‐propyl alcohol and triglycol instead of water produced the isostructural [MoIV3MoV6MoVI4O32(μ3‐OH)(μ2‐OR)py9](R=CH3, 2; C2H5, 3; C3H7, 4; C2H4OH, 5), providing the first examples of MoIV3−POMs containing bridging alkoxyl groups. The addition of [CrIIIMo6O24]9− led to the substitution of {MoV=O}3+ with {CrIII‐py}3+ in the allomer [MoIV3MoV5MoVI4CrIIIO32(μ‐OH)2py10] (6). Using a mixture of Mo3 and MoW2 precursors afforded WVI‐incorporated allomer [MoIV3MoV6MoVIWVI3O32(μ‐OH)2py9] (7). The complete substitution of MoVI with WVI by using a mixture of the Mo2W, MoW2 and W3 precursors produced the diamagnetic [MoIV3MoV6WVI4O33(μ3‐OH)py9]− (syn‐8) resulting from the anti→syn conversion between the top and bottom M3 triads concomitant with MoV‐MoV bonding. Both anti‐1‐7 and syn‐8 have been characterized by X‐ray single crystal structural analyses. The spin distribution and magnetic interactions have been investigated by temperature‐dependent magnetic susceptibility and DFT theoretical calculations. Heterogeneous hydrogen transfer catalysis has been examined by the Lewis catalysis field (LCF) theory.
Defluorination of Fluorophenols by a Nonheme Iron(IV)‐Oxo Species: Observation of a New Intermediate Along the Reaction
Authors: Bagha Umesh Kumar , Yadav Rolly , Mokkawes Thirakorn , Satpathy Jagnyesh Kumar , Kumar Devesh , Sastri Chivukula V. , de Visser Sam P.
Published: April 2023

High‐valent iron(IV)‐oxo intermediates are versatile oxidants in the biotransformation of various substrates by metalloenzymes and catalyze essential reactions for human health as well as in the biodegradation of toxic organic pollutants in the environment. Herein, we report a biomimetic system that efficiently reacts with halophenols through defluorination reactions and characterize various short‐lived intermediates along the reaction mechanism. We study the reactivity pattern of a nonheme iron(IV)‐oxo species with a series of trihalophenols (X=F, Cl, Br). A combined experimental and computational study reveals that the oxidative dehalogenation of 2,4,6‐trifluorophenol is initiated with an H‐atom abstraction from the phenolic group by the iron(IV)‐oxo species resulting in the formation of a phenolate radical and an iron(III)‐hydroxo species. This iron(III)‐hydroxo species forms an adduct with the oxidized substrate with λmax at 558 nm which subsequently decays to give quinones as products.
A pH‐ and Metal‐Actuated Molecular Shuttle in Water
Authors: Kriat Amine , Pascal Simon , Kauffmann Brice , Ferrand Yann , Bergé‐Lefranc David , Gigmes Didier , Siri Olivier , Kermagoret Anthony , Bardelang David
Published: April 2023

The structure of the Viologen‐Phenylene‐Imidazole (VPI) guest, previously shown to be bound by cucurbit[7]uril (CB[7]) with binding modes depending on pH and silver ions, has been extended by adding hydrophobic groups on the two extremities ofVPIbefore investigations of CB[7] binding by NMR, ITC, X‐ray diffraction, UV‐vis and fluorescence spectroscopies. With an imidazole station extended by a naphthalene group (VPI‐N), binding modes of CB[7] are similar to those previously observed. However, with the viologen extended by a tolyl group (T‐VPI), CB[7] preferentially sits on stationT, shuttling between theTandPstations at acid pH or after Ag+addition. The CB[7] ⋅ T‐VPIcomplex thus behaves as a metal‐actuated thermodynamicstop‐and‐gomolecular shuttle featured by fast and autonomous ring translocation between two stations and a continuum for fractional station occupancy solely and easily controlled by Ag+concentration.
The Impact of the Solvent Dielectric Constant on A←NH3Dative Bond Depends on the Nature of the Lewis Electron‐Pair Systems
Authors: Manna Debashree , Lo Rabindranath , Nachtigallová Dana , Trávníček Zdeněk , Hobza Pavel
Published: April 2023

The present work aims to determine to what extent the value of the dielectric constant of the solvent can influence the dative bond in Lewis electron pair bonding systems. For this purpose, two different systems, namely H3B←NH3and {Zn←(NH3)}2+, were studied in selected solvents with significantly different dielectric constants. Based on the results from state‐of‐the‐art computational methods using DFT, constrained DFT, energy decomposition analyses, solvent accessible surface area, and charge transfer calculations, we found that the stability of the neutral H3B←NH3system increases with increasing solvent polarity. In contrast, the opposite trend is observed for the positively charged {Zn←(NH3)}2+. The observed changes are attributed to different charge redistributions in neutral and charged complexes, which are reflected by a different response to the solvent and are quantified by changes in solvation energies.
UV‐Blocking and Light‐Responsive Poly (ϵ‐Caprolactone)/ZIF‐8 Multifunctional Composite Films for Efficient Antibacterial Activities
Authors: Wang Cuijuan , Feng Siwen , Tang Hongwen , Tan Lichuan , Fan Shuyan , Sun Zeyu , Han Xinping
Published: April 2023

Antibacterial photodynamic therapy (APDT) has received considerable attention owing to its superiority. ZIF‐8 was used to address the poor stability of the photosensitizer Rose Bengal (RB) encapsulation to synthesize RB@ZIF‐8 NPs, which were doped into a composite film with poly (ϵ‐caprolactone) (PCL) and polyvinyl alcohol‐quaternary ammonium chitosan (PVA‐QCS) as substrates to form composite films (PQZ). The composite films exhibited excellent photodynamic sterilization and good resistance to bacterial adhesion. The tensile strength of the film increased to 43.4 MPa, which was approximately 1.8 times that of the PCL film. With the addition of SiO2 and RB@ZIF‐8 NPs, the film exhibited water repellency and UV‐blocking properties. RAW264.7 cells were selected using the MTT method to confirm that the composite films had excellent biocompatibility and had no significant inhibitory effect on cell growth and reproduction. PQZ multifunctional composite films show potential as novel APDT antimicrobial materials for food packaging.
A CommonC2‐Symmetric 2,2’‐Biphenol Building Block and its Application in the Synthesis of (+)‐di‐epi‐Gonytolide A
Authors: Greb Julian , Drennhaus Till , Klischan Moritz K. T. , Schroeder Zachary W. , Frey Wolfgang , Pietruszka Jörg
Published: April 2023

A variety of biaryl polyketides exhibit remarkable bioactivities. However, their synthetic accessibility is often challenging. Herein, the enantioselective preparation and synthetic application of an axially chiral 2,2’‐biphenol building block is outlined that represents a common motif of these intriguing natural products. Based on the highly regioselective and scalable bromination of a phenol precursor, a coupling process by Lipshutz cuprate oxidation was developed. A copper‐mediated deracemization strategy proved to be superior to derivatization or kinetic resolution approaches. Key steps in the overall building block synthesis were rationalized through DFT studies. Utilizing the 2,2’‐biphenol, a highly diastereoselective five step synthesis of formerly unknown (+)‐di‐epi‐gonytolide A was developed, thus showcasing the building block's general potential for the synthesis of natural products and their derivatives. En route, the first enantioselective construction of a chromone dimer intermediate was established.
Contemporary insights into the epidemiology, impact and treatment of secondary tricuspid regurgitation across the heart failure spectrum
Authors: Heitzinger Gregor , Pavo Noemi , Koschatko Sophia , Jantsch Charlotte , Winter Max‐Paul , Spinka Georg , Dannenberg Varius , Kastl Stefan , Prausmüller Suriya , Arfsten Henrike , Dona Carolina , Nitsche Christian , Halavina Kseniya , Koschutnik Matthias , Mascherbauer Katharina , Gabler Cornelia , Strunk Guido , Hengstenberg Christian , Hülsmann Martin , Bartko Philipp E. , Goliasch Georg
Published: April 2023

Aim

Tricuspid regurgitation secondary to heart failure (HF) is common with considerable impact on survival and hospitalization rates. Currently, insights into epidemiology, impact, and treatment of secondary tricuspid regurgitation (sTR) across the entire HF spectrum are lacking, yet are necessary for healthcare decision‐making.

Methods and results

This population‐based study included data from 13 469 patients with HF and sTR from the Viennese community over a 10‐year period. The primary outcome was long‐term mortality. Overall, HF with preserved ejection fraction was the most frequent (57%, n = 7733) HF subtype and the burden of comorbidities was high. Severe sTR was present in 1514 patients (11%), most common among patients with HF with reduced ejection fraction (20%, n = 496). Mortality of patients with sTR was higher than expected survival of sex‐ and age‐matched community and independent of HF subtype (moderate sTR: hazard ratio [HR] 6.32, 95% confidence interval [CI] 5.88–6.80, p < 0.001; severe sTR: HR 9.04; 95% CI 8.27–9.87, p < 0.001). In comparison to HF and no/mild sTR patients, mortality increased for moderate sTR (HR 1.58, 95% CI 1.48–1.69, p < 0.001) and for severe sTR (HR 2.19, 95% CI 2.01–2.38, p < 0.001). This effect prevailed after multivariate adjustment and was similar across all HF subtypes. In subgroup analysis, severe sTR mortality risk was more pronounced in younger patients (<70 years). Moderate and severe sTR were rarely treated (3%, n = 147), despite availability of state‐of‐the‐art facilities and universal health care.

Conclusion

Secondary tricuspid regurgitation is frequent, increasing with age and associated with excess mortality independent of HF subtype. Nevertheless, sTR is rarely treated surgically or percutaneously. With the projected increase in HF prevalence and population ageing, the data suggest a major burden for healthcare systems that needs to be adequately addressed. Low‐risk transcatheter treatment options may provide a suitable alternative.
Empagliflozin in heart failure with preserved ejection fraction with and without atrial fibrillation
Authors: Filippatos Gerasimos , Farmakis Dimitrios , Butler Javed , Zannad Faiez , Ferreira João Pedro , Ofstad Anne Pernille , Iwata Tomoko , Brueckmann Martina , Pocock Stuart J. , Packer Milton , Anker Stefan D. ,   on behalf of the EMPEROR‐Preserved Trial Committees and Investigators
Published: April 2023

Aims

Atrial fibrillation/flutter (AF) is common in heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and associated with worse outcomes. Empagliflozin reduces cardiovascular death or HF hospitalizations and slows estimated glomerular filtration rate (eGFR) decline in patients with HF and LVEF >40%. We aimed to assess the efficacy and safety of empagliflozin in improving outcomes in patients with HF and LVEF >40% with and without AF.

Methods and results

In this pre‐defined secondary analysis of EMPEROR‐Preserved, we compared the effects of empagliflozin versus placebo on the primary and secondary endpoints and safety outcomes, stratified by baseline AF, defined as AF reported in any electrocardiogram before empagliflozin initiation or in medical history. Among 5988 patients randomized, 3135 (52%) had baseline AF; these patients were older, with worse functional class, more previous HF hospitalizations and higher natriuretic peptides compared to those without AF (all p < 0.001). After a median of 26 months, empagliflozin reduced cardiovascular death or HF hospitalization compared to placebo to a similar extent in patients with and without AF (hazard ratio [HR] 0.78 [95% confidence interval 0.66–0.93] vs. 0.78 [0.64–0.95], interaction p = 0.96). Empagliflozin also reduced total HF hospitalizations (HR 0.73 [0.57–0.94] vs. 0.72 [0.54–0.95], interaction p = 0.94) and annual eGFR decline (difference = 1.368 vs. 1.372 ml/min/1.73 m2/year, interaction p = 0.99) consistently in patients with and without AF. There was no increase in serious adverse events with empagliflozin versus placebo in patients with and without AF.

Conclusions

In patients with HF and ejection fraction >40%, empagliflozin reduced the risk of serious HF events and slowed the eGFR decline regardless of baseline AF.
Thermolysis of Geminal Diazido Malonamides: Simple Access to Tetrazoles and Functionalization of In Situ Formed Isocyanates
Authors: Bensberg Kathrin , Kunz Kevin A. , Kirsch Stefan F.
Published: April 2023

In recent years, the development of synthetic methods to afford nitrogen‐containing heterocycles has become increasingly popular. Among these, tetrazoles – an important class of aromatic heterocycles – are of significant interest for example, in medicinal chemistry serving as important bioisosteres. Herein, we present a method to easily access C‐substituted tetrazoles via thermolysis of geminal diazido malonamides. Formation and functionalization of in situ formed isocyanates and corresponding reactions were also studied.
Sydnone Methides: Intermediates between Mesoionic Compounds and Mesoionic N‐Heterocyclic Olefins
Authors: Mummel Sebastian , Lederle Felix , Hübner Eike G. , Namyslo Jan C. , Nieger Martin , Schmidt Andreas
Published: April 2023

Sydnone methides represent an almost unknown class of mesoionic compounds which possess exocyclic carbon substituents instead of oxygen (sydnones) or nitrogen (sydnone imines) in the 5‐position of a 1,2,3‐oxadiazolium ring. Unsubstituted 4‐positions give rise to the generation of anionic N‐heterocyclic carbenes by deprotonation. Preparations of new sydnone methides are described here. They can be represented by mesomeric structures with either exocyclic carbanionic groups like −C(CN)2−, −C(CN)(COOMe)−, −C(CN)(CONH2)−, and −C(CN)(SO2Me)−, or with the corresponding exocyclic C=C double bonds as a common feature with mesoionic N‐heterocyclic olefins. An X‐ray single structure analysis revealed a length of 140.7(3) pm of the exocyclic bond in the solid state. From the coalescence temperature (55 °C) determined by a series of 13C NMR experiments (150 MHz) at various temperatures, an energy of rotation of 18.5 Kcal/mol was calculated for this bond. The 13C NMR signals of the anionic N‐heterocyclic carbenes, from which the 2‐mesityl‐substituted anionic NHC proved to be stable up to 10 °C, are highly shifted upfield (δcarbene=157.9 ppm−160.5 ppm). The carbenes can be reacted in situ with elemental selenium and chlorophosphanes to yield sydnone methide selenoethers after methylation and 4‐phosphanylsydnone methides in good to excellent yields, respectively.
Rh(III)‐Catalyzed Cross Dehydrogenative Coupling of N‐Phenyl Substituent with Thiophenes
Authors: Wei Wen‐Yi , Gong Zi‐Rong , Chai Xin‐Yue , Xu Yan‐Jun , Dong Lin
Published: April 2023

Rhodium(III)‐catalyzed cross‐dehydrogenative coupling involves a highly efficient C−C bond formation from N‐phenyl‐7‐azaindole frameworks, thiophenes. Various novel 7‐azaindole derivatives have been successfully developed with good substrate applicability.