bluuebunny/crossref_metadata_2025 huggingface dataset:
FRET‐Based Cathepsin Probes for Simultaneous Detection of Cathepsin B and D Activities
Authors: Zhang Zhengxiao , Nakata Eiji , Shibano Yuya , Morii Takashi
Published: August 2022

Fluorescent cathepsin probes were prepared by modification of peptidic substrates for cathepsin B (CTSB) and cathepsin D (CTSD) with FRET pairs. Fluorophores with distinguishable emission characteristics were applied to CTSB and CTSD probes with their appropriate quenchers to simultaneously monitor the activity of CTSB and/or CTSD. Conjugation of both the CTSB and CTSD probes with short single‐stranded DNA drastically increased their reactivity to cathepsins over the parent probes possibly by improving their solubility. The activity of CTSB and CTSD were simultaneously detected by using these orthogonal FRET‐based cathepsin probes.
Incorporation of an Asymmetric Mo−Fe−S Cluster as an Artificial Cofactor into Nitrogenase
Authors: Tanifuji Kazuki , Jasniewski Andrew J. , Lee Chi Chung , Solomon Joseph B. , Nagasawa Takayuki , Ohki Yasuhiro , Tatsumi Kazuyuki , Hedman Britt , Hodgson Keith O. , Hu Yilin , Ribbe Markus W.
Published: August 2022

Nitrogenase employs a sophisticated electron transfer system and a Mo−Fe−S−C cofactor, designated the M‐cluster [(cit)MoFe7S9C]), to reduce atmospheric N2 to bioaccessible NH3. Previously, we have shown that the cofactor‐free form of nitrogenase can be repurposed as a protein scaffold for the incorporation of a synthetic Fe−S cluster [Fe6S9(SEt)2]4−. Here, we demonstrate the utility of an asymmetric Mo−Fe−S cluster [Cp*MoFe5S9(SH)]3− as an alternative artificial cofactor upon incorporation into the cofactor‐free nitrogenase scaffold. The resultant semi‐artificial enzyme catalytically reduces C2H2 to C2H4, and CN− into short‐chain hydrocarbons, yet it is clearly distinct in activity from its [Fe6S9(SEt)2]4−‐reconstituted counterpart, pointing to the possibility to employ molecular design and cluster synthesis strategies to further develop semi‐artificial or artificial systems with desired catalytic activities.
An oleanolic acid derivative, K73‐03, inhibits pancreatic cancer cells proliferation in vitro and in vivo via blocking EGFR/Akt pathway
Authors: Zhou Zheng , Dong Yaokun , Li Na , Niu Mengyue , Wang Shisheng , Zhou Yuanzhang , Sun Zhaolin , Chu Peng , Tang Zeyao
Published: August 2022

Oleanolic acid (OA) and its derivatives show potent anticancer function. Pancreatic cancer (PC) is the fourth core motive of cancer‐related deaths worldwide. Epidermal growth factor receptor (EGFR) has been implicated in PC and has been validated as a therapeutic target. Our study demonstrated that K73‐03, an OA derivative, was identified as a potent inhibitor of EGFR by using reverse pharmacophore screening and molecular dynamics simulation assays. Moreover, Western blot analysis showed that K73‐03 markedly suppressed the levels of phosphorylated‐EGFR (p‐EGFR) and phosphorylated‐Akt (p‐Akt). The inhibitory effect of K73‐03 on PC cells was assessed in vitro and in vivo. Mechanistically, K73‐03 effectively inhibited the cell proliferation of PC cells, and induced apoptosis and autophagy of ASPC‐1 cells in a dose‐dependent manner. Additionally, pretreatment with chloroquine, an autophagy inhibitor, significantly inhibited K73‐03‐induced autophagy and enhanced K73‐03‐induced apoptotic cell death. K73‐03 also strongly repressed ASPC‐1 cells xenograft growth in vivo. Thus, all these findings provided new clues about OA analog K73‐03 as an effective anticancer agent targeted EGFR against ASPC‐1 cells, it is worth further evaluation in the future.
Estrogen receptor variant ER‐α36 facilitates estrogen signaling via EGFR in glioblastoma
Authors: Qu Chao , Wang Cui , Li Hongyan , Li Ying , Han Chao , Tao Xiaofeng , Guan Xin , Zhang Yejun , Chen Meng , Liu Jing , Zou Wei
Published: August 2022

Glioblastoma (GBM) is a deadly and common primary brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity. Sex differences may play a role in patient outcome. Previous studies showed that ER‐α36, a variant of the estrogen receptor (ER), mediated non‐genomic estrogen signaling and is highly expressed in many ER‐negative malignant tumors. ER‐α36 also associates with epidermal growth factor receptor (EGFR). The primary purpose of this study is to investigate the cross talk between ER‐α36 and EGFR in estrogen‐mediated GBM cell proliferation. Here, we showed that ER‐α36 was highly expressed and confirmed that ER‐α36 co‐labels with EGFR in human GBM samples using immunohistochemical techniques. We also investigated the mechanisms of estrogen‐induced proliferation in ER‐α‐negative cell lines. We found that GBM cells showed varying responsive to mitogenic estrogen signaling which correlated with ER‐α36 expression, and knockdown of ER‐α36 diminished the response. Exposure to estrogen also caused upregulation of cyclin protein expression in vitro. We also found that low concentration of estrogen promoted SRC‐Y‐416 and inhibited SRC‐Y‐527 phosphorylation, corresponding with activated SRC signaling. Inhibiting SRC or EGFR abolished estrogen‐induced mitogenic signaling, including cyclin expression and MAPK phosphorylation. Cumulatively, our results demonstrate that ER‐α36 promotes non‐genomic estrogen signaling via the EGFR/SRC/MAPK pathway in GBM. This may be important for the treatment of ER‐α‐negative GBMs that retain high level of ER‐α36, since estrogen may be a viable therapeutic target for these patients.
Heterobimetallic Gold/Ruthenium Complexes Synthesized via Post‐functionalization and Applied in Dual Photoredox Gold Catalysis
Authors: Bayer Lea , Birenheide Bernhard S. , Krämer Felix , Lebedkin Sergei , Breher Frank
Published: August 2022

The synthesis of heterobimetallic AuI/RuII complexes of the general formula syn‐ and anti‐[{AuCl}(L1∩L2){Ru(bpy)2}][PF6]2 is reported. The ditopic bridging ligand L1∩L2 refers to a P,N hybrid ligand composed of phosphine and bipyridine substructures, which was obtained via a post‐functionalization strategy based on Diels‐Alder reaction between a phosphole and a maleimide moiety. It was found that the stereochemistry at the phosphorus atom of the resulting 7‐phosphanorbornene backbone can be controlled by executing the metal coordination and the cycloaddition reaction in a different order. All precursors, as well as the mono‐ and multimetallic complexes, were isolated and fully characterized by various spectroscopic methods such as NMR, IR, and UV‐vis spectroscopy as well as cyclic voltammetry. Photophysical measurements show efficient phosphorescence for the investigated monometallic complex anti‐[(L1∩L2){Ru(bpy)2}][PF6]2 and the bimetallic analogue syn‐[{AuCl}(L1∩L2){Ru(bpy)2}][PF6]2, thus indicating a small influence of the {AuCl} fragment on the photoluminescence properties. The heterobimetallic AuI/RuII complexes syn‐ and anti‐[{AuCl}(L1∩L2){Ru(bpy)2}][PF6]2 are both active catalysts in the P‐arylation of aryldiazonium salts promoted by visible light with H‐phosphonate affording arylphosphonates in yields of up to 91 %. Both dinuclear complexes outperform their monometallic counterparts.
Modulation of the Sorption Characteristics for an H‐bonded porous Architecture by Varying the Chemical Functionalization of the Channel Walls
Authors: Roques Nans , Tovar‐Molle Anthony , Duhayon Carine , Brandès Stéphane , Spieß Alex , Janiak Christoph , Sutter Jean‐Pascal
Published: August 2022

Five isostructural microporous supramolecular architectures prepared by H‐bonded assembly between the hexa‐anionic complex [Zr2(Ox)7]6− (Ox=oxalate, (C2O4)2−) and tripodal cations (H3‐TripCH2‐R)3+ with R=H, CH3, OH and OBn (Bn=CH2Ph) are reported. The possibility to obtain the same structure using a mixture of tripodal cations with different R group (R=OH and R=CH3) has also been successfully explored, providing a unique example of three‐component H‐bonded porous framework. The resulting SPA‐1(R) materials feature 1D pores decorated by R groups, with apparent pore diameters ranging from 3.0 to 8.5 Å. Influence of R groups on the sorption properties of these materials is evidenced through CO2 and H2O vapor sorption/desorption experiments, as well as with I2 capture/release experiments in liquid media. This study is one of the first to demonstrate the possibility of tuning the porosity and exerting precise control over the chemical functionalization of the pores in a given H‐bonded structure, without modifying the topology of the reference structure, and thus finely adjusting the sorption characteristics of the material.
Nachhaltige Unterrichtsvorschläge zur (Mikro)‐Plastikproblematik
Authors: Kreienhop Nils , Beeken Marco
Published: August 2022

Plastikmüll und Mikroplastik lassen sich mittlerweile selbst an den entlegensten Orten der Erde nachweisen. Auch wenn die konkreten Gefahren und Folgen für Menschen und Tiere noch unbekannt sind, gilt als gesichert, dass der Mensch auch mit der Freisetzung neuartig modifizierter Substanzen einen großen Einfluss auf das ökologische Gleichgewicht der Erde hat. In diesem Artikel wird das Themenfeld (Mikro)‐Plastik im Kontext der Bildung für nachhaltige Entwicklung diskutiert, um darauf aufbauend Impulse für eine erfolgreiche Thematisierung im schulischen Unterricht zu geben. Anhand ausgewählter Experimente für den Chemieunterricht werden wichtige Aspekte wie das Verhalten von Kunststoffen in der Umwelt und die Entwicklung aktueller Lösungsansätze zur Reinigung unserer Umwelt von Plastikpartikeln erörtert. Ziel ist es, junge Menschen für wissenschaftliche Forschung zu begeistern und zu befähigen, sich aktiv an gesellschaftlichen Diskursen für eine nachhaltige Entwicklung zu beteiligen.
Detection and localization of image tampering in digital images with fused features
Authors: Ahmad Mohassin , Khursheed Farida
Published: August 2022

In digital forensics, image tamper detection and localization have attracted increased attention in recent days, where the standard methods have limited description ability and high computational costs. As a result, this research introduces a novel picture tamper detection and localization model. Feature extraction, tamper detection, as well as tamper localization are the three major phases of the proposed model. From the input digital images, a group of features like “Scale‐based Adaptive Speeded Up Robust Features (SA‐SURF), Discrete Wavelet Transform (DWT) based Patched Local Vector Pattern (LVP) features, HoG feature with harmonic mean based PCA and MBFDF” are extracted. Then, with this extracted feature strain the “optimized Convolutional Neural Network (CNN)” will be trained in the tamper detection phase. Since it is the key decision‐maker about the presence/absence of tamper, its weighting parameters are fine‐tuned via a novel improved Sea‐lion Customized Firefly algorithm (ISCFF) model. This ensures the enhancement of detection accuracy. Once an image is recognized to have tampers, then it is essential to identify the tamper localization. In the tamper localization phase, the copy‐move tampers are localized using the SIFT features, splicing tampers are localized using the DBN and the noise inconsistency is localized with a newly introduced threshold‐based tamper localization technique. The simulation outcomes illustrate that the adopted model attains better tamper detection as well as localization performance over the existing methods.
Prediction of the Phase Composition Profile of Three‐Compound Mixtures in Liquid‐Liquid Equilibrium: A Chemoinformatics Approach
Authors: Carrera Gonçalo V. S. M. , Cruz Mariana L. , Klimenko Kyrylo , Esperança José M. S. S. , Aires‐de‐Sousa João
Published: August 2022

Machine‐learning models were developed to predict the composition profile of a three‐compound mixture in liquid‐liquid equilibrium (LLE), given the global composition at certain temperature and pressure. A chemoinformatics approach was explored, based on the MOLMAP technology to encode molecules and mixtures. The chemical systems involved an ionic liquid (IL) and two organic molecules. Two complementary models have been optimized for the IL‐rich and IL‐poor phases. The two global optimized models are highly accurate, and were validated with independent test sets, where combinations of molecule1+molecule2+IL are different from those in the training set. These results highlight the MOLMAP encoding scheme, based on atomic properties to train models that learn relationships between features of complex multi‐component chemical systems and their profile of phase compositions.
In SilicoInteractions of the Components from theSchinus terebinthifoliusExtract with Human Tyrosinase
Authors: Bezerra Julia N. , Spadeto João Paulo M. , Daré Joyce K. , Almeida Wanda Pereira , Freitas Matheus P. , Cormanich Rodrigo A.
Published: August 2022

The anti‐tyrosinase activity of the leaf extract ofSchinus terebinthifolius, also known as Brazilian peppertree, was evaluated using multiplein silicoapproaches, such as molecular homology, molecular docking, MM‐GBSA, molecular dynamics, MM‐PBSA, QSAR, and skin permeability predictions. With these computational tools, the compounds that downregulate tyrosinase enzyme activity could be evaluated, and more potent molecules could be identified. The results indicated that various compounds, especially luteolin, are accountable for the anti‐tyrosinase activity ofS. terebinthifolius. For cosmetic application, further studies with luteolin are especially recommended, for having presented a good performance both in theoretical inhibition (30.92 kJ mol−1) and skin permeability (LogKp=−6.62 cm−1).
Tailoring Electronic Structure of Copper Twin Boundaries Toward Highly Efficient Nitrogen Reduction Reaction
Authors: Dai Tianyi , Wang Zhili , Wen Zi , Lang Xingyou , Jiang Qing
Published: August 2022

Electrocatalytic nitrogen reduction reaction (NRR) is a promising technique to resolve the carbon emission in energy‐intensive ammonia production in industry, which, however, is hampered by the lack of efficient catalysts. Herein, by density functional theory (DFT) calculations, it was demonstrated that the twin boundary (TB) of copper could effectively relieve the N2 activation barrier in NRR. The d orbitals overlapping mode on twin boundary edge (TBE) was quite different from that on its basal plane, where the dxz, dyz orbitals induced unbalanced electron occupation states in π*–px, py orbitals of the adsorbed N2, which could effectively activate the N≡N bond. Particularly, doping transition metals (TMs) onto Cu‐TBE could further improve its NRR catalytic behavior, and the Re−Cu(111)‐TBE showed the lowest limiting potential (UL) of −0.27 V among 25 considered TMs. Moreover, the Re−Cu(111)‐TBE could effectively suppress the competing hydrogen evolution reaction even under working potentials. This work has provided a deep understanding of TB in catalysis from an electronic structure point of view, paving a way for further studies of TB into advanced utilization.
Nitrogen Disturbance Awakening the Intrinsic Activity of Nickel Phosphide for Boosted Hydrogen Evolution Reaction
Authors: Yang Caixia , Wang Zhiqiang , Li Zhendong , Pan Yichen , Jiang Linwei , Li Caicai , Wang Chao , Sun Qingfeng
Published: August 2022

Invited for this month′s cover is the group of Qingfeng Sun at the Zhejiang A&F University. The image shows that the N‐doped Ni2P exhibits excellent electrocatalytic activity for hydrogen evolution reaction (HER). The Research Article itself is available at 10.1002/cssc.202200072.
CRMP2 and CRMP4 are required for the formation of commissural tracts in the developing zebrafish forebrain
Authors: Guo Youjia , Oliveros Carolina Fiallos , Ohshima Toshio
Published: August 2022

Axonal connections between the two sides of the brain are essential for processing sensorimotor functions, especially in animals with bilateral symmetry. The anterior commissure and postoptic commissure are two crucial axonal projections that develop early in the zebrafish central nervous system. In this study, we characterized the function of collapsin response mediator protein 2 (CRMP2) and CRMP4 in patterning the development of the anterior and postoptic commissures by analyzing morpholino‐knockdown zebrafish morphants and CRISPR/Cas9‐edited gene‐knockout mutants. We observed a loss of commissural structures or a significant reduction in axon bundles connecting the two hemispheres, but the defects could be largely recovered by co‐injecting CRMP2 or CRMP4 mRNA. Loss of both CRMP2 and CRMP4 function resulted in a synergistic increase in the number of commissural defects. To elucidate the mechanism by which CRMP2 and CRMP4 provide guidance cues for the development of the anterior and postoptic commissures, we included neuropilin 1a (Nrp1a) morphants and double morphants (CRMP2/Nrp1a and CRMP4/Nrp1a) for analysis. Our experimental results indicated that CRMP2 and CRMP4 might mediate their activities through the common semaphorin 3/Nrp1a signaling pathway.
Determinants of acute kidney injury in children with new onset type 1 diabetes: A cohort study of children aged <15 years: Auckland, New Zealand (2006–2016)
Authors: Pittman Fiona , Di Somma Harry , Wong William , Prestidge Chanel , Reed Peter , Gunn Alistair J. , Jefferies Craig
Published: August 2022

Objective

Acute kidney injury (AKI) may contribute to the risk of diabetic kidney disease, however, there have been limited studies of the incidence of AKI in well‐defined populations of children with type 1 diabetes. The aim was to quantify AKI in children presenting with new onset type 1 diabetes from the regional paediatric diabetes service, Auckland, New Zealand.

Research Design and Methods

A retrospective analysis of a prospectively identified cohort study of children and adolescents presenting from 2006 to 2016 with type 1 diabetes aged <15 years. AKI was defined using Kidney Disease/Improving Global Outcomes serum creatinine criteria.

Results

There were 586 subjects: 52% male, with mean (SD) age 8.9 (3.8) years, with 151(25.8%) in diabetic ketoacidosis (DKA). AKI was present in 47%, 278/586, AKI was increased in those with DKA (125/151 (83%) DKA vs. 153/435 (35%) no‐DKA). Univariable analysis showed that increased HbA1c, higher glucose levels, lower BMI SDS, lower bicarbonate and pH levels were all associated with AKI (p < .001). In multivariable analysis, AKI was associated with DKA and higher glucose levels independently. The majority of cases were stage 1 (203/278 [73%]), or stage 2 AKI 62/278 (22%). 13/278 (5%) had severe, Stage 3 AKI, and all presented in DKA (13/151 (8%) vs. 0/435 (0%) without DKA, p < .001).

Conclusion

In this regional paediatric, cohort AKI is a common complication of children presenting with new onset type 1 diabetes. AKI is independently associated with higher glucose levels and DKA, and all cases of Stage 3 AKI were associated with DKA.
Removal of heavy metals from industrial wastewater using microbial fuel cell
Authors: Al‐Asheh Sameer , Bagheri Marzieh , Aidan Ahmad
Published: August 2022

Removal efficiency of gold from a solution of pure tetrachloroaurate ions was investigated using microbial fuel cell (MFC) technology. The effects of type of catholyte solution and initial gold concentration on the removal efficiency were considered. Due to its presence at high levels in the gold wastewater, the effect of copper ions on the removal efficiency of the gold ions was also studied. The effects of pH and initial biomass concentration on the gold removal efficiency was also determined. The results showed that after 5 h contact time, 95% of gold removal efficiency from a wastewater containing 250 ppm of initial gold ions at ambient temperature using 80 g/L yeast concentration was achieved. After 48 h of the cell's operation under the same condition, 98.86% of AuCl4– ions were successfully removed from the solution. At initial gold concentration in the waste solution of 250 ppm, pH 2, and initial yeast concentration of 80 g/L, 100% removal efficiency of the gold was achieved. On the other hand, the most suitable condition for copper removal was found at a pH of 5.2, where 53% removal efficiency from the waste solution was accomplished.
Let There Be Charge: Using Streetlights to Enable Vehicle Electrification
Authors: Simović Uroš , Clémençon‐Charles Elena , Flignor Max
Published: August 2022

As electric vehicle (EV) adoption continues to grow, a significant investment in public charging infrastructure is needed. And investment in charging infrastructure is underway in parts of the country following targets set by the Biden Administration and American automakers for EVs to comprise up to 50 percent of new vehicle sales by 2030. This is in addition to the Infrastructure Investment and Jobs Act funding, which allocates $7.5 billion for programs and grants focused on expanding EV charging infrastructure, with a goal of reaching 500,000 public electric chargers in the United States.
Postoperative morphologic changes of the isthmocele and clinical impact in patients treated by channel‐like (360°) hysteroscopic technique
Authors: Casadio Paolo , Raffone Antonio , Alletto Andrea , Filipponi Francesco , Raimondo Diego , Arena Alessandro , La Rosa Mariangela , Virgilio Agnese , Franceschini Camilla , Gubbini Giampietro , Franchini Mario , Paradisi Roberto , Lenzi Jacopo , Travaglino Antonio , Mollo Antonio , Carugno Josè , Seracchioli Renato
Published: August 2022

Objective

To evaluate the changes in (1) residual myometrial thickness (RMT), (2) cesarean scar defect (CSD) size, and (3) clinical symptoms, before and after channel‐like (360°) hysteroscopic resection for the treatment of CSD.

Methods

A single‐center, observational, prospective, cohort study was carried out enrolling all symptomatic patients of childbearing age, diagnosed with CSD and routinely scheduled for channel‐like (360°) hysteroscopic resection from July 2020 to July 2021 at the Division of Gynecology and Human Reproduction Physiopathology, Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero‐Univeristaria di Bologna. University of Bologna, Italy. The primary outcome was the difference in mean RMT before and after the procedure. Secondary outcomes were the differences before and 4 months after the surgery in: (1) CSD size measured by transvaginal ultrasound, (2) visual analog scale (VAS) scores for the symptoms, and (3) abnormal uterine bleeding (AUB) rate. Lastly, patients' satisfaction was assessed by the global impression of improvement (PGI‐I) score.

Results

We found a significant difference before and after the procedure in: (1) mean RMT (+2.0 mm; P < 0.001); mean size of the CSD (base: +1.6 mm; height: −2.5 mm; transverse diameter: −3.2 mm; volume: −263.7 mm3; P < 0.001); (2) mean VAS score for dyspareunia (−5.84; P < 0.001), dysmenorrhea (−8.94; P < 0.001), pelvic pain (−2.94; P < 0.001); (3) AUB rate (91% vs. 3%; P < 0.001). Lastly, the mean PGI‐I score ± SD was 1.7 ± 0.9.

Conclusion

Channel‐like (360°) hysteroscopic resection for the treatment of patients with symptomatic CSD may lead to an increase in RMT, decrease in CSD, and improvement of symptoms after the procedure, with high patient satisfaction.
Succinate dehydrogenase‐deficient malignant paraganglioma complicated by succinate dehydrogenase‐deficient renal cell carcinoma
Authors: Yamaguchi Yoshitomo , Yokoyama Minato , Takemoto Akira , Nakamura Yuki , Fukuda Shohei , Uehara Sho , Tanaka Hajime , Yoshida Soichiro , Matsuoka Yoh , Fujii Yasuhisa
Published: August 2022

Introduction

SDH Gene mutation is known to be a common cause of pheochromocytoma/paraganglioma and renal cell carcinoma. Here, we report a case of succinate dehydrogenase B‐deficient paraganglioma, which has a high risk of metastasis and recurrence, complicated by succinate dehydrogenase‐deficient renal cell carcinoma, which is rare and accounts for approximately 0.1% of all renal cell carcinomas.

Case presentation

A 50‐year‐old man underwent en bloc resection of a retroperitoneal tumor and the right kidney for retroperitoneal paraganglioma and right renal tumor. Both tumors showed negative expressions of succinate dehydrogenase B in immunostaining. The patient was diagnosed with succinate dehydrogenase‐deficient paraganglioma and succinate dehydrogenase‐deficient renal cell carcinoma. Seventeen months later, retroperitoneal lymphadenectomy revealed lymph node metastasis of the paraganglioma. Deletion of the SDHB gene was revealed by genome sequencing of the lymph node.

Conclusion

This is the first reported case of synchronously diagnosed succinate dehydrogenase‐deficient paraganglioma and succinate dehydrogenase‐deficient renal cell carcinoma.
Dentoalveolar Defects of Hypophosphatasia are Recapitulated in a Sheep Knock-In Model
Authors: Mohamed Fatma F. , Chavez Michael B. , Huggins Shannon , Bertels Joshua , Falck Alyssa , Suva Larry J. , Foster Brian L. , Gaddy Dana
Published: August 2022

Hypophosphatasia (HPP) is the inherited error-of-metabolism caused by mutations in ALPL, reducing the function of tissue-nonspecific alkaline phosphatase (TNAP/TNALP/TNSALP). HPP is characterized by defective skeletal and dental mineralization and is categorized into several clinical subtypes based on age of onset and severity of manifestations, though premature tooth loss from acellular cementum defects is common across most HPP subtypes. Genotype–phenotype associations and mechanisms underlying musculoskeletal, dental, and other defects remain poorly characterized. Murine models that have provided significant insights into HPP pathophysiology also carry limitations including monophyodont dentition, lack of osteonal remodeling of cortical bone, and differing patterns of skeletal growth. To address this, we generated the first gene-edited large-animal model of HPP in sheep via CRISPR/Cas9-mediated knock-in of a missense mutation (c.1077C>G; p.I359M) associated with skeletal and dental manifestations in humans. We hypothesized that this HPP sheep model would recapitulate the human dentoalveolar manifestations of HPP. Compared to wild-type (WT), compound heterozygous (cHet) sheep with one null allele and the other with the targeted mutant allele exhibited the most severe alveolar bone, acellular cementum, and dentin hypomineralization defects. Sheep homozygous for the mutant allele (Hom) showed alveolar bone and hypomineralization effects and trends in dentin and cementum, whereas sheep heterozygous (Het) for the mutation did not exhibit significant effects. Important insights gained include existence of early alveolar bone defects that may contribute to tooth loss in HPP, observation of severe mantle dentin hypomineralization in an HPP animal model, association of cementum hypoplasia with genotype, and correlation of dentoalveolar defects with alkaline phosphatase (ALP) levels. The sheep model of HPP faithfully recapitulated dentoalveolar defects reported in individuals with HPP, providing a new translational model for studies into etiopathology and novel therapies of this disorder, as well as proof-of-principle that genetically engineered large sheep models can replicate human dentoalveolar disorders. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Genetic polymorphisms in the mismatch repair pathway (MMR) genes contribute to hematological and gastrointestinal toxicity in North Indian lung cancer patients treated with platinum‐based chemotherapy
Authors: Singh Sidhartha , Singh Navneet , Sharma Siddharth
Published: August 2022

The present study investigated the relationship between MLH1, MSH2, MSH3, and MSH6 polymorphisms and toxicity due to platinum‐based doublet chemotherapy for North Indian lung cancer patients. Polymerase chain reaction‐restriction fragment length polymorphism technique was used to assess the polymorphism. For MSH2 IVS1 + 9G > C polymorphism variant type genotype reported a 1.4‐fold increased risk of anemia (AOR = 1.4; 95% CI = 0.98–1.99; p = 0.04) and decreased risk of developing gastrointestinal toxicity (diarrhea) (AOR = 0.53; 95% CI = 0.28–1.01; p = 0.04). Further, we also reported a 10‐fold increased risk of developing severe grade anorexia in combined genotype (GC + CC) (AOR = 9.18; 95% CI = 0.98–86.1; p = 0.05). For MSH2 T > C/‐6 polymorphism, variant type reported a 3‐fold and 2‐fold increased risk of developing severe grade leukopenia (AOR = 3.37; 95% CI = 1.44–7.88; p = 0.005) and neutropenia respectively (AOR = 2.23; 95% CI = 1.07–4.66; p = 0.03). For MSH3 G > A polymorphism, heterozygous (GA) and combined genotype (GA + AA) reported a 7‐fold and 6‐fold increased risk of developing anemia (AOR = 7.23; 95% CI = 1.51–34.6; p = 0.01, AOR = 6.39; 95% CI = 1.53–26.6; p = 0.01). Our results suggest that polymorphisms in DNA mismatch repair genes are associated with hematological, and gastrointestinal toxicities and might be considered a predictor for pretreatment evaluation in lung cancer patients.
Investigation of the effect of boron on thyroid functions and biochemical parameters in hypothyroid induced‐rats
Authors: Kan Fahriye , Kucukkurt Ismail
Published: August 2022

In the study investigating the effects of boron on thyroid hormones and some biochemical parameters in hypothyroid rats, 49 Wistar Albino male rats were divided into seven groups; (Control (C), Hypothyroidism (H), boron groups (B10, and B20), hypothyroid + boron groups (HB10 and HB20), and Treatment (T). Four groups (H, HB10, HB20, and T) were administered 10 mg/kg (B10 and HB10), 20 mg/kg (B20 and HB20) boron for 3 weeks, respectively after hypothyroidism was induced using Propycil® containing propylthiouracil (PTU). Thyroid hormone analyses and biochemical measurements were made from the serum and thyroid gland tissue was examined histopathologically. According to the findings, the fT3 level increased in the B10 group compared to the control group (p < 0.05). While AST, ALT, and ALP activities were found to be higher in the hypothyroid group than in the control group, AST and ALP activities in the HB10 and HB20 groups decreased to values close to the control group. Total cholesterol levels were found to be lower in boron‐given groups compared to control and hypothyroid groups (p < 0.05). Sodium iodide symporter (NIS) immunoreactivity was found to be high in hypothyroid rat groups. As a result, it was observed that the increased AST and ALP activities in rats decreased with boron administration. The serum hormone levels measured in the study are not sufficient to understand the effect of boron on the thyroid gland, and it was concluded that further studies at the molecular level are needed to understand the effects of boron on the thyroid gland.
Hepcidin regulates neuronal ferroptosis: A mechanism for postoperative cognitive dysfunction
Authors: Shen Heping , Zhai Liping , Wang Genghuan
Published: August 2022

Toll‐like receptor 4 (TLR4) is a signaling molecule responsible for the expression of hepcidin (Hepc), while myeloid differentiation protein 2 (MD2) is one major accessory protein of TLR4. This study focuses on exploring the neurocyte ferroptosis mediated through the regulation of Hepc expression by MD2, which is also one of the mechanisms for postoperative cognitive dysfunction (POCD). An experimental study was carried out using aged wild‐type (Wt) and MD2 transgenic (Tg) mice. The neurocyte ferroptosis and POCD in the mice were assessed following splenectomy. Morris water maze was utilized to assess the neurocognitive abilities, hematoxylin and eosin (H&E) assay was performed to examine histopathology, and Nissl staining was used to evaluate the neurocyte damage. The Fe2+, superoxide dismutase(SOD), malondialdehyde (MDA), glutathione(GSH), and glutathione peroxidase 4 (GPX4) levels were determined with kits. The expressions of transferrin receptor (TFR), Hepc, and MD2 were measured by Western blotting, while the expressions of TFR and GPX4 were measured by immunohistochemical staining. In Tg mice, we observed neurocyte ferroptosis and POCD following treatment with an MD2 inhibitor. PC12 cells were used as a neurocyte model. Ferroptosis was induced after treatment with an MD2 inhibitor, and the cell viability was assayed by Cell Counting Kit‐8. Immunofluorescent staining was used to measure the TFR and GPX4 expressions. Meanwhile, the intracellular levels of Fe2+, SOD, MDA, GSH, GPX4, and Hepc were also measured. POCD occurred among aged Wt and Tg mice. The Tg‐POCD mice had more apparent POCD than the Wt‐POCD mice. Nissl and H&E staining revealed neurocyte damage in brain tissues. Besides this, the Fe2+ and MDA expressions were upregulated, while the SOD, GSH, and GPX4 expressions were downregulated. Elevations in tissue levels of TFR, Hepc, and MD2 were observed, which were higher than those of Wt‐POCD mice. After treatment with an MD2 inhibitor, the POCD could be prominently ameliorated in Tg‐POCD mice, the Fe2+ and MDA levels could be reduced, while the SOD, GSH, and GPX4 levels could be elevated. In the PC12 model, ferroptosis could be suppressed by inhibiting the expression of MD2. MD2 is capable of regulating neurocyte ferroptosis by promoting Hepc expression, which has great potential as a novel target for POCD therapy.
White to brown adipocyte transition mediated by Apigenin via VEGF‐PRDM16 signaling
Authors: Sreekumar Sreelekshmi , Vijayan Vinu , Singh Fathe , Sudhakar Manu , Lakra Rachita , Korrapati Purna Sai , Kiran Manikantan Syamala
Published: August 2022

The dysregulated energy metabolism in white adipose tissues results in derangement of biological signaling resulting in obesity. Lack of vascularization in these white adipose tissues is one of the major reasons for dysregulated energy metabolism. Not much work has been done in this direction to understand the role of angiogenesis in white adipose tissue metabolism. In the present study, we evaluated the effect of angiogenic modulator in the metabolism of white adipocyte (WAC). Bioactive Apigenin was selected and its angiogenic ability was studied. Apigenin was shown to be highly proangiogenic hence the effect of Apigenin on de novo and trans‐differentiation of WAT was studied. Apigenin showed enhanced de novo differentiation and trans‐differentiation of mouse WAC into brown‐like phenotype. To understand the effect of Apigenin on adipose tissue vasculature, coculture studies were conducted. Cross talk between endothelial cell and adipocytes were observed in coculture studies. Gene expression studies of cocultured cells revealed that browning of WAC occurred by triggering the expression of Vascular endothelial growth factor A. The study provides a new insight for inducing metabolic shift in WACs by modulation of angiogenesis in WAC microenvironment by the upregulation of PRDM16 cascade to trigger browning for the treatment of obesity.
Altered muscle oxidative phenotype impairs exercise tolerance but does not improve after exercise training in multiple sclerosis
Authors: Spaas Jan , Goulding Richie P. , Keytsman Charly , Fonteyn Lena , van Horssen Jack , Jaspers Richard T. , Eijnde Bert O. , Wüst Rob C.I.
Published: August 2022

Background

Patients with multiple sclerosis (MS) experience reduced exercise tolerance that substantially reduces quality of life. The mechanisms underpinning exercise intolerance in MS are not fully clear. This study aimed to determine the contributions of the cardiopulmonary system and peripheral muscle in MS‐induced exercise intolerance before and after exercise training.

Methods

Twenty‐three patients with MS (13 women) and 20 age‐matched and sex‐matched healthy controls (13 women) performed a cardiopulmonary exercise test. Muscle fibre type composition, size, succinate dehydrogenase (SDH) activity, capillarity, and gene expression and proteins related to mitochondrial density were determined in vastus lateralis muscle biopsies. Nine MS patients (five women) were re‐examined following a 12 week exercise training programme consisting of high‐intensity cycling interval and resistance training.

Results

Patients with MS had lower maximal oxygen uptake compared with healthy controls (V̇O2peak, 25.0 ± 8.5 vs. 35.7 ± 6.4 mL/kg/min, P < 0.001). The lower gas exchange threshold (MS: 14.5 ± 5.5 vs. controls: 19.7 ± 2.9 mL/kg/min, P = 0.01) and slope of V̇O2 versus work rate (MS: 9.5 ± 1.7 vs. controls: 10.8 ± 1.1 mL/min/W, P = 0.01) suggested an intramuscular contribution to exercise intolerance in patients with MS. Muscle SDH activity was 22% lower in MS (P = 0.004), and strongly correlated with several indices of whole‐body exercise capacity in MS patients (e.g. V̇O2peak, Spearman's ρ = 0.81, P = 0.002), but not healthy controls (ρ = 0.24, P = 0.38). In addition, protein levels of mitochondrial OXPHOS complexes I (−40%, P = 0.047) and II (−45%, P = 0.026) were lower in MS patients versus controls. Muscle capillary/fibre ratio correlated with V̇O2peak in healthy controls (ρ = 0.86, P < 0.001) but not in MS (ρ = 0.35, P = 0.22), and did not differ between groups (1.41 ± 0.30 vs. 1.47 ± 0.38, P = 0.65). Expression of genes involved in mitochondrial function, such as PPARA, PPARG, and TFAM, was markedly reduced in muscle tissue samples of MS patients (all P < 0.05). No differences in muscle fibre type composition or size were observed between groups (all P > 0.05). V̇O2peak increased by 23% following exercise training in MS (P < 0.001); however, no changes in muscle capillarity, SDH activity, gene or protein expression were observed (all P > 0.05).

Conclusions

Skeletal muscle oxidative phenotype (mitochondrial complex I and II content, SDH activity) is lower in patients with MS, contributing to reduced exercise tolerance. However, skeletal muscle mitochondria appeared resistant to the beneficial effects of exercise training, suggesting that other physiological systems, at least in part, drive the improvements in exercise capacity following exercise training in MS.
Quartic graphs with minimum spectral gap
Authors: Abdi Maryam , Ghorbani Ebrahim
Published: August 2022

Aldous and Fill conjectured that the maximum relaxation time for the random walk on a connected regular graph with vertices is . This conjecture can be rephrased in terms of the spectral gap as follows: the spectral gap (algebraic connectivity) of a connected ‐regular graph on vertices is at least , and the bound is attained for at least one value of . We determine the structure of connected quartic graphs on vertices with a minimum spectral gap which enables us to show that the minimum spectral gap of connected quartic graphs on vertices is . From this result, the Aldous–Fill conjecture follows for .
Effects of boosted mRNA and adenoviral‐vectored vaccines on immune responses to omicron BA.1 and BA.2 following the heterologous CoronaVac/AZD1222 vaccination
Authors: Suntronwong Nungruthai , Kanokudom Sitthichai , Auphimai Chompoonut , Assawakosri Suvichada , Thongmee Thanunrat , Vichaiwattana Preeyaporn , Duangchinda Thaneeya , Chantima Warangkana , Pakchotanon Pattarakul , Chansaenroj Jira , Puenpa Jiratchaya , Nilyanimit Pornjarim , Srimuan Donchida , Thatsanatorn Thaksaporn , Sudhinaraset Natthinee , Wanlapakorn Nasamon , Mongkolsapaya Juthathip , Poovorawan Yong
Published: August 2022

The coronavirus 2019 omicron variant has surged rapidly and raises concerns about immune evasion even in individuals with complete vaccination, because it harbors mutations. Here we examine the capability of booster vaccination following CoronaVac/AZD1222 prime to induce neutralizing antibodies (NAbs) against omicron (BA.1 and BA.2) and T‐cell responses. A total of 167 participants primed with heterologous CoronaVac/AZD1222 for 4–5 months were enrolled, to receive AZD1222, BNT162b2, or mRNA‐1273 as a third dose. Reactogenicity was recorded. Immunogenicity analyses of severe acute respiratory syndrome coronavirus 2‐binding antibodies were measured using enzyme‐linked immunosorbent assay. The NAb titers against omicron BA.1 and BA.2 were determined using the focus reduction neutralization test (FRNT50) and total interferon‐γ responses were measured to observe the T‐cell activation. A substantial loss in neutralizing potency to omicron variant was found at 4–5 months after receiving the heterologous CoronaVac/AZD1222. Following booster vaccination, a significant increase in binding antibodies and neutralizing activities toward delta and omicron variants was observed. Neutralization to omicron BA.1 and BA.2 were comparable, showing the highest titers after boosted mRNA‐1273 followed by BNT162b2 and AZD1222. In addition, individuals boosted with messenger RNA (mRNA) vaccines develop a T‐cell response to spike protein, whereas those boosted with AZD1222 did not. Reactogenicity was mild to moderate without serious adverse events. Our findings demonstrated that mRNA booster vaccination is able to overcome waning immunity to provide antibodies that neutralize omicron BA.1 and BA.2, as well as a T‐cell response.
Label‐free surface‐enhanced Raman spectroscopy detection of prostate cancer combined with multivariate statistical algorithm
Authors: Zhao Xin , Xu Qingjiang , Lin Yamin , Du Weiwei , Bai Xin , Gao Jiamin , Li Tao , Huang Yimei , Yu Yun , Wu Xiang , Lin Juqiang
Published: August 2022

The purpose of this study was to detect human plasma for screening prostate cancer (PCa) and benign prostatic hyperplasia (BPH) based on surface‐enhanced Raman spectroscopy (SERS) and multivariate statistical algorithms. The test was to detect 106 plasma samples, which originated from 39 normal subjects, 26 patients with PCa and 41 patients with BPH. Significant differences in peak intensity at 495, 636, 1135, 1205, and 1675 cm−1 can be observed from the difference spectrogram, which contributes to initially distinguish the cancer group from the normal group. Then, the multivariate statistical techniques, including principal component analysis (PCA) and linear discriminant analysis (LDA) diagnostic algorithms, as well as recursive weighted partial least square (PLS) method and support vector machine (SVM) algorithm, were used to analyze the spectral data. For PCa versus normal group and BPH versus normal group, the classification accuracy of PCA‐LDA was 96.80% and 97.50%, respectively, and the classification accuracy of PLS‐SVM was 100.00% and 100.00%, respectively. In the diagnosis of PCa and BPH, the sensitivity, specificity and accuracy of PCA‐LDA were 65.40%, 75.60%, and 71.06% respectively, and the area under the curve (AUC) value of the receiver operating characteristic (ROC) curve was 0.788, while the sensitivity, specificity and accuracy of PLS‐SVM were 88.46%, 87.80%, and 88.06%, respectively, and the AUC value was 0.881. The diagnostic results of PLS‐SVM are better than PCA‐LDA, which supported that PLS‐SVM algorithm has greater potential than PCA‐LDA algorithm in the pre‐diagnosis and screening of PCa.
Physicochemical characterization and fatty acid profiles of testa oils from various coconut (Cocos nucifera L.) genotypes
Authors: Shunmugiah Veluchamy Ramesh , Mary Rose , Beegum Puthiya P. Shameena , Pandiselvam Ravi , Padmanabhan Sugatha , Sathyan Neenu , Shil Sandip , Niral Vittal , Musuvadi Ramarathinam Manikantan , Lokesha Ankanahalli Narayanashetty , Shivashankara Kodathalu Seetharamaiah , Hebbar Kukkehalli Balachandra
Published: August 2022

BACKGROUND

Cocos nucifera (L.) is an important plantation crop with immense but untapped nutraceutical potential. Despite its bioactive potential, the biochemical features of testa oils of various coconut genotypes are poorly understood. Hence, in this study, the physicochemical characteristics of testa oils extracted from six coconut genotypes – namely West Coast Tall (WCT), Federated Malay States Tall (FMST), Chowghat Orange Dwarf (COD), Malayan Yellow Dwarf (MYD), and two Dwarf × Dwarf (D × D hybrids) viz., Cameroon Red Dwarf (CRD) × Ganga Bondam Green Dwarf (GBGD) and MYD × Chowghat Green Dwarf (CGD) – were analyzed.

RESULTS

The proportion of testa in the nuts (fruits) (1.29–3.42%), the proportion of oil in the testa (40.97–50.56%), and biochemical components in testa oils – namely proxidant elements Fe (34.17–62.48 ppm) and Cu (1.63–2.77 ppm), and the total phenolic content (6.84–8.67 mg GAE/100 g), and phytosterol content (54.66–137.73 mg CE/100 g) varied depending on the coconut genotypes. The saturated fatty acid content of testa oils (67.75 to 78.78%) was lower in comparison with that of coconut kernel oils. Similarly, the lauric acid (26.66–32.04%), myristic (18.31–19.60%), and palmitic acid (13.43–15.71%,) content of testa oils varied significantly in comparison with the coconut kernel oils (32–51%, 17–21% and 6.9–14%, respectively). Liquid chromatography–mass spectrometry (LC–MS) analysis revealed the presence of 18 phenolic acids in coconut testa oil. Multivariate analysis revealed the biochemical attributes that defined the principal components loadings. Hierarchical clustering analysis of the genotypes showed two distinct clusters.

CONCLUSION

This study reveals the genotypic variations in the nutritionally important biochemical components of coconut testa oils. The relatively high concentration of polyunsaturated fatty acids (PUFA) and polyphenol content in testa oils warrant further investigation to explore their nutraceutical potential. © 2022 Society of Chemical Industry.
Heterologous expression of C30 carotenoid biosynthetic gene crtNM from Lactiplantibacillus plantarum
Authors: Gou Zongqin , Song Xin , Wang Guangqiang , Xia Yongjun , Ai Lianzhong , Xiong Zhiqiang
Published: August 2022

BACKGROUND

Probiotic lactic acid bacterium Lactiplantibacillus plantarum is widely used in the dairy and other fermented food industries. L. plantarum AR113 harbors a C30 carotenoid operon crtNM based on genomic analysis, but the yield of C30 carotenoid is only 8.1 μg g‐1 DCW.

RESULTS

To improve the productivity of C30 carotenoid, crtNM from L. plantarum AR113 was cloned and reconstructed in Escherichia coli BL21(DE3). The proteins crtN and crtM were successfully expressed based on a sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS‐PAGE) analysis, and the carotenoid was detected using high‐performance liquid chromatography (HPLC) and liquid chromatography–mass spectrometry (LC–MS). In comparison with the constitutive promoter P44, the use of the inducible T7 promoter significantly increased the carotenoid content in E. coli. The fermentation conditions were also optimized with induction by 0.5 mmol/L IPTG at 20 °C for 7 h. The yield of C30 carotenoid reached 154.5 μg g‐1 DCW, which was 18‐fold higher than that of L. plantarum AR113. The 2,2‐diphenyl‐1‐picryl (DPPH) and 2,2′‐azino‐bis (3‐ethylbenzothiazoline‐6sulfonic acid (ABTS) radical scavenging capacity of C30 carotenoids synthesized by heterologous expression in E. coli was also higher than that of the antioxidant food additive butylated hydroxytoluene.

CONCLUSIONS

Our findings suggest that E. coli has strong potential as a basic chassis for the production of C30 carotenoids from Lactiplantibacillus with high antioxidant activity. © 2022 Society of Chemical Industry.
Treatment delay and treatment pattern modifications among epithelial ovarian cancer patients during the COVID‐19 pandemic: A retrospective cohort study
Authors: Moterani Vinicius Cesar , Moterani Nino Jose Wilson , Candido dos Reis Francisco Jose
Published: August 2022

Background and Objectives

The coronavirus disease 2019 (COVID‐19) pandemic disrupted healthcare access and medical treatment, including oncological care. Treatment delay in ovarian cancer could impact survival. We aimed to assess if there were delays and treatment changes in a cohort of epithelial ovarian cancer patients.

Methods

A retrospective cohort of epithelial ovarian cancer patients included cases diagnosed during the first 22 months of the COVID‐19 pandemic in the state of Sao Paulo and those diagnosed in the 22 months preceding the outbreak. Time‐to‐treat was measured in days. In each group, surgery and chemotherapy proportions were assessed according to healthcare insurance status.

Results

A 56.2% reduction in epithelial ovarian cancer diagnosis was identified during the pandemic group compared to the prepandemic group; fewer patients were diagnosed in stage I (p < 0.01). Time‐to‐treat increased from 18.9 to 23 days (p < 0.01). Surgery in the public sector fell from 74.6% to 65.3% during the pandemic, compared to 87.1% to 68.8% in the private sector.

Conclusion

There were fewer overall diagnoses, reduced stage I diagnosis, increased time‐to‐treat, and a reduction in the proportion of patients submitted to surgery. Brazil's public healthcare system demonstrated a higher resiliency to treatment change than the private sector.