bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biohybrid 3D Printing of a Tissue‐Sensor Platform for Wireless, Real‐Time, and Continuous Monitoring of Drug‐Induced Cardiotoxicity
Authors: Yong Uijung , Kim Donghwan , Kim Hojoong , Hwang Dong Gyu , Cho Sungkeon , Nam Hyoryung , Kim Sejin , Kim Taeyeong , Jeong Unyong , Kim Keehoon , Chung Wan Kyun , Yeo Woon‐Hong , Jang Jinah 
Published: December 2022

AbstractDrug‐induced cardiotoxicity is regarded as a major hurdle in the early stages of drug development. Although there are various methods for preclinical cardiotoxicity tests, they cannot completely predict the cardiotoxic potential of a compound due to the lack of physiological relevance. Recently, 3D engineered heart tissue (EHT) has been used to investigate cardiac muscle functions as well as pharmacological effects by exhibiting physiological auxotonic contractions. However, there is still no adequate platform for continuous monitoring to test acute and chronic pharmacological effects in vitro. Here, a biohybrid 3D printing method for fabricating a tissue‐sensor platform, composed of a bipillar‐grafted strain gauge sensor and EHT, is first introduced. Two pillars are three‐dimensionally printed as grafts onto a strain gauge‐embedded substrate to promote the EHT contractility and guide the self‐assembly of the EHTs along with the strain gauge. In addition, the integration of a wireless multi‐channel electronic system allows for continuous monitoring of the EHT contractile force by the tissue‐sensor platform and, ultimately, for the observation of the acute and chronic drug effects of cardiotoxicants. In summary, biohybrid 3D printing technology is expected to be a potential fabrication method to provide a next‐generation tissue‐sensor platform for an effective drug development process.
Dissolvable Self‐Locking Microneedle Patches Integrated with Immunomodulators for Cancer Immunotherapy
Authors: Joo Seung‐Hwan , Kim Jaehyun , Hong Juhyeong , Fakhraei Lahiji Shayan , Kim Yong‐Hee 
Published: December 2022

AbstractAdvancements in micro‐resolution 3D printers have significantly facilitated the development of highly complex mass‐producible drug delivery platforms. Conventionally, due to the limitations of micro‐milling machineries, dissolvable microneedles (MNs) are mainly fabricated in cone‐shaped geometry with limited drug delivery accuracy. Herein, to overcome the limitations of conventional MNs, a novel projection micro‐stereolithography 3D printer‐based self‐locking MN for precise skin insertion, adhesion, and transcutaneous microdose drug delivery is presented. The geometry of self‐locking MN consists of a sharp skin‐penetrating tip, a wide skin interlocking body, and a narrow base with mechanical supports fabricated over a flexible hydrocolloid patch to improve the accuracy of skin penetration into irregular surfaces. Melanoma, a type of skin cancer, is selected as the model for the investigation of self‐locking MNs due to its irregular and uneven surface. In vivo immunotherapy efficacy is evaluated by integrating SD‐208, a novel transforming growth factor‐β (TGF‐β) inhibitor that suppresses the proliferation and metastasis of tumors, and anti‐PD‐L1 (aPD‐L1 Ab), an immune checkpoint inhibitor that induces T cell‐mediated tumor cell death, into self‐locking MNs and comparing them with intratumoral injection. Evaluation of (aPD‐L1 Ab)/SD‐208 delivery effectiveness in B16F10 melanoma‐bearing mice model confirms significantly improved dose efficacy of self‐locking MNs compared with intratumoral injection.
Microenvironmentally Responsive Chemotherapeutic Prodrugs and CHEK2 Inhibitors Self‐Assembled Micelles: Protecting Fertility and Enhancing Chemotherapy
Authors: Wu Meng , Xue Liru , Guo Yican , Dong Xiaoqi , Chen Zhaojun , Wei Simin , Yi Xiaoqing , Li Yinuo , Zhang Jinjin , Zhou Su , Wu Mingfu , Lou Xiaoding , Dai Jun , Xia Fan , Wang Shixuan 
Published: December 2022

AbstractChemotherapy is a widely used and effective adjuvant treatment for cancer, and it has unavoidable damage to female fertility, with statistics showing 38% of women who have received chemotherapy are infertile. How to reduce fertility toxicity while enhancing the oncologic chemotherapy is a clinical challenge. Herein, co‐delivery micelles (BML@PMP) are developed, which are composed of a reduction‐sensitive paclitaxel prodrug (PMP) for chemotherapy and a CHEK2 inhibitor (BML277) for both fertility protection and chemotherapy enhancement. BML@PMP achieves fertility protection through three actions: (1) Due to the enhanced permeability and retention (EPR) effect, BML@PMP is more enriched in the tumor, while very little in the ovary (about 1/10th of the tumor). (2) Glutathione (GSH) triggers the release of PTX, and with low levels of GSH in the ovary, the amount of PTX released in the ovary is correspondingly reduced. (3) BML277 inhibits oocyte apoptosis by inhibiting the CHEK2‐TAp63α pathway. Because of the different downstream targets of CHEK2 in tumor cells and oocytes, BML277 also enhances chemotherapeutic efficacy by reducing DNA damage repair which is activated through the CHEK2 pathway. This bidirectional effect of CHEK2 inhibitor‐based co‐delivery system represents a promising strategy for improving oncology treatment indices and preventing chemotherapy‐associated fertility damage.
Anion‐Vacancy‐Defect Passivation of a 2D‐Layered Tin‐Based Perovskite Thin‐Film Transistor with Sulfur Doping
Authors: Cho Jae‐Hyeok , Go Ji‐Young , Bui Tan Tan , Mun Seunguk , Kim Yunseok , Ahn Kyunghan , Noh Yong‐Young , Kim Myung‐Gil 
Published: December 2022

AbstractMetal halide perovskites have attracted a considerable amount of research attention with significant progress made in the field of optoelectronics. Despite their outstanding electrical characteristics, structural defects impede their potential performance due to the polycrystalline nature of solution‐processed perovskite films. Herein, the effective p‐type doping and defect passivation of phenethylammonium tin iodide ((PEA)2SnI4) perovskite films using xanthate additives as a sulfur source is reported. Sulfur can be introduced to the iodine vacancies mainly at the grain boundaries of the perovskite film, passivating the electrical defects originating from the iodine vacancy and increasing the hole concentration. The Fermi‐level shift toward the valence band maximum of the sulfur‐doped perovskite film is confirmed using ultraviolet photoemission spectroscopy, resulting in p‐type doping. Finally, the electrical performance improvement for the 0.2% sulfur‐doped (PEA)2SnI4 thin‐film transistor with a mobility of 1.45 cm2 V−1 s−1, an on/off ratio of 2.9 × 105 is demonstrated, and hysteresis of 10 V is reduced.
Unravelling plant diversification: Intraspecific genetic differentiation in hybridizingAnacyclusspecies in the western Mediterranean Basin
Authors: Bruno Agudo A. , Xavier Picó F. , Mateo Rubén G. , Marcer Arnald , Torices Rubén , Álvarez Inés 
Published: December 2022

AbstractPremiseThe interfertile speciesAnacyclus clavatus,A. homogamos, andA. valentinusrepresent a plant complex coexisting in large anthropic areas of the western Mediterranean Basin with phenotypically mixed populations exhibiting a great floral variation. The goal of this study was to estimate the genetic identity of each species, to infer the role of hybridization in the observed phenotypic diversity, and to explore the effect of climate on the geographic distribution of species and genetic clusters.MethodsWe used eight nuclear microsatellites to genotype 585 individuals from 31 populations of threeAnacyclusspecies for population genetic analyses by using clustering algorithms based on Bayesian models and ordination methods. In addition, we used ecological niche models and niche overlap analyses for both the species and genetic clusters. We used an expanded data set, including 721 individuals from 129 populations for ecological niche models of the genetic clusters.ResultsWe found a clear correspondence between species and genetic clusters, except forA. clavatusthat included up to three genetic clusters. We detected individuals with admixed genetic ancestry inA. clavatusand in mixed populations. Ecological niche models predicted similar distributions for species and genetic clusters. For the two specific genetic clusters ofA. clavatus, ecological niche models predicted remarkably different areas.ConclusionsGene flow betweenAnacyclusspecies likely explains phenotypic diversity in contact areas. In addition, we suggest that introgression could be involved in the origin of one of the twoA. clavatusgenetic clusters, which also showed ecological differentiation.
A de novo hexokinase 1 (HK1) variant presenting as Boucher–Neuhäuser syndrome
Authors: Peretz Ryan H. , Zein Wadih M. , Hufnagel Robert B. , Ku Christine , Godfrey Rena , Wolfe Lynne , Adams David , Gahl William , Toro Camilo 
Published: December 2022

AbstractBoucher–Neuhäuser syndrome (BNHS) is characterized by chorioretinal dystrophy, hypogonadotropic hypogonadism, and cerebellar dysfunction and atrophy. The disorder has been associated with biallelic pathogenic variants in the patatin‐like phospholipase domain‐containing protein 6 (PNPLA6) gene. We present an individual with a clinical diagnosis consistent with BNHS who lacked any PNPLA6 variants but on quartet family exome sequencing had a de novo variant in the hexokinase 1 (HK1) gene (NM_000188.2 [GRCh37/hg19]: g.71139826G>A, c.1240G>A, p.Gly414Arg), suggesting genetic heterogeneity for BNHS. Longitudinal follow‐up indicated neurological deterioration, neuropsychiatric symptoms, and progressive cerebellar atrophy. The BNHS phenotype overlaps and expands the known HK1 genotypic and phenotypic spectrum. Individuals with variants in HK1 should undergo evaluation for hypogonadotropic hypogonadism, potentially amenable to treatment.
Dermatological manifestations, management, and care in RASopathies
Authors: Kavamura Maria Ines , Leoni Chiara , Neri Giovanni 
Published: December 2022

AbstractRASopathies are rare genetic disorders caused by germline pathogenic variants in genes belonging to the RAS/MAPK pathway, which signals cell proliferation, differentiation, survival and death. The dysfunction of such signaling pathway causes syndromes with overlapping clinical manifestations. Skin and adnexal lesions are the cardinal clinical signs of RASopathies, such as cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, formerly known as LEOPARD syndrome, Costello syndrome, neurofibromatosis (NF1), Legius syndrome, Noonan‐like syndrome with loose anagen hair (NSLH) and Noonan syndrome. As NF1, one of the most common RASopathies, described in 1882, has its clinical features well delineated, we will focus on the dermatological diagnosis, management and care of non‐NF1 RASopathies, which are less known and more recently described. Dermatological manifestations are important clinical diagnostic elements that can aid differential diagnosis among RASopathies. They can affect dermis and epidermis, causing pigmented lesions (melanocytic nevi, café‐au‐lait spots, and lentigines), hyperkeratosis (keratosis pilaris, ulerythema ophryogenes, and palmoplantar keratosis) or hyperplasia. To date there are rare known links to malignancy, but oftentimes skin lesions require close attention because they can highly affect quality of life.
Optic nerve sheath diameter correlates to intracranial pressure in spontaneous CSF leak patients
Authors: Tilak Ashwini M. , Yang Lydia C. , Morgan Jake , Peña‐Garcia Jaime , Thompson Maxwell , Burleson Samuel , Atkins Amanda , Sheehan Delaney , Cho Do‐Yeon , Woodworth Bradford A. , Grayson Jessica W. 
Published: December 2022

AbstractBackgroundSpontaneous cerebrospinal fluid (sCSF) leaks develop from pressure erosion due to idiopathic intracranial hypertension, treatment of which is paramount to preventing recurrence. Direct measurements of intracranial pressure (ICP) for monitoring response to treatment via lumbar drain (LD) or ventriculostomy are invasive and have risks. The objectives of this study are to determine whether ultrasonographic measurements of optic nerve sheath diameter (ONSD) correlate with LD ICP in patients with sCSF leaks undergoing treatment, and whether ONSDs are larger in patients with sCSF leaks than controls.MethodsSubjects with sCSF leaks and controls were prospectively recruited. ONSD, sex, and body mass index (BMI) were analyzed. For sCSF leak subjects, ultrasonography was performed at the time of LD opening and each pressure check postoperatively, including the acetazolamide response. In control patients, measurements were obtained at the time of surgery. Pearson's correlation between ONSD and ICP was performed.ResultsSubjects with sCSF leaks (n = 9, age 52.4 ± 9.5, all female) and controls (n = 8, age 60.1 ± 14.8, two females) had significantly different BMIs, 38.4 ± 8.1 vs. 29.2 ± 4.8, t(15) = 2.793, p = 0.014. ONSD was strongly correlated with ICP measurements (r = 0.583, p = 0.002). However, percentage change in ONSD and ICP measurements were more strongly correlated (r = 0.733, p < 0.001). Patients with sCSF leaks had significantly higher ONSDs than controls, 0.63 cm ± 0.044 vs. 0.56 cm ± 0.074, t(15) = 2.329, p = 0.034.ConclusionONSD significantly correlated with ICP in sCSF leak patients and was wider in sCSF leak subjects than controls. Ultrasonography has utility in monitoring the ICP response to acetazolamide.
The First Synthesis of Subporphyrins
Authors: Shimizu Soji 
Published: December 2022

AbstractBecause of the rich coordination chemistry and unique optical and electrochemical properties, porphyrin analogues have been intensively investigated. Among them, subporphyrins have been long‐awaited molecules, with only their boron complexes known to date because of the crucial role of the central boron atom as a template in synthesis. The challenges related to the synthesis of a genuine subporphyrin (boron‐free) have finally been met and reported in a recent article from Kim, Osuka, and Song. A key strategy of their synthesis lies in the introduction of an exocyclic double bond at themeso‐position and subsequent reduction to obtain macrocyclic conjugation. Considering the fact that the development of porphyrin chemistry is ultimately linked to the availability of free base porphyrins, this seminal work will facilitate studies on coordination chemistry and applications in materials science.
Na2Ba[Na2Sn2S7]: Structural Tolerance Factor‐Guided NLO Performance Improvement
Authors: Li Rui‐An , Liu Qian‐Qian , Liu Xin , Liu Youquan , Jiang Xingxing , Lin Zheshuai , Jia Fei , Xiong Lin , Chen Ling , Wu Li‐Ming 
Published: December 2022

AbstractThe strong mutual coupling of and even the opposite change in the key parameters, such as the band gap (Eg) and second‐order harmonic generation (SHG), leads to the extreme scarcity in high‐performance IR nonlinear optical (NLO) chalcogenides. Herein, we report 8 new sulfides, Na2Ba[(AgxNa1−x)2Sn2S7] (1, x=0; 1 series, x=0.1–0.6; Na2Ba[(Li0.58Na0.42)2Sn2S7], 1‐0.6Li); Na2Sr[Cu2Sn2S7] (2); and Na2Ba[Cu2Sn2S7] (3). We use the structural tolerance factor (
) to connect the chemical composition, crystal structure, and NLO properties. Guided by these correlations, a better balance between Eg and SHG is realized in 1, which exhibits a large Eg of 3.42 eV and excellent NLO properties (SHG: 1.5×AGS; laser‐induced damage threshold: 12×AGS), representing the best performance among the known Hg‐ or As‐free sulfides to date.
Simple plant‐based production and purification of the assembled human ferritin heavy chain as a nanocarrier for tumor‐targeted drug delivery and bioimaging in cancer therapy
Authors: Knödler Matthias , Opdensteinen Patrick , Sankaranarayanan Ramya Ambur , Morgenroth Agnieszka , Buhl Eva Miriam , Mottaghy Felix M. , Buyel Johannes Felix 
Published: December 2022

AbstractNanoparticles are used as carriers for the delivery of drugs and imaging agents. Proteins are safer than synthetic nanocarriers due to their greater biocompatibility and the absence of toxic degradation products. In this context, ferritin has the additional benefit of inherently targeting the membrane receptor transferrin 1, which is overexpressed by most cancer cells. Furthermore, this self‐assembling multimeric protein can be loaded with more than 2000 iron atoms, as well as drugs, contrast agents, and other cargos. However, recombinant ferritin currently costs ~3.5 million € g−1, presumably because the limited number of producers cannot meet demand, making it generally unaffordable as a nanocarrier. Because plants can produce proteins at very‐large‐scale, we developed a simple, proof‐of‐concept process for the production of the human ferritin heavy chain by transient expression in Nicotiana benthamiana. We optimized the protein yields by screening different compartments and 5′‐untranslated regions in PCPs, and selected the best‐performing construct for production in differentiated plants. We then established a rapid and scalable purification protocol by combining pH and heat treatment before extraction, followed by an ultrafiltration/diafiltration size‐based separation process. The optimized process achieved ferritin levels of ~40 mg kg−1 fresh biomass although depth filtration limited product recovery to ~7%. The purity of the recombinant product was >90% at costs ~3% of the current sales price. Our method therefore allows the production of affordable ferritin heavy chain as a carrier for therapeutic and diagnostic agents, which is suitable for further stability and functionality testing in vitro and in vivo.
Chromosome evolution of Escherichia coli Nissle 1917 for high‐level production of heparosan
Authors: Yu Yanying , Gong Bingxue , Wang Huili , Yang Guixia , Zhou Xianxuan 
Published: December 2022

AbstractHeparosan is a crucial‐polysaccharide precursor for the chemoenzymatic synthesis of heparin, a widely used anticoagulant drug. Presently, heparosan is mainly extracted with the potential risk of contamination from Escherichia coli strain K5, a pathogenic bacterium causing urinary tract infection. Here, a nonpathogenic probiotic, E. coli strain Nissle 1917 (EcN), was metabolically engineered to carry multiple copies of the 19‐kb kps locus and produce heparosan to 9.1 g/L in fed‐batch fermentation. Chromosome evolution driven by antibiotics was employed to amplify the kps locus, which governed the synthesis and export of heparosan from EcN at 21 mg L−1 OD−1. The average copy number of kps locus increased from 1 to 24 copies per cell, which produced up to 104 mg L‐1 OD−1 of heparosan in the shaking flask cultures of engineered strains. The following in‐frame deletion of recA stabilized the recombinant duplicates of chromosomal kps locus and the productivity of heparosan in continuous culture for at least 56 generations. Fed‐batch fermentation of the engineered strain EcN8 was carried out to bring the yield of heparosan up to 9.1 g/L. Heparosan from the fermentation culture was further purified at a 75% overall recovery. The structure of purified heparosan was characterized and further modified by N‐sulfotransferase with 3′‐phosphoadenosine‐5′‐phosphosulfate as the sulfo‐donor. The analysis of element composition showed that heparosan was N‐sulfated by over 80%. These results indicated that duplicating large DNA cassettes up to 19‐kb, followed by high‐cell‐density fermentation, was promising in the large‐scale preparation of chemicals and could be adapted to engineer other industrial‐interest bacteria metabolically.
Trace‐level determination of potential genotoxic impurities in quetiapine fumarate using LC–MS
Authors: Kavitapu DasameswaraRao , Gopireddy Ramana Reddy , Maruthapillai Arthanareeswari , Murty Jayanti Naga Sri Rama Chandra , Katari Naresh Kumar 
Published: December 2022

AbstractA novel LC–MS method was developed and validated to determine three potential genotoxic impurities, namely 2‐(2‐aminophenylthio)benzoic acid hydrochloride, 2‐aminothiophenol, and 2‐(2‐aminophenylthio)benzonitrile, at trace level (~1.6 ppm) in quetiapine fumarate drug substance, an antipsychotic drug. These impurities are potentially genotoxic and therefore should be controlled at or below specific acceptance limits. An InertSustain AQ‐C18 column (250 × 4.6 mm, 5 μm) in reversed‐phase mode with the column temperature at 45°C was used. The mobile phase was 0.1% trifluoroacetic acid in water and acetonitrile with gradient elution mode, and the run time was 45 min. The flow rate was 0.8 ml/min. A mass spectrometer was used to quantify the amount of impurities using electrospray ionization mode at specific m/z 245.9, 126.0, and 226.9 for 2‐(2‐aminophenylthio)benzoic acid hydrochloride, 2‐aminothiophenol, and 2‐(2‐aminophenylthio) benzonitrile, respectively. The method was found to be sensitive and possessed excellent linearity in the concentration ranges from the limit of quantification to 150% of the permitted level (0.47–2.36 μg/ml) with correlation coefficients above 0.999. The results showed that the method was specific, precise, linear, and accurate for the estimation of these three impurities in quetiapine fumarate.
Government eco‐innovation incentives in a recycling system: A Stackelberg‐type model
Authors: Bimonte Giovanna , Ioppolo Giuseppe , Senatore Luigi , Trincone Barbara 
Published: December 2022

AbstractAs past economic progress has come at the expense of diminishing natural resources, increasing pollution and widespread damage to ecosystems around the world, an imperative we must respond to is to seek ways in which to achieve economic, social, and environmental sustainability, including actions aimed at a circular economy and eco‐innovation. Recycling has numerous implications for the environment, economic and production performance, employment, and production of wealth. The environmental regulator must therefore consider all the aspects of the waste cycle when deciding the right policies to maximize social welfare. We consider three types of agents involved in a Stackelberg game: manufacturers, importers and sellers (MIS), recyclers, and the government acting as an Environmental Protection Agency (EPA). In our model, we introduce the cost to adopt new technology for eco‐innovation per unit produced by the MIS, resulting in the possibility to reduce the weight of the advanced recycling fees if they invest more in the aptitude to be recycled of their products. The results give interesting prompts to investigate the relationship between environmental taxation and ecological incentives.
Photobiomodulation augments the effects of mitochondrial transplantation in the treatment of spinal cord injury in rats by facilitating mitochondrial transfer to neurons via Connexin 36
Authors: Zhu Zhijie , Li Xin , Wang Xuankang , Zuo Xiaoshuang , Ma Yangguang , Gao Xue , Liang Zhuowen , Zhang Zhihao , Song Zhiwen , Ding Tan , Ju Cheng , Li Penghui , Li Kun , Zhang Jiawei , Quan Huilin , Wang Zhe , Hu Xueyu 
Published: December 2022

AbstractMitochondrial transplantation is a promising treatment for spinal cord injury (SCI), but it has the disadvantage of low efficiency of mitochondrial transfer to targeted cells. Here, we demonstrated that Photobiomodulation (PBM) could promote the transfer process, thus augmenting the therapeutic effect of mitochondrial transplantation. In vivo experiments, motor function recovery, tissue repair, and neuronal apoptosis were evaluated in different treatment groups. Under the premise of mitochondrial transplantation, the expression of Connex36 (Cx36), the trend of mitochondria transferred to neurons, and its downstream effects, such as ATP production and antioxidant capacity, were evaluated after PBM intervention. In in vitro experiments, dorsal root ganglia (DRG) were cotreated with PBM and 18β‐GA (a Cx36 inhibitor). In vivo experiments showed that PBM combined with mitochondrial transplantation could increase ATP production and reduce oxidative stress and neuronal apoptosis levels, thereby promoting tissue repair and motor function recovery. In vitro experiments further verified that Cx36 mediated the transfer of mitochondria into neurons. PBM could facilitate this progress via Cx36 both in vivo and in vitro. The present study reports a potential method of using PBM to facilitate the transfer of mitochondria to neurons for the treatment of SCI.