bluuebunny/crossref_metadata_2025 huggingface dataset:
Diphenyleneiodonium efficiently inhibits the characteristics of a cancer stem cell model derived from induced pluripotent stem cells
Authors: Monzur Sadia , Hassan Ghmkin , Afify Said M. , Kumon Kazuki , Mansour Hager , Nawara Hend M. , Sheta Mona , Abu Quora Hagar A. , Zahra Maram H. , Xu Yanning , Fu Xiaoyin , Seno Akimasa , Wikström Per , Szekeres Ferenc L. M. , Seno Masaharu
Published: March 2022

Diphenyleneiodonium (DPI) has long been evaluated as an anticancer drug inhibiting NADPH oxidase, the IC50 in several cancer cell lines was reported 10 µM, which is too high for efficacy. In this study, we employed miPS‐Huh7cmP cells, which we previously established as a cancer stem cell (CSC) model from induced pluripotent stem cells, to reevaluate the efficacy of DPI because CSCs are currently one of the main foci of therapeutic strategy to treat cancer, but generally considered resistant to chemotherapy. As a result, the conventional assay for the cell growth inhibition by DPI accounted for an IC50 at 712 nM that was not enough to define the effectiveness as an anticancer drug. Simultaneously, the wound‐healing assay revealed an IC50 of approximately 500 nM. Comparatively, the IC50 values shown on sphere formation, colony formation, and tube formation assays were 5.52, 12, and 8.7 nM, respectively. However, these inhibitory effects were not observed by VAS2780, also a reputed NADPH oxidase inhibitor. It is noteworthy that these three assays are evaluating the characteristic of CSCs and are designed in the three‐dimensional (3D) culture methods. We concluded that DPI could be a suitable candidate to target mitochondrial respiration in CSCs. We propose that the 3D culture assays are more efficient to screen anti‐CSC drug candidates and better mimic tumor microenvironment when compared to the adherent monolayer of 2D culture system used for a conventional assay, such as cell growth inhibition and wound‐healing assays.
Ligand‐Controlled Site‐ and Enantioselective Carbene Insertion into Carbon‐Silicon Bonds of Benzosilacyclobutanes
Authors: Huo Jingfeng , Zhong Kangbao , Xue Yazhen , Lyu MyeeMay , Ping Yifan , Ouyang Wenbai , Liu Zhenxing , Lan Yu , Wang Jianbo
Published: March 2022

We report herein a highly efficient palladium‐catalyzed carbene insertion into strained Si−C bonds of benzosilacyclobutanes, which provides an efficient method to access α‐chiral silanes. With a sterically hindered ligand, carbene insertion into the C(sp3)−Si bond of benzosilacyclobutanes occurred in excellent site‐ and enantioselectivity, while C(sp2)−Si bond insertion occurred selectively with less sterically hindered ligands. Reaction mechanism, in particular the roles of the chiral ligands in controlling the site‐selectivity of the insertion reactions, are elucidated by using hybrid density functional theory.
Photoswitching Affinity and Mechanism of Multivalent Lectin Ligands
Authors: Osswald Uwe , Boneberg Johannes , Wittmann Valentin
Published: March 2022

Multivalent receptor–ligand binding is a key principle in a plethora of biological recognition processes. Immense binding affinities can be achieved with the correct spatial orientation of the ligands. Accordingly, the incorporation of photoswitches, which can be used to reversibly change the spatial orientation of molecules, into multivalent ligands is a means to alter the binding affinity and possibly also the binding mode of such ligands. We report a divalent ligand for the model lectin wheat germ agglutinin (WGA) containing an arylazopyrazole photoswitch. This switch, which has recently been introduced as an alternative to the more commonly used azobenzene moiety, is characterized by almost quantitative E/Z photoswitching in both directions, high quantum yields, and high thermal stability of the Z isomer. The ligand was designed in a way that only one of the isomers is able to bridge adjacent binding sites of WGA leading to a chelating binding mode. Photoswitching induces an unprecedentedly high change in lectin binding affinity as determined by isothermal titration calorimetry (ITC). Furthermore, additional dynamic light scattering (DLS) data suggest that the binding mode of the ligand changes from chelating binding of the E isomer to crosslinking binding of the Z isomer.
Late‐Stage Dehydroxyazidation of Alcohols Promoted by Trifunctional Hypervalent Azido‐Iodine(III) Reagents
Authors: Yang Xiao‐Guang , Du Feng‐Huan , Li Jun‐Jie , Zhang Chi
Published: March 2022

The development of convenient new methods for the synthesis of organic azides is highly desirable. Herein, we report a practical method for dehydroxyazidation of alcohols via an SN2 pathway involving PPh3 and trifunctional benziodazolone‐based hypervalent azido‐iodine(III) reagents, which function as an electrophilic center, an azido source, and a base. This mild, chemoselective method was used for late‐stage azidation of structurally complex alcohols, as well as for a new synthetic route to the antiepileptic drug rufinamide. The reaction mechanism was also investigated both experimentally and computationally.
Design of Photoactive Covalent Organic Frameworks as Heterogeneous Catalyst for Preparation of Thiophosphinates from Phosphine Oxides and Thiols
Authors: Qiao Huijie , Yang Liting , Yang Xiubei , Wang Jialin , Chen Ya , Zhang Lin , Sun Wuxuan , Zhai Lipeng , Mi Liwei
Published: March 2022

Two new covalent organic frameworks (COFs) were synthesized from 4,4′,4′′,4′′′‐(pyrene‐1,3,6,8‐tetrayl)tetraaniline and 2,5‐dimethoxyterephthalaldehyde (Py‐DMTA‐COF) or 2′,5′‐dimethoxy‐[1,1′:4′,1′′‐terphenyl]‐4,4′′‐dicarbaldehyde (Py‐DMTPDA‐COF) under solvothermal conditions. These two COFs were further facilely developed as efficient photocatalytic platforms for the synthesis of thiophosphinates. Py‐DMTA‐COF exhibited better photocatalytic activity, broad substrate applicability, and excellent recycling capacity for the preparation of thiophosphinates from P(O)H compounds and thiols compared to Py‐DMTPDA‐COF. This methodology was further extended to the seamless gram‐scale production of target phosphorothioate derivatives. The results demonstrate that COFs can provide a robust platform for developing metal‐free, base‐free, highly efficient, and reusable heterogeneous photocatalysts for organic transformations.
Epigenetic Anti‐Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue
Authors: Traube Franziska R. , Brás Natércia F. , Roos Wynand P. , Sommermann Corinna C. , Diehl Tamara , Mayer Robert J. , Ofial Armin R. , Müller Markus , Zipse Hendrik , Carell Thomas
Published: March 2022

5‐Aza‐2’‐deoxycytidine (Decitabine, AzadC) is a nucleoside analogue, which is in clinical use to treat patients with myelodysplastic syndrome or acute myeloid leukemia. Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2’‐deoxycytidine (dC) to 5‐methyl‐dC (mdC). Consequently, AzadC treatment leads to a global loss of mdC, which presumably results in a reactivation of silenced genes, among them tumor suppressor and DNA damage response genes. Because AzadC suffers from severe instability, which limits its use in the clinic, a more sophisticated AzadC derivative would be highly valuable. Here, we report that a recently developed carbocyclic AzadC analogue (cAzadC) blocks DNMT1 in the AML cell line MOLM‐13 as efficient as AzadC. Moreover, cAzadC has a surprisingly strong anti‐proliferative effect and leads to a significantly higher number of double strand breaks compared to AzadC, while showing less off‐target toxicity. These results show that cAzadC triggers more deleterious repair and apoptotic pathways in cancer cells than AzadC, which makes cAzadC a promising next generation epigenetic drug.
Geography and social network influence on crowdfunding a French microbrewery
Authors: Cuénoud Thibault , Dang Rey , Houanti L’Hocine , Hikkerova Lubica
Published: March 2022

The objective of this article is to explore the influence of home bias and the moderating role of social networks (and more particularly family and friends—F&F) in the crowdfunding of a microbrewery in a French region (a lucrative business that uses a territorial solidarity process). We have chosen the case study as methodology to show that neither home bias nor F&F have a significant influence on amounts paid by individuals in crowdfunding. The results are specific to the case studied and are comparable to those of social enterprise. They explain but also justify the behavioural diversity crowdfunding can induce.
Design, Synthesis, and Characterization of a Novel Fluoroprobe for Live Human Islet Cell Imaging of Serotonin 5‐HT1A Receptor
Authors: Garvey Robert W. , Lacivita Enza , Niso Mauro , Duszyńska Beata , Harris Paul E. , Leopoldo Marcello
Published: March 2022

Mounting evidence suggests that the serotonin system serves in signal transmission to regulate insulin secretion in pancreatic islets of Langerhans. Among the 5‐HT receptor subtype found in pancreatic islets, serotonin receptor 1A (5‐HT1A) demonstrates a unique ability to inhibit β‐cell insulin secretion. We report the design, synthesis, and characterization of two novel fluorescent probes for the 5‐HT1A receptor. The compounds were prepared by conjugating the scaffold of the 5‐HT1A receptor agonist 8‐OH‐DPAT with two fluorophores suitable for live‐cell imaging. Compound 5a {5‐(dimethylamino)‐N‐[5‐[(8‐hydroxy‐1,2,3,4‐tetrahydronaphthalen‐2‐yl)(propyl)amino]pentyl]naphtalen‐1‐sulfonammide} showed high affinity for the 5‐HT1A receptor (Ki=1.8 nM). Fluoroprobe 5a was able to label the 5‐HT1A receptor in pancreatic islet cell cultures in a selective manner, as the fluorescence emission was significantly attenuated by co‐administration of the 5‐HT1A receptor antagonist WAY‐100635. Thus, fluoroprobe 5a showed useful properties to further characterize this unique receptor‘s role.
Puckering the Planar Landscape of Fragments: Design and Synthesis of a 3D Cyclobutane Fragment Library
Authors: Hamilton David J. , Beemsterboer Marieke , Carter Caroline M. , Elsayed Jasmina , Huiberts Rilana E. M. , Klein Hanna F. , O'Brien Peter , de Esch Iwan J. P. , Wijtmans Maikel
Published: March 2022

Fragment‐based drug discovery (FBDD) has a growing need for unique screening libraries. The cyclobutane moiety was identified as an underrepresented yet attractive three‐dimensional (3D) scaffold. Synthetic strategies were developed via a key 3‐azido‐cyclobutanone intermediate, giving potential access to a range of functional groups with accessible growth vectors. A focused set of 33 novel 3D cyclobutane fragments was synthesised, comprising three functionalities: secondary amines, amides, and sulfonamides. This library was designed using Principal Component Analysis (PCA) and an expanded version of the rule of three (RO3), followed by Principal Moment of Inertia (PMI) analysis to achieve both chemical diversity and high 3D character. Cis and trans ring isomers of library members were generated to maximise the shape diversity obtained, while limiting molecular complexity through avoiding enantiomers. Property analyses of the cyclobutane library indicated that it fares favourably against existing synthetic 3D fragment libraries in terms of shape and physicochemical properties.
An ensemble method for feature selection and an integrated approach for mitigation of distributed denial of service attacks
Authors: Chanu Usham Sanjota , Singh Khundrakpam Johnson , Chanu Yambem Jina
Published: March 2022

Distributed denial of service attacks (DDoS) penetrate numerous computer system and implant malicious codes thereby making them ready for launching a collaborative attack. These attacks paralyze the target system mainly the web server by exhausting their network resources of the target server. The threats posed by DDoS attacks on the Internet demands for effective detection and mitigation methods of these attacks. In the paper, we proposed an integrated method for detection and mitigation of DDoS attack using machine learning and a line of defenses respectively. The detection phase consists of feature selection through ensemble feature selection algorithm and classification using machine learning algorithm. Feature selection algorithms are important as they reduce the dimension of the dataset. The selection of an efficient classification model will improve the detection rate of the proposed system. In the mitigation phase, we introduce two lines of defense to minimize the exhaustion of the victim server's resources. Using the existing dataset, we show experimentally that it is possible to detect the presence of attacks and mitigate them to a minimum level. The proposed integrated method yields an accuracy of 97.8% in detecting the attacks and able to reduce the utilization of processors upto an average of 25.95%.
Evaluating macro‐ and micro‐mineral contents and agronomic traits of Turkish oat landraces
Authors: Kilinç Fatih Mehmet , Sakiroglu Muhammet , Yilmaz Cafer Hakan , Akkaya Aydın , Dokuyucu Tevrican , Gezginç Hasan , Yüce İlker , Dumlupinar Ziya
Published: March 2022

The cultivated oat (Avena sativa L. and A. byzantina Coch.) is an important annual cereal and forage plant. A large collection of historical oat landraces gathered from different diversity centers is maintained in various seed banks. A historical oat collection consisted of 174 Turkish landraces were evaluated for agronomic performance and mineral nutrient content. The experiment was arranged in an augmented design with six replications of 10 check cultivars and 29 landraces in each block. The most important finding of the study was that the landraces manifested a wide range of variation in all agronomic traits and that some historical landraces outperformed the check cultivars. Since it was dry for the grain‐filling period (GFP) in 2019, some drought‐tolerant landraces were identified. In addition, the top 10 landraces for yield and mineral content were also identified based on each year's performance as well as on the 3‐yr average. The landrace TL69/PI411401 was found to be prominent for high calcium (Ca), magnesium (Mg), phosphorus (P), boron (B), and zinc (Zn) content; TL86/PI167378 for Ca, P, potassium (K), and iron (Fe) contents; and TL71/PI411414 for Ca, P, B, and Zn content.
Mechanism of Preferential Hydrogenation of Hydroxymethyl Group to Aldehyde Group in 5‐Hydroxymethylfurfural over W2C‐Based Catalyst
Authors: Tai Wei , Fu Shuai , Liu Ting‐Hao , Yang Hua‐Qing , Hu Chang‐Wei
Published: March 2022

A W4C2 cluster was used to model a W2C catalyst with the armchair model of activated carbon support, noted as W4C2/AC. Over W4C2/AC, the mechanism for the hydrogenation of both −H2OH and −CHO groups in 5‐hydroxymethylfurfural (HMF) was theoretically studied in tetrahydrofuran at GGA‐PBE/DNP level. 5‐Methylfurfural was the major product from only hydrodehydration of the −CH2OH group, whereas 2,5‐dihydroxymethylfuran was the minor product from the hydrogenation of both −CH2OH and −CHO groups. The rate‐determining steps were concerned with the −C(H)2−H bond formation for the hydrodehydration of −CH2OH group, and the −(OH)(H)−H bond formation for the hydrogenation of −CHO group. Kinetically, W‐sites promoted the hydrodehydration of −CH2OH group and inhibited the hydrogenation of −CHO group. This stemmed from the strong Lewis acidity of W‐sites, which easily accepted the lone‐pair electrons of the oxygen atom in the −C(OH)(H)− group, making −C(OH)(H)−H bond formation hard, and hampering the hydrogenation of the −CHO group.
Sustainable Catalytic Transformation of Biomass‐Derived 5‐Hydroxymethylfurfural to 2,5‐Bis(hydroxymethyl)tetrahydrofuran
Authors: Chien Truong Cong , Kumar Mishra Dinesh , Hyeok Ko Sang , Jin Kim Yong , Suh Young‐Woong
Published: March 2022

5‐Hydroxymethylfurfural (5‐HMF), one of the most important platform molecules in biorefinery, can be directly obtained from a vast diversity of biomass materials. Owing to the reactive functional groups (−CHO and −CH2OH) in the structure, this versatile building block undertakes several transformations to provide a wealth of high value‐added products. Among numerous well‐established paradigms, the catalytic hydrogenation of 5‐HMF towards 2,5‐bis(hydroxymethyl)tetrahydrofuran (BHMTHF) is of great interest because this downstream diol can be exploited in a wide range of industrial applications. Not surprisingly, incessant endeavors from both academia and industry to upgrade this catalytic process have been established over the years. The main aim of this Review was to provide a comprehensive overview on the development of heterogeneous metal catalysts for the 5‐HMF‐to‐BHMTHF transformation. Herein, the rational design and utility of hydrogenating catalysts were elaborated in many aspects including metal types (Ni, Co, Pd, Ru, Pt, and bimetals), solid supports, preparation method, recyclability, operating conditions, and reaction regime (batch and continuous flow). In addition, the assessment of cooperative catalysts to convert carbohydrates into BHMTHF under one‐pot cascade, tentative mechanism, as well as prospects and challenges for the chemo‐selective hydrogenation of 5‐HMF were also highlighted.
Hierarchical Pores‐Confined Ultrasmall Cu Nanoparticles for Efficient Oxidation of 5‐Hydroxymethylfurfural
Authors: Lu Qingwen , Zhao Xin , Fang Ruiqi , Li Yingwei
Published: March 2022

Pyrolysis is one of the most widely utilized protocols for the preparation of nanoconfined metal species for heterogeneous catalysis, but it still suffers from the uncontrollable composition evolution process with undesired metal sintering and porous structure collapse. Herein, a novel and versatile molten salt‐assisted pyrolysis strategy was demonstrated for the preparation of ultrasmall transition‐metal nanoparticles embedded in hollow hierarchical carbon skeletons. The preparation only involved the fabrication of metal‐organic framework templates and subsequent pyrolysis with the addition of KCl−KBr molten salt, which played a crucial role in pore size extending and metal sintering inhibiting. Benefitting from the encapsulation effect, the as‐synthesized Cu@HHC materials exhibited remarkable catalytic performance and recycling stability in the selective oxidation of biomass‐derived 5‐hydroxymethylfurfural into 2,5‐diformylfuran under mild reaction conditions.
Golden codeword‐based generalized spatial modulation
Authors: Sibanda Nathael , Xu Hongjun , Pillay Narushan
Published: March 2022

Conventional‐generalized spatial modulation (C‐GSM) is an
multiple‐input multiple‐output (MIMO) spatial modulation (SM) scheme that transmits the same complex amplitude/phase modulation symbol from multiple active transmit antennas. By using two active transmit antennas during a transmission interval, C‐GSM is capable of achieving high spectral efficiencies. However, as the size of the signal constellation/domain increases, the minimum Euclidean distances (ED) between the symbols decrease. Hence, this leads to a degradation of the average bit error rate (ABER) performance of the scheme. Hence, motivated to improve the error performance of C‐GSM schemes, first, this study proposes a new scheme called Golden codeword‐based generalized spatial modulation (GCW‐GSM), which combines C‐GSM and the Golden code to take advantage of the benefits of both while avoiding their drawbacks. The proposed scheme uses conventional quadrature amplitude modulation (C‐QAM), and it is investigated over Rayleigh frequency‐flat fading channels with additive white Gaussian noise. Second, a closed‐form expression of the theoretical average bit error probability of the proposed GCW‐GSM scheme is formulated. Compared to simulation results, it proves to be increasingly tight at high signal‐to‐noise ratio values. Finally, the proposed scheme performance over the Rayleigh‐frequency‐flat fading channel is compared to that over the Rician channel. An improvement in the error performance of
with spectral efficiency of
is seen in
C‐16QAM GCW‐GSM over
C‐256QAM conventional‐spatial modulation and
C‐256QAM C‐GSM schemes at a bit error rate (BER) of
. The
C‐16QAM GCW‐GSM scheme exhibits an improvement in the error performance of
with spectral efficiency of
over the
C‐64QAM conventional quadrature spatial modulation scheme at a BER of
. Finally, the
16‐QAM GCW‐GSM under Rayleigh fading has a performance gain of 3 dB over
16‐QAM GCW‐GSM under Rician fading with a Rician K factor of 3.
New benzothienopyrimidine derivatives as dual EGFR/ARO inhibitors: Design, synthesis, and their cytotoxic effect on MCF‐7 breast cancer cell line
Authors: Sobh Eman A. , Khalil Nadia A. , Faggal Samar I. , Hassan Marwa S. A.
Published: March 2022

New cytotoxic agents based on benzothienopyrimidine scaffold were designed, synthesized, and evaluated against the MCF‐7 breast cancer line in comparison to erlotinib and letrozole as reference drugs. Eight compounds demonstrated up to 20‐fold higher anticancer activity than erlotinib, and five of these compounds were up to 11‐fold more potent than letrozole in MTT assay. The most promising compounds were evaluated for their inhibitory activity against EGFR and ARO enzymes. Compound 12, which demonstrated potent dual EGFR and ARO inhibitory activity with IC50 of 0.045 and 0.146 µM, respectively, was further evaluated for caspase‐9 activation, cell cycle analysis, and apoptosis. The results revealed that the tested compound 12 remarkably induced caspase‐9 activation (IC50 = 16.29 ng/ml) caused cell cycle arrest at the pre‐G1/G1 phase and significantly increased the concentration of cells at both early and late stage of apoptosis. In addition, it showed a higher safety profile on normal MCF‐10A cells, and higher antiproliferative activity on cancer cells (IC50 = 8.15 µM) in comparison to normal cells (IC50 = 41.20 µM). It also revealed a fivefold higher selectivity index than erlotinib towards MCF‐7 cancer cells. Docking studies were performed to rationalize the dual inhibitory activity of compound 12.
Genetic and phenotypic profiling of supranormal ejection fraction reveals decreased survival and underdiagnosed heart failure
Authors: Forrest Iain S. , Rocheleau Ghislain , Bafna Shantanu , Argulian Edgar , Narula Jagat , Natarajan Pradeep , Do Ron
Published: March 2022

Aims

Individuals with supranormal left ventricular ejection fraction (snLVEF; LVEF >70%) have increased mortality. However, the genetic and phenotypic profile of snLVEF remains unknown. This study aimed to determine the relationship of both snLVEF genetic risk and phenotype with survival and underdiagnosed heart failure (HF).

Methods and results

A snLVEF genetic risk score (GRS) was applied and cases of snLVEF were identified in 486 754 individuals across two population‐based cohorts (BioMe Biobank and UK Biobank). The snLVEF GRS and phenotype were evaluated for association with survival, as well as HF diagnosis, markers, symptoms, and medications. Of 486 754 participants, the median age was 58 years, 20 069 (4.1%) died, and 10 088 (2.1%) had diagnosed HF. Both snLVEF GRS (hazard ratio [HR] 1.1 for top 10% vs. bottom 10% GRS; p = 0.002) and phenotype (HR 1.4; p = 0.003) were associated with increased all‐cause mortality. Both snLVEF GRS and phenotype were associated with reduced HF diagnosis (odds ratio [OR] 0.97 and OR 0.63, respectively; both p ≤0.002). However, the snLVEF GRS and phenotype were both associated with elevated brain natriuretic peptide (BNP) levels (146 and 185 pg/ml increase, respectively; p <0.001), including 268 out of 455 (59%) individuals with snLVEF phenotype who had BNP >100 pg/ml. Among 476 666 participants without HF diagnoses, snLVEF GRS and phenotype were associated with increased HF symptoms (e.g. exertional dyspnoea OR 1.4 and OR 1.3; p <0.003) and HF medications (e.g. loop diuretic OR 1.2 and OR 1.03; p <0.02). Associations were consistent in hypertensive individuals without cardiac comorbidities.

Conclusions

Genetic predisposition to and presence of snLVEF are associated with decreased survival and underdiagnosed HF.
Use of evidence‐based therapy in heart failure with reduced ejection fraction across age strata
Authors: Stolfo Davide , Lund Lars H. , Becher Peter Moritz , Orsini Nicola , Thorvaldsen Tonje , Benson Lina , Hage Camilla , Dahlström Ulf , Sinagra Gianfranco , Savarese Gianluigi
Published: March 2022

Aims

In older patients, guideline‐directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (<40%; HFrEF) is not contraindicated, but adherence to guidelines is limited. We investigated the implementation of GDMT in HFrEF across different age strata in a large nationwide cohort.

Methods and results

Patients with HFrEF and HF duration ≥3 months registered in the Swedish HF Registry between 2000–2018 were analysed according to age. Multivariable logistic and multinomial regressions were fitted to investigate factors associated with underuse/underdosing. Of 27 430 patients, 31% were <70 years old, 34% 70–79 years old, and 35% ≥80 years old. Use of treatments progressively decreased with increasing age. Use of renin–angiotensin system/angiotensin receptor–neprilysin inhibitors, beta‐blockers and mineralocorticoid receptor antagonists was 80%, 88% and 35% in age ≥80 years; 90%, 93% and 47% in age 70–79 years; and 95%, 95% and 54% in age <70 years, respectively. Among patients with an indication, use of implantable cardioverter defibrillator and cardiac resynchronization therapy (CRT) was 7% and 23% in age ≥ 80 years; 22% and 42% in age 70–79 years; and 29% and 50% in age <70 years, respectively. Older patients were less likely treated with target doses or combinations of HF medications. Except for CRT, after extensive adjustments, age was inversely associated with the likelihood of GDMT use and target dose achievement.

Conclusion

In HFrEF, gaps persist in the use of medications and devices. In disagreement with current recommendations, older patients remain undertreated. Improving strategies and a more individualized approach for implementing use of GDMT in HFrEF are required, particularly in older patients.
Synthesis of V‐Shaped Bis‐coumarins through Aldol Reaction/Double Lactonization Cascade Reaction from Bis(2‐hydroxyphenyl)methanone and Meldrum's Acid
Authors: Wang Ding , Ma Zhishuang , Xi Jin , Wang Nana , Wang Tao , Liang Yong , Zhang Zunting
Published: March 2022

A concise and efficient method was developed for the synthesis of chromeno[3,4‐c]chromene‐6,7‐dione using readily available bis(2‐hydroxyphenyl)methanone and Meldrum's acid. The protocol displays a broad substrate scope and good functional group tolerance, including alkyl, alkoxyl, aryl, and halogens. These π‐extended scaffolds showed blue‐green fluorescence with a large Stokes shift. The photophysical studies revealed that 2‐position substituted chromeno[3,4‐c]chromene‐6,7‐dione caused a significant bathochromic shift.
The Perkin Strategy for the Synthesis of Large Carboxy‐Substituted Polycyclic Aromatic Compounds
Authors: Sturm Ludmilla , Aribot Frédéric , Soliman Luc , Bock Harald , Durola Fabien
Published: March 2022

An efficient and versatile synthetic approach has been developed for the synthesis of large carboxy‐substituted polycyclic arenes. This strategy relies on Perkin reactions between arylacetic and arylglyoxylic acids for the formation of flexible precursors. A subsequent rigidification step, by catalyst‐ or light‐induced intramolecular cyclization reactions, then yields fully condensed polycyclic aromatic compounds. Protection and deprotection techniques have been developed to allow the controlled assembly of a large number of building blocks. This method can now be applied to the formation of planar or non‐planar, linear or macrocyclic species of various sizes.
Objective discrimination of fur type based on electrophoresis optimized for fur‐hair proteins
Authors: Sekimoto Yuri , Tokai Arisa , Aritaki Muneshige , Ando Takeshi , Masuda Takeshi
Published: March 2022

The accurate identification of animal species used for fur is important for conserving endangered animals, stopping illegal fur distribution, and addressing consumer concerns. Animal species used for fur are currently differentiated by observing species‐specific morphological fur‐hair features through a microscope. Although this method is simple, the results may differ among inspectors owing to its subjective nature. To develop an objective approach for differentiating animal species based on fur, we utilized the electrophoretic patterns of fur‐hair proteins. First, we optimized protein extraction methods to produce clear electrophoretic patterns from fur‐hair proteins. Then, we obtained 324 electrophoretic patterns from 54 fur samples belonging to 24 different animals; 216 of the 324 patterns were used for the construction of a discrimination model using two‐way orthogonal partial least squares discriminant analysis. The model correctly discriminated between all the remaining 108 patterns without any false negatives or positives. Moreover, this model could discriminate between fur samples from closely related species that are difficult to distinguish using conventional microscopic identification because of the visual similarity of the fur hairs.
Aqueous electrochemistry: The toolbox for life's emergence from redox disequilibria
Authors: Nitschke Wolfgang , Schoepp‐Cothenet Barbara , Duval Simon , Zuchan Kilian , Farr Orion , Baymann Frauke , Panico Francesco , Minguzzi Alessandro , Branscomb Elbert , Russell Michael J.
Published: March 2022

The second law of thermodynamics leaves no doubt that life on planet Earth and its inherent substantial decrease in entropy is fundamentally based on mechanisms converting environmental free energy into the spatial and temporal order of metabolic processes. This argument holds for present life as much as it does for its very beginnings some 4 billion years ago. In this contribution, we try to strip down free energy conversion in extant life (known as “bioenergetics” to the biologists) to its basic principles with the aim to potentially retrodict the nature of the pre‐biotic precursor which drove life into existence. We demonstrate that these basic principles are deeply rooted in aqueous electrochemistry and strongly rely on inorganic redox compounds. The question of life's emergence, generally considered to fall into the realm of organic chemistry, should therefore rather be recognized as an electrochemical problem and its ultimate elucidation will need to strongly implicate the community of electrochemical scientists.
Modeling of the operating characteristics of photovoltaic modules based on particle swarm optimization
Authors: Provensi Lucas Lima , Grala Gabriel Henrique , Zukeram Junior Emílio Soitsi , Alcantara Glaucio Pedro , Krummenauer Rafael , Andrade Cid Marcos Gonçalves
Published: March 2022

This work evaluates the use of particle swarm optimization to extract the parameters that represent a photovoltaic cell in the model of one diode and five parameters (1D5P) to obtain current versus voltage characteristic curves (I × V) of a photovoltaic module operating under a wide range of temperature and irradiation scenarios. In all the modeling and simulation processes, only information of the module's data sheet provided by the manufacturers was used, without depending on results from other simulations or external data collections. To validate the study, the simulation of the current versus voltage (I × V) curves of a commercial photovoltaic module was made, and this was compared with data provided by the manufacturer and also compared with Chenni's method, which is consolidated by the literature. Errors of less than 0.3% were obtained for the simulations performed under the standard test conditions and in temperature and irradiation situations commonly found in practice, as is the case, of G = 700 W/m2 and Tc = 40°C, the 1D5P method showed an average error of approximately 1%, slightly surpassing the Chenni's method where the error was approximately 1.4%.

Statement of Industrial Relevance

In developing countries, such as Brazil, a significant increase in the portion referring to solar energy in the Brazilian energy grid is noted. As in 2016, this portion was only 0.02%, though in 2020, according to the Brazilian Solar Energy Association (ABSOLAR),1 this portion had an increase of 75 times and reached the value of 1.5%. In addition, ABSOLAR's forecast for 2030 is that solar energy will reach 10% of the Brazilian energy grid. One of the reasons for this is that industrial consumer units are increasingly looking for alternative energy sources due to high energy inflation. Photovoltaic generators are an excellent option for industries because they are clean and sustainable energy.2 It is silent and brings a financial return for the investor. Although, even with all the benefits, the photovoltaic generator has a high acquisition cost, especially for consumer units that demand much energy, as is the case of industries. Thus, correct and precise dimensioning for the photovoltaic generator is necessary. One way to increase the accuracy of dimensioning is to use simulation of the photovoltaic modules, which is the objective of this article.

Novelty or Significance

The developed method uses the particle swarm optimization with constriction factor to simulate I × V curves of a photovoltaic module for any temperature and irradiation values, using only the module's datasheet information. This study demonstrates that the proposed method presents more accurate results than consolidated methods in the literature, as is the case with the Chenni's method.3
Quality evaluation of oil by cold‐pressed peanut from different growing regions in China
Authors: Huang Ying , Liu Changsheng , Huang Fenghong , Zhou Qi , Zheng Chang , Liu Rui , Huang Jiazhang
Published: March 2022

In this study, twenty‐six peanut varieties and their cold‐pressed oils from eleven provinces in China were investigated for their oil content, acid value, peroxide value, fatty acid profiles, bioactive constituents, and induction period (IP) of lipid oxidation. Meanwhile, the effect of the geographical origin of peanut on the quality of cold‐pressed peanut oils (CPOs) was studied. The average acid value of CPOs in southern China was higher than that in northern China (0.49 mg KOH/g versus 0.22 mg KOH/g, p > .05). In addition, the average of oleic acid content, ratio of oleic acid to linoleic acid (O/L), and IP were also higher in southern China than that in northern China (p < .05). However, the average content of campesterol, β‐sitosterol, total phytosterol, linoleic acid, and ratio of unsaturated fatty acid to saturated fatty acid (UFA/SFA) exhibited reverse results (p < .05). At last, the comprehensive evaluation of CPOs based on principal component analysis (PCA) was performed. In all samples, Silihong from Liaoning province, northern China was No.1, and Zhonghua 21 from Xiaogan City, Hubei Province was No.4 which was the first one from southern China. Moreover, heat map clustering analysis further revealed the differences and similarities among different samples, and those results were in accordance with the comprehensive evaluation results.
Qualitative and quantitative analyses of chemical components of Citri Sarcodactylis Fructus from different origins based on UPLC–Q–Exactive Orbitrap–MS and GC–MS
Authors: Ning Jinrong , Wang Kanghui , Yang Wanling , Liu Mengshi , Tian Jingyuan , Wei Minyan , Zheng Guodong
Published: March 2022

Ultra‐high‐performance liquid chromatography–Q–Exactive Orbitrap–mass spectrometry (MS) and gas chromatography (GC)–MS were performed for the qualitative and quantitative analyses of Citri Sarcodactylis Fructus (CSF) from different origins. The contents of eight major CSF components, namely 5,7‐dimethoxycoumarin, scopoletin, hesperidin, tangeretin, nobiletin, limonin, nomilin, and stachydrine, were quantitatively analyzed. Clustering analysis and principal component analysis (PCA) were, respectively, performed to classify and compare the 10 CSF batches. One hundred and two volatile components were identified accordingly by comparing retention times, reference standards, parent peaks, fragment peaks, and findings from relevant literature. Moreover, high content of 5,7‐dimethoxycoumarin and stachydrine was detected in all the CSFs, especially in CSF‐Zhe. Therefore, the high content component coumarin “5,7‐dimethoxycoumarin” was suggested to be quality analysis component rather than hesperidin. Additionally, characteristic compounds were found to distinguish different CSFs. This work was a comprehensive study about the components of various CSF. It distinguished the basic differences in the compositions of CSF from different origins. Eventually, it provided experimental and systematic bases for the quality control analysis of CSF, which has potential application in the further research.
Structural connectivity associated with familial risk for mental illness: A meta‐analysis of diffusion tensor imaging studies in relatives of patients with severe mental disorders
Authors: Xu Mengyuan , Zhang Wenjing , Hochwalt Paul , Yang Chengmin , Liu Naici , Qu Jiao , Sun Hui , DelBello Melissa P. , Lui Su , Nery Fabiano G.
Published: March 2022

Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) are heritable conditions with overlapping genetic liability. Transdiagnostic and disorder‐specific brain changes associated with familial risk for developing these disorders remain poorly understood. We carried out a meta‐analysis of diffusion tensor imaging (DTI) studies to investigate white matter microstructure abnormalities in relatives that might correspond to shared and discrete biomarkers of familial risk for psychotic or mood disorders. A systematic search of PubMed and Embase was performed to identify DTI studies in relatives of SCZ, BD, and MDD patients. Seed‐based d Mapping software was used to investigate global differences in fractional anisotropy (FA) between overall and disorder‐specific relatives and healthy controls (HC). Our search identified 25 studies that met full inclusion criteria. A total of 1,144 relatives and 1,238 HC were included in the meta‐analysis. The overall relatives exhibited decreased FA in the genu and splenium of corpus callosum (CC) compared with HC. This finding was found highly replicable in jack‐knife analysis and subgroup analyses. In disorder‐specific analysis, compared to HC, relatives of SCZ patients exhibited the same changes while those of BD showed reduced FA in the left inferior longitudinal fasciculus (ILF). The present study showed decreased FA in the genu and splenium of CC in relatives of SCZ, BD, and MDD patients, which might represent a shared familial vulnerability marker of severe mental illness. The white matter abnormalities in the left ILF might represent a specific familial risk for bipolar disorder.
Zapline‐plus: A Zapline extension for automatic and adaptive removal of frequency‐specific noise artifacts in M/EEG
Authors: Klug Marius , Kloosterman Niels A.
Published: March 2022

Removing power line noise and other frequency‐specific artifacts from electrophysiological data without affecting neural signals remains a challenging task. Recently, an approach was introduced that combines spectral and spatial filtering to effectively remove line noise: Zapline. This algorithm, however, requires manual selection of the noise frequency and the number of spatial components to remove during spatial filtering. Moreover, it assumes that noise frequency and spatial topography are stable over time, which is often not warranted. To overcome these issues, we introduce Zapline‐plus, which allows adaptive and automatic removal of frequency‐specific noise artifacts from M/electroencephalography (EEG) and LFP data. To achieve this, our extension first segments the data into periods (chunks) in which the noise is spatially stable. Then, for each chunk, it searches for peaks in the power spectrum, and finally applies Zapline. The exact noise frequency around the found target frequency is also determined separately for every chunk to allow fluctuations of the peak noise frequency over time. The number of to‐be‐removed components by Zapline is automatically determined using an outlier detection algorithm. Finally, the frequency spectrum after cleaning is analyzed for suboptimal cleaning, and parameters are adapted accordingly if necessary before re‐running the process. The software creates a detailed plot for monitoring the cleaning. We highlight the efficacy of the different features of our algorithm by applying it to four openly available data sets, two EEG sets containing both stationary and mobile task conditions, and two magnetoencephalography sets containing strong line noise.
Immunocompromised rabbit model of chronic HEV reveals liver fibrosis and distinct efficacy of different vaccination strategies
Authors: He Qiyu , Zhang Fan , Shu Jingyi , Li Shuangshuang , Liang Zhaochao , Du Minghao , Liu Xing , Liu Tianxu , Li Manyu , Yin Xin , Pan Qiuwei , Lu Fengmin , Wang Ling , Wang Lin
Published: March 2022

Background and Aims

HEV infection can lead to chronicity and rapid progression to liver fibrosis and cirrhosis in immunocompromised organ transplant recipients. Robust animal models are urgently needed to study the pathogenesis and test the efficacy of vaccines and antiviral drugs in immunosuppressed settings.

Approach and Results

Cyclosporin A was used to induce immunosuppression. Rabbits were challenged with genotype 3 or 4 HEV (i.e., the rabbit‐derived HEV3 and human‐derived HEV3 or HEV4). We assessed HEV markers within 13 weeks post inoculation (wpi) and pathological changes by hematoxylin and eosin and Masson staining at 4, 8, or 13 wpi. Chronic HEV infection was successfully established in immunocompromised rabbits. HEV RNA and/or antigens were detected in the liver, kidney, intestine, urine, and cerebrospinal fluid samples. Chronically infected animals exhibited typical characteristics of liver fibrosis development. Intrahepatic transcriptomic analysis indicated activation of both innate and adaptive immunity. Establishment of HEV chronicity likely contributed to the inhibited T‐cell immune response. Ribavirin is effective in clearing HEV infection in immunocompromised rabbits. Most interestingly, vaccination completed before immunosuppression conferred full protection against both HEV3 and HEV4 infections, but vaccination during immunosuppression was only partially protective, and the efficacy did not improve with increased or additional vaccine doses.

Conclusions

The immunocompromised rabbit model of both chronic HEV3 and HEV4 infection that was established captured the key features of chronic HEV infection in transplant patients, including liver fibrogenesis, and revealed the distinct effectiveness of vaccination administered before or under immunosuppression. This rabbit model is valuable for understanding the pathogenesis of chronic hepatitis E, as well as for evaluating antiviral agents and vaccines.
Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis
Authors: Lei Lin , Bruneau Alix , El Mourabit Haquima , Guégan Justine , Folseraas Trine , Lemoinne Sara , Karlsen Tom Hemming , Hoareau Bénédicte , Morichon Romain , Gonzalez‐Sanchez Ester , Goumard Claire , Ratziu Vlad , Charbord Pierre , Gautheron Jérémie , Tacke Frank , Jaffredo Thierry , Cadoret Axelle , Housset Chantal
Published: March 2022

Background and Aims

In liver fibrosis, myofibroblasts derive from HSCs and as yet undefined mesenchymal cells. We aimed to identify portal mesenchymal progenitors of myofibroblasts.

Approach and Results

Portal mesenchymal cells were isolated from mouse bilio‐vascular tree and analyzed by single‐cell RNA‐sequencing. Thereby, we uncovered the landscape of portal mesenchymal cells in homeostatic mouse liver. Trajectory analysis enabled inferring a small cell population further defined by surface markers used to isolate it. This population consisted of portal fibroblasts with mesenchymal stem cell features (PMSCs), i.e., high clonogenicity and trilineage differentiation potential, that generated proliferative myofibroblasts, contrasting with nonproliferative HSC‐derived myofibroblasts (‐MF). Using bulk RNA‐sequencing, we built oligogene signatures of the two cell populations that remained discriminant across myofibroblastic differentiation. SLIT2, a prototypical gene of PMSC/PMSC‐MF signature, mediated profibrotic and angiogenic effects of these cells, which conditioned medium promoted HSC survival and endothelial cell tubulogenesis. Using PMSC/PMSC‐MF 7‐gene signature and slit guidance ligand 2 fluorescent in situ hybridization, we showed that PMSCs display a perivascular portal distribution in homeostatic liver and largely expand with fibrosis progression, contributing to the myofibroblast populations that form fibrotic septa, preferentially along neovessels, in murine and human liver disorders, irrespective of etiology. We also unraveled a 6‐gene expression signature of HSCs/HSC‐MFs that did not vary in these disorders, consistent with their low proliferation rate.

Conclusions

PMSCs form a small reservoir of expansive myofibroblasts, which, in interaction with neovessels and HSC‐MFs that mainly arise through differentiation from a preexisting pool, underlie the formation of fibrotic septa in all types of liver diseases.
Accurate long‐term prediction of death for patients with cirrhosis
Authors: Goldberg David , Mantero Alejandro , Kaplan David , Delgado Cindy , John Binu , Nuchovich Nadine , Emanuel Ezekiel , Reese Peter P.
Published: March 2022

Background and Aims

Cirrhosis is a major cause of death and is associated with extensive health care use. Patients with cirrhosis have complex treatment choices due to risks of morbidity and mortality. To optimally counsel and treat patients with cirrhosis requires tools to predict their longer‐term liver‐related survival. We sought to develop and validate a risk score to predict longer‐term survival of patients with cirrhosis.

Approach and Results

We conducted a retrospective cohort study of adults with cirrhosis with no major life‐limiting comorbidities. Adults with cirrhosis within the Veterans Health Administration were used for model training and internal validation, and external validation used the OneFlorida Clinical Research Consortium. We used four model‐building approaches including variables predictive of cirrhosis‐related mortality, focused on discrimination at key time points (1, 3, 5, and 10 years). Among 30,263 patients with cirrhosis ≤75 years old without major life‐limiting comorbidities and complete laboratory data during the baseline period, the boosted survival tree models had the highest discrimination, with 1‐year, 3‐year, 5‐year, and 10‐year survival rates of 0.77, 0.81, 0.84, and 0.88, respectively. The 1‐year, 3‐year, and 5‐year discrimination was nearly identical in external validation. Secondary analyses with imputation of missing data and subgroups by etiology of liver disease had similar results to the primary model.

Conclusions

We developed and validated (internally and externally) a risk score to predict longer‐term survival of patients with cirrhosis. This score would transform management of patients with cirrhosis in terms of referral to specialty care and treatment decision‐making for non‐liver‐related care.