bluuebunny/crossref_metadata_2025 huggingface dataset:
Next‐Generation Cancer‐Specific Hybrid Theranostic Nanomaterials: MAGE‐A3 NIR Persistent Luminescence Nanoparticles Conjugated to Afatinib for In Situ Suppression of Lung Adenocarcinoma Growth and Metastasis
Authors: Chan Ming‐Hsien , Huang Wen‐Tse , Wang Jing , Liu Ru‐Shi , Hsiao Michael
Published: March 2020

The rate of lung cancer has gradually increased in recent years, with an average annual increase of 15%. Afatinib (AFT) plays a key role in preventing non‐small cell lung carcinoma (NSCLC) growth and spread. To increase the efficiency of drug loading and NSCLC cell tracking, near infrared‐persistent luminescence nanomaterials (NIR PLNs), a silica shell‐assisted synthetic route for mono‐dispersal, are developed and used in the nanovehicle. After optimizing their physical and chemical properties, the NIR PLNs are able to absorb light energy and emit NIR luminescence for several hours. In this research, NIR PLNs are functionalized for drug‐carrying capabilities. Effective accumulation of target drugs, such as AFT, using PLN nanomaterials can lead to unique anticancer therapeutic benefits (AFT‐PLN). To minimize side effects and increase drug accumulation, nanomaterials with targeting abilities are used instead of simple drugs to inhibit the growth of tumor cells. Thus, the specific targeting aptamer, MAGE‐A3 (MAp) is identified, and the PLN to increase its targeting ability (AFT‐PLN@MAp) accordingly modified. The advancement of nanoscale techniques in the field of lung cancer is urgently needed; this research presents a plausible diagnostic strategy and a novel method for therapeutic administration.
Understanding Graduating Pediatric Emergency Medicine Fellow Priorities for Career Pathways and Faculty Recruitment for Academic or Community Emergency Departments
Authors: Sampayo Esther M. , Agrawal Pooja , Mittiga Matthew R. , Klasner Ann E. , Kim In , Scarfone Richard , Chang Todd P.
Published: March 2020

Objectives

Factors influencing the employment of pediatric emergency medicine (PEM) fellows in a career in academic medicine versus community emergency department (ED) settings have not previously been explored. The purpose of this study was to explore PEM fellows' priorities in selecting jobs and to identify factors that influence their decisions regarding career choices through a multicenter, qualitative approach. We also explored program directors' beliefs about graduates' job selection priorities.

Methods

This was a cross‐sectional study among a convenience sample of PEM fellows and PEM fellowship program directors and/or associate program directors in the United States. The data were collected in 2017, using a qualitative methodology known as free listing. The fellows and program directors were solicited through the American Academy of Pediatrics Section on Emergency Medicine. Using content analysis, all free‐listing responses from participant samples were categorized into 14 distinct groupings. Thematic saturation was achieved, and member checking was performed to ensure trustworthiness.

Results

A sample of 63 fellows from six geographically diverse programs and 41 program and/or associate program directors were surveyed. Location, schedule/work‐life balance and compensation were the most frequently cited factors taken into consideration for employment; these are not specific to PEM as a career choice. Other factors included patient population and ED resources. When deciding between academic and community employment, similar areas for the PEM physician emerged on both sides of the dichotomy: work–life balance, clinical hours, burnout, and acuity/patient complexity.

Conclusions

There are universal factors that PEM physicians consider when choosing employment. The information elicited from this exploratory technique can inform content for national survey or other qualitative work to achieve richer descriptions of reported items and dichotomies to guide fellow recruitment and retention strategies.
Phase 2 study of hyper‐CMAD with liposomal vincristine for patients with newly diagnosed acute lymphoblastic leukemia
Authors: Sasaki Koji , Kantarjian Hagop , Wierda William , Ravandi‐Kashani Farhad , Jorgensen Jeffrey , Wang Sa A. , Khoury Joseph , Daver Naval , Burger Jan , Di Nardo Courtney D. , Jain Nitin , Short Nicholas J. , Estrov MD Zeev , Konopleva MD, PhD Marina , Ohanian DO Maro , Garcia‐Manero Guillermo , Kadia Tapan , Alvarado‐Valero Yesid , Yilmaz Musa , Pierce Sherry , Garris Rebecca , Ingram April , Cortes Jorge , OʼBrien Susan , Jabbour Elias
Published: March 2020

Liposomal vincristine is designed to reduce neurotoxicity and increase dose intensity delivery, and has been approved as salvage therapy in relapsed/refractory acute lymphoblastic leukemia (ALL). Our aim was to evaluate the response rate, toxicities, and outcome of adults with newly diagnosed ALL who received liposomal vincristine, rather than regular vincristine in combination with intensive chemotherapy (Hyper‐CMAD). In a single‐center, phase 2 study, patients ≥18 years with newly‐diagnosed B‐cell ALL were eligible to receive hyper‐CMAD alternating with high‐dose methotrexate and cytarabine. Rituximab was administered in CD20 positive ALL. Tyrosine kinase inhibitors (imatinib or dasatinib) were added in Philadelphia chromosome‐positive (Ph‐positive) ALL. Thirty‐one patients were enrolled, median follow‐up of 59 months (0.3‐70). Thirteen patients (42%) had CD20 positive ALL, and 21 (68%) had Ph‐positive ALL. Thirty (97%) achieved complete remission (CR). All 26 patients with abnormal karyotype achieved complete cytogenetic response (CCyR), and 27/30 (90%) achieved negative minimal residual disease status by multicolor flow cytometry. Of 20 evaluable Ph‐positive ALL patients, major molecular response (MMR) was achieved in 19 patients (95%); complete molecular response (CMR) in 14 (70%). Grade 3/4 peripheral neuropathy was observed in five (16%) with all grade peripheral neuropathy in 21 (68%). With a median follow‐up of 59 months, 21 (68%) patients are alive. The 5‐year CR duration and survival rates were 73% and 61%, respectively. Ten (32%) patients died: one, sepsis on C1D10; four, unknown; one, post‐transplant complications; four, relapse. Hyper‐CMAD with liposomal vincristine is safe and demonstrated high response and survival rates in newly diagnosed ALL.
Intraspecific and interspecific investigations of skeletal DNA methylation and femur morphology in primates
Authors: Housman Genevieve , Quillen Ellen E. , Stone Anne C.
Published: March 2020

Objectives

Epigenetic mechanisms influence the development and maintenance of complex phenotypes and may also contribute to the evolution of species–specific phenotypes. With respect to skeletal traits, little is known about the gene regulation underlying these hard tissues or how tissue‐specific patterns are associated with bone morphology or vary among species. To begin exploring these topics, this study evaluates one epigenetic mechanism, DNA methylation, in skeletal tissues from five nonhuman primate species which display anatomical and locomotor differences representative of their phylogenetic groups.

Materials and Methods

First, we test whether intraspecific variation in skeletal DNA methylation is associated with intraspecific variation in femur morphology. Second, we identify interspecific differences in DNA methylation and assess whether these lineage‐specific patterns may have contributed to species–specific morphologies. Specifically, we use the Illumina Infinium MethylationEPIC BeadChip to identify DNA methylation patterns in femur trabecular bone from baboons (n = 28), macaques (n = 10), vervets (n = 10), chimpanzees (n = 4), and marmosets (n = 6).

Results

Significant differentially methylated positions (DMPs) were associated with a subset of morphological variants, but these likely have small biological effects and may be confounded by other variables associated with morphological variation. Conversely, several species–specific DMPs were identified, and these are found in genes enriched for functions associated with complex skeletal traits.

Discussion

Overall, these findings reveal that while intraspecific epigenetic variation is not readily associated with skeletal morphology differences, some interspecific epigenetic differences in skeletal tissues exist and may contribute to evolutionarily distinct phenotypes. This work forms a foundation for future explorations of gene regulation and skeletal trait evolution in primates.
A chomped chimp: New evidence of tooth marks on an adult chimpanzee (Pan troglodytes verus)
Authors: Eller Andrea R. , Pobiner Briana , Friend Sadie , Austin Rita M. , Hofman Courtney A. , Sholts Sabrina B.
Published: March 2020

Objectives

To describe and interpret previously unreported marks on the dry cranium of an adult chimpanzee (Pan troglodytes verus) from Côte d'Ivoire at the Smithsonian's National Museum of Natural History (USNM 450071).

Materials and Methods

All marks on the cranium were documented and assessed through physical examination of the specimen, photography, micro‐computed tomography (micro‐CT), and 3D laser scanning. Pits and punctures were measured with digital calipers for comparison with published carnivore tooth mark measurements.

Results

The cranium shows perimortem or postmortem damage to the temporal, occipital, and maxillary regions that is not recent. Size and color variation in the marks suggest two damage events, possibly involving chewing by different animals, at least one of which was a large‐bodied mammal. The 22 tooth pits and punctures (0.89–8.75 mm in maximum length and 0.88–6.63 mm in breadth) overlap in size with those inflicted by wild leopards, the most significant predators of common chimpanzees due to their largely overlapping ecological distributions.

Conclusions

Based on qualitative and quantitative evidence, we conclude that leopards are the most likely cause of the most prominent marks on the cranium. However, we cannot rule out the additional possibility of other chimpanzees, although there are no published studies of chimpanzee tooth marks for direct comparison. This study is the most extensive documentation to date of a modern adult chimpanzee skull exhibiting tooth marks by a large mammal, thus providing new evidence to help identify and interpret other events of predation and scavenging of large‐bodied apes in the modern and fossil records.
Nanoarchitektonik als ein Ansatz zur Erzeugung bioähnlicher hierarchischer Organisate
Authors: Ariga Katsuhiko , Jia Xiaofang , Song Jingwen , Hill Jonathan P. , Leong David Tai , Jia Yi , Li Junbai
Published: March 2020

Die Eingliederung von Nichtgleichgewichtsprozessen in die Abfolge von Selbstassemblierungsverfahren wäre ein effektives Mittel zur Etablierung bioähnlicher hochfunktionalisierter hierarchischer Assemblierungen. Als eine neue Methode jenseits der Selbstassemblierung wurde die Nanoarchitektonik eingeführt, deren Ziel die Herstellung funktioneller Materialsysteme aus nanoskopischen Einheiten durch die methodische Zusammenführung der Nanotechnologie mit anderen wissenschaftlichen Disziplinen einschließlich der organischen Synthese, der supramolekularen Chemie, der Mikrofabrikation und von Bioprozessen ist. Die Nutzung von Nichtgleichgewichtsfaktoren in konventionellen Selbstassemblierungsprozessen wird auf der Grundlage von Beispielen zur gesteuerten Assemblierung, der Langmuir‐Blodgett‐Technologie und der schichtweisen Assemblierung diskutiert. Insbesondere werden Beispiele zur Herstellung hierarchischer funktioneller Strukturen mithilfe bioaktiver Komponenten wie Proteinen oder durch die Kombination von Biokomponenten mit zweidimensionalen Nanomaterialien beschrieben.
Nickel(II)‐Mediated Reversible Thiolate/Disulfide Conversion as a Mimic for a Key Step of the Catalytic Cycle of Methyl‐Coenzyme M Reductase
Authors: Bhandari Anirban , Mishra Saikat , Maji Ram Chandra , Kumar Akhilesh , Olmstead Marilyn M. , Patra Apurba K.
Published: March 2020

According to the well‐accepted mechanism, methyl‐coenzyme M reductase (MCR) involves Ni‐mediated thiolate‐to‐disulfide conversion that sustains its catalytic cycle of methane formation in the energy saving pathways of methanotrophic microbes. Model complexes that illustrate Ni‐ion mediated reversible thiolate/disulfide transformation are unknown. In this paper we report the synthesis, crystal structure, spectroscopic properties and redox interconversions of a set of NiII complexes comprising a tridentate N2S donor thiol and its analogous N4S2 donor disulfide ligands. These complexes demonstrate reversible NiII‐thiolate/NiII‐disulfide (both bound and unbound disulfide‐S to NiII) transformations via thiyl and disulfide monoradical anions that resemble a primary step of MCR's catalytic cycle.
Stable meso–meso‐Linked 2NH‐Corrole Radical Dimers as a Key Intermediate to Corrole Tape
Authors: Ooi Shota , Adinarayana B. , Shimizu Daiki , Tanaka Takayuki , Osuka Atsuhiro
Published: March 2020

While oxidation of 5,5′,15,15′‐tetramesityl‐10‐10′‐linked 3NH‐corrole dimer with DDQ gave the corresponding triply linked 2NH‐corrole tape, the use of an equimolar amount of p‐chloranil as a milder oxidant resulted in the formation of a 10‐10′‐linked neutral 2NH‐corrole radical dimer as a stable product. The stability of this peculiar product is ascribed largely to strong antiferromagnetic interaction of the two spins. Further oxidation of this diradical produced corrole tape, suggesting its involvement as a reaction intermediate to the corrole tape. Oxidation of 10‐10′‐linked bis‐pyridine‐coordinated CoIII corrole dimer with DDQ produced a cobalt corrole radical dimer and a doubly linked corrole dimer both as stable compounds bearing pyridine and cyanide axial ligands. This type of oxidative transformation involving neutral diradical intermediates is a unique reaction mechanism specific for corrole dimers.
More Twins in the Scientific Literature of the 21st Century
Authors: Mainkar Prathama S. , Vankamamidi Ambica , Chandrasekhar Srivari
Published: March 2020

This Essay highlights the complex issue of twinning in science publications. Historical accounts present cases where two scientists focused on the same problem and came up with the same solution following different paths. This has changed in the present day. The concurrent publication of rather similar research papers from different groups has increased in frequency since 2010. In the past, twinning in research publications was serendipitous, and there was a healthy competition among teams working on similar projects. Today, twinning has become more frequent. This can be attributed to the urge of researchers to have publications on popular topics, the tendency to base research programs on popular keywords, and funding agencies preferentially supporting certain areas of research. With vast amounts of literature being generated, editorial offices and referees may not be able to find these twins very easily. As we inch away from human ingenuity towards artificial intelligence, twinning may become even more frequent.
Catalytic evaluation of copper (II)N‐salicylidene‐amino acid Schiff base in the various catalytic processes
Authors: Al‐Hussein Maryam F.I. , Adam Mohamed Shaker S.
Published: March 2020

N‐Salicylidene amino acid Schiff base sodium sulfonate salt, as a tridentate dibasic chelating ligand, was obtained from the common condensation of salicylaldehyde‐5‐sodium sulfonate with tyrosine (HPST). The internal formed ligand coordinated to Cu2+ion in an aqueous media affording new Cu (II)‐complex (Cu‐PST), which characterized by various physico‐chemicals spectral tools. The mononuclear complex was evaluated as a homogeneous and heterogeneous catalyst in the (ep)oxidation protocols of 1,2‐cyclooctene and benzyl alcohol. Heterogeneously, Cu‐PST was immobilized on Fe3O4‐SiO2, as nanoparticles. The heterogeneous catalyst was characterized by infrared, X‐ray diffraction, scanning electron microscopy, transmission electron microscopy, energy‐dispersive spectroscopy, Brunauer−Emmett−Teller and magnetism. Homogeneously, the temperature, solvent and oxidant influences were examined in the catalytic reactions to realize the best reaction conditions. Cu‐catalyst exhibited better catalytic performance in the (ep)oxidation processes homogeneously than that in the heterogeneous phase at 80°C for 2 hr in acetonitrile. Reusability of the homogeneous catalyst was for a maximum of three times in the (ep)oxidation reaction, whereas the heterogeneous catalyst was active for six times. A mechanistic pathway was proposed for both catalysts, comparatively.
Step‐by‐step synthesis of copper(I) complex supported on platinum nanoparticle‐decorated mesoporous silica hollow spheres and its remarkable catalytic performance in Sonogashira coupling reaction
Authors: Abolhosseini Shahrnoy Abdolghafar , Mahjoub Ali Reza , Shokrollahi Sudabeh , Ezzati Nasim , Elsner Kristiane , Koch Christoph T.
Published: March 2020

In this study, a step‐by‐step method for the synthesis of platinum nanoparticles and copper(I) complex supported on mesoporous silica hollow spheres (Pt‐MSHSs‐Cu) is introduced. Scanning electron microscopy, transmission electron microscopy, powder X‐ray diffraction, Fourier transform infrared spectroscopy, nitrogen adsorption–desorption, energy‐dispersive X‐ray spectrometry, X‐ray photoelectron spectroscopy, and elemental and thermogravimetric analyses were applied for characterization of the surface, structure, size, phase composition, and morphology of the synthesized materials. The characterized material, Pt‐MSHSs‐Cu, was used as an efficient and heterogeneous catalyst in the Sonogashira coupling reaction under different reaction conditions. In comparison with MSHSs, Cu(I)‐functionalized MSHSs (MSHSs‐Cu), and Pt‐MSHSs samples, the Pt‐MSHSs‐Cu catalyst exhibited significantly increased catalytic performance with 91.50% yield. Therefore, the results obtained suggested a synergistic effect derived from platinum nanoparticles, MSHSs substrate, and copper(I) complex, which enhanced the rate of the Sonogashira coupling reaction.
Multifunctional mussel‐inspired Gelatin and Tannic acid‐based hydrogel with pH‐controllable release of vitamin B12
Authors: Nath Jayashree , Saikia Priyanka Pratim , Handique Junali , Gupta Kuldeep , Dolui Swapan Kumar
Published: March 2020

Hydrogels have emerged to be an impeccable material for a large variety of applications over the past few decades. In the field of biomedical applications, remarkable progress has been observed in the effort of fabricating numerous hydrogel systems. In this work, gelatin and tannic acid‐based stretchable and adhesive hydrogel has been synthesized to study the release behavior of vitamin B12. Successful formation of the synthesized hydrogels was confirmed by Fourier transform infrared and X‐ray diffraction analysis. The morphology of the surfaces and the cross section of such hydrogels were studied with Scanning electron microscopy analysis. Swelling behavior of our hydrogel was studied with Design Expert software. The maximum swelling of the hydrogel was found to be around 137 g/g. Adhesive property was demonstrated on various surfaces to observe the adhesiveness of the fabricated hydrogel. Blood compatibility study was also performed. The release behavior of vitamin B12was performed in two different pH media and it was found to have enhanced value in the fluid mimicking the intestine. This work provides a new prospect for designing hydrogels with stretchable and adhesive properties with pH‐controllable drug delivery applications along with other promising applications in various fields of research.
Physical–chemical and structural stability of PHBV/wheat straw fibers based biocomposites under food contact conditions
Authors: Angellier‐Coussy Hélène , Kemmer Diana , Gontard Nathalie , Peyron Stéphane
Published: March 2020

This aricle aims at investigating for the first time the ability of using poly(3‐hydroxylbutyrate‐co‐3‐hydroxyvalerate) (PHBV)/wheat straw fibers (WSF) biocomposites as food contact materials for packaging applications. For that purpose, the impact of the filler size and content on overall migration and mechanical properties was assessed under standardized testing conditions using the food simulant liquids (FSL). Very high overall migration values were noticed in the case of hydrophilic FSL, that is, water, acetic acid 3% (wt/vol), ethanol 20% (vol/vol), and ethanol 95% (vol/vol), related to the leaching of water extractable components of WSF. Low migration values were obtained in contact with isooctane and olive oil, demonstrating the possibility of using biocomposites in contact with fatty products. To answer the lack of methodologies to simulate different types of food for which PHBV‐based composites could be more specifically dedicated, including food products of low or intermediate water activity such as fruits and vegetable, bread, and cheese, a new range of new solid food models based on agar‐agar gels have been developed. Results showed that the water activity (aw) was the main parameter governing the overall migration of PHBV/WSF materials, suggesting that such composite materials could only be used as food contact materials in the case of food products with an awequal or lower than 0.90.
Fishers, dams, and the potential survival of the world's rarest turtle, Rafetus swinhoei, in two river basins in northern Vietnam
Authors: Le Duc Olivier , Van Thong Pham , Leprince Benjamin , Bordes Cedric , Tuan Anh Nguyen , Benansio John Sebit , Pacini Nic , Luu Vinh Quang , Luiselli Luca
Published: March 2020

Next to cetaceans and megafishes, freshwater turtles are the most iconic endangered freshwater species.

A detailed questionnaire survey conducted with more than 100 individuals from fishing communities in northern Vietnam was used to investigate the current status of Southeast Asian turtles and provides new hope concerning the survival of Rafetus swinhoei, for which recent official records in the wild are limited to a single individual in Vietnam.

The survey included the entire Vietnamese portion of the Da River in Hoa Binh and Son La provinces, as well as the Chu and Ma river system in Thanh Hoa Province, as they are the last sites where the world's rarest and largest Asian softshell turtle has been seen. The questionnaire, conducted in Vietnamese, focused on demographic details, fishing intensity and gear, the status of fishing grounds, and the frequency of interaction with turtles.

The great majority of fishers could recognize different turtle species from photographs and describe their preferential breeding habitats; not all knew that they are protected. A few confirmed that more than once each year they still encounter freshwater turtles during their fishing activities.

This survey provides detailed information on sites where freshwater turtles are still seen in northern Vietnam and broadens our hope that wild individuals of the extremely rare R. swinhoei may still be present in the remaining riparian wetlands of these biodiverse, dammed, and controlled river basins in North Vietnam.
The personal information sphere: An integral approach to privacy and related information and communication rights
Authors: Eskens Sarah
Published: March 2020

Data protection laws, including the European Union General Data Protection Regulation, regulate aspects of online personalization. However, the data protection lens is too narrow to analyze personalization. To define conditions for personalization, we should understand data protection in its larger fundamental rights context, starting with the closely connected right to privacy. If the right to privacy is considered along with other European fundamental rights that protect information and communication flows, namely, communications confidentiality; the right to receive information; and freedom of expression, opinion, and thought, these rights are observed to enable what I call a “personal information sphere” for each person. This notion highlights how privacy interferences affect other fundamental rights. The personal information sphere is grounded in European case law and is thus not just an academic affair. The essence of the personal information sphere is control, yet with a different meaning than mere control as guaranteed by data protection law. The personal information sphere is about people controlling how they situate themselves in information and communication networks. It follows that, to respect privacy and related rights, online personalization providers should actively involve users in the personalization process and enable them to use personalization for personal goals.
Multi‐informant International Perspectives on the Facilitators and Barriers to Employment for Autistic Adults
Authors: Black Melissa H. , Mahdi Soheil , Milbourn Benjamin , Scott Melissa , Gerber Alan , Esposito Christopher , Falkmer Marita , Lerner Matthew D. , Halladay Alycia , Ström Eva , D'Angelo Axel , Falkmer Torbjorn , Bölte Sven , Girdler Sonya
Published: March 2020

Employment rates for autistic individuals are poor, even compared to those from other disability groups. Internationally, there remains limited understanding of the factors influencing employment across the stages of preparing for, gaining, and maintaining employment. This is the third in a series of studies conducted as part of an International Society for Autism Research (INSAR) policy brief intended to improve employment outcomes for autistic individuals. A multi‐informant international survey with five key stakeholder groups, including autistic individuals, their families, employers, service providers, and researchers, was undertaken in Australia, Sweden, and the United States to understand the facilitators and barriers to employment for autistic adults. A total of 687 individuals participated, including autistic individuals (n = 246), family members (n = 233), employers (n = 35), clinicians/service providers (n = 123), and researchers (n = 50). Perceptions of the facilitators and barriers to employment differed significantly across both key stakeholder groups and countries, however, ensuring a good job match and focusing on strengths were identified by all groups as important for success. Key barriers to employment included stigma, a lack of understanding of autism spectrum disorder (ASD) and communication difficulties. Results suggest that a holistic approach to employment for autistic individuals is required, aimed at facilitating communication between key stakeholders, addressing attitudes and understanding of ASD in the workplace, using strength‐based approaches and providing early work experience. Autism Res 2020, 13: 1195‐1214. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Lay Summary

Autistic individuals experience significant difficulty getting and keeping a job. This article presents a survey study involving autistic individuals, their families, employers, service providers and researchers in Australia, Sweden, and the United States to understand their perspectives on the factors that support or act as barriers to employment. While perspectives varied across key stakeholders, strategies such as using a holistic approach, targeting workplace attitudes and understanding, focusing on strengths, and providing early work experience are important for success.
A Cyclin D1‐Specific Single‐Chain Variable Fragment Antibody that Inhibits HepG2 Cell Growth and Proliferation
Authors: Wu Yan , Tang Weiwei , Cao Yuhua , Jiang Dazhi , Zhao Liangzhong , Zhao Jialiang , Zhang Ying , Li Chengjuan , Cheng Cheng , Wang Shuai , Yang Fang , Zhu Xun , Li Guiying
Published: March 2020

Cyclin D1 is a key regulatory factor of the G1 to S transition during cell cycle progression. Aberrant cyclin D gene amplification and abnormal protein expression have been linked to hepatocellular carcinoma (HCC) tumorigenesis. Intrabodies, effective anticancer therapies that specifically inhibit target protein function within all intracellular compartments, may block cyclin D1 function. Here, a single‐chain variable fragment (scFv) antibody against cyclin D1 (ADκ) selected from a human semi‐synthetic phage display scFv library is expressed in Escherichia coli as soluble ADκ. Purified ADκ specifically binds to recombinant and endogenous cyclin D1 with high affinity. To enable blocking of intracellular cyclin D1 activity, an endoplasmic reticulum (ER) retention signal sequence is added to the ADκ sequence to encode anti‐cyclin D1 intrabody ER‐ADκ. Transfection of HepG2 cells with expression vector encoding ER‐ADκ elicited intracellular ER‐ADκ expression leading to cyclin D1 binding, significant G1 phase arrest, and apoptosis that are mechanistically tied to decreased intracellular phosphorylated retinoblastoma protein (Rb) levels. Meanwhile, ER‐ADκ dramatically inhibited subcutaneous human HCC xenografts growth in nude mice in vivo after injection of tumors with expression vector encoding ER‐ADκ. These results demonstrate the potential of intrabody‐based cyclin D1 targeting therapy as a promising treatment for HCC.
Multi‐Omics Reveals Impact of Cysteine Feed Concentration and Resulting Redox Imbalance on Cellular Energy Metabolism and Specific Productivity in CHO Cell Bioprocessing
Authors: Ali Amr S. , Chen Rachel , Raju Ravali , Kshirsagar Rashmi , Gilbert Alan , Zang Li , Karger Barry L. , Ivanov Alexander R.
Published: March 2020

Chinese hamster ovary (CHO) cells are currently the primary host cell lines used in biotherapeutic manufacturing of monoclonal antibodies (mAbs) and other biopharmaceuticals. Cellular energy metabolism and endoplasmic reticulum (ER) stress are known to greatly impact cell growth, viability, and specific productivity of a biotherapeutic; but the molecular mechanisms are not fully understood. The authors previously employed multi‐omics profiling to investigate the impact of a reduction in cysteine (Cys) feed concentration in a fed‐batch process and found that disruption of the redox balance led to a substantial decline in cell viability and titer. Here, the multi‐omics findings are expanded, and the impact redox imbalance has on ER stress, mitochondrial homeostasis, and lipid metabolism is explored. The reduced Cys feed activates the amino acid response (AAR), increases mitochondrial stress, and initiates gluconeogenesis. Multi‐omics analysis reveals that together, ER stress and AAR signaling shift the cellular energy metabolism to rely primarily on anaplerotic reactions, consuming amino acids and producing lactate, to maintain energy generation. Furthermore, the pathways are demonstrated in which this shift in metabolism leads to a substantial decline in specific productivity and altered mAb glycosylation. Through this work, meaningful bioprocess markers and targets for genetic engineering are identified.
Systems metabolic engineering of Bacillus subtilis for efficient biosynthesis of 5‐methyltetrahydrofolate
Authors: Yang Han , Liu Yanfeng , Li Jianghua , Liu Long , Du Guocheng , Chen Jian
Published: March 2020

5‐Methyltetrahydrofolate (5‐MTHF) is the major form of folate in human plasma and is the only folate form that can penetrate the blood–brain barrier. It has been widely used for the prevention and treatment of various diseases. It is mainly produced by chemical synthesis. However, the low production rate cannot meet the increasing demand. In addition, chemical synthesis is potentially detrimental to the environment. Despite various microorganisms synthetizing 5‐MTHF, an efficient 5‐MTHF bioproduction approach is lacking because of the tight regulation of the 5‐MTHF pathway and limited metabolic flux toward the folic acid pathway. In this study, the 5‐MTHF synthetic pathway in Bacillus subtilis was systematically engineered to realize 5‐MTHF accumulation and further improve 5‐MTHF production. Specifically, the 5‐MTHF synthesis pathway with dihydrofolate (DHF) as the precursor was strengthened to shift the metabolic flux to 5‐MTHF biosynthesis by replacing the native yitJ gene with Escherichia coli metF, knockout of purU, and overexpressing dfrA. The intracellular level of 5‐MTHF increased 26.4‐fold, reaching 271.64 µg/L. Next, the 5‐MTHF precursor supply pathway was strengthened by co‐overexpression of folC, pabB, folE, and yciA. This resulted in a 93.2‐fold improvement of the 5‐MTHF titer, which reached 960.27 µg/L. Finally, the clustered regularly interspaced short palindromic repeats interference system was used to identify key genes in the competitive and catabolic pathways for repression to further shift the metabolic flux toward 5‐MTHF biosynthesis. The repression of genes thyA (existing in the purine metabolic pathway), pheA (existing in the competitive metabolic pathway), trpE (existing in the competitive metabolic pathway), and panB (existing in the pantoate synthesis pathway) significantly increased the titer of 5‐MTHF. By repressing the pheA gene, the 5‐MTHF titer reached 1.58 mg/L, which was 153.8‐fold that of the wild‐type strain of B. subtilis 168. Through medium optimization, the 5‐MTHF titer reached 1.78 mg/L, which was currently the highest titer of 5‐MTHF in B. subtilis. Apart from the highest titer of 5‐MTHF, the highest titer of total folates including 5‐MTHF, 5‐FTHF, folic acid, and THF could reach 3.31 mg/L, which was 8.5‐fold that in B. subtilis. To the best of our knowledge, the 5‐MTHF and total folate titers reported here are the highest using a Generally regarded as safe (GRAS) bacterium as the production host. Overall, this study provides a good starting point for further metabolic engineering to achieve efficient biosynthesis of 5‐MTHF by GRAS bacteria.
Immobilization of horseradish peroxidase onto Purolite® A109 and its anthraquinone dye biodegradation and detoxification potential
Authors: Šekuljica Nataša Ž. , Jovanović Jelena R. , Jakovetić Tanasković Sonja M. , Ognjanović Nevena D. , Gazikalović Ivana V. , Knežević‐Jugović Zorica D. , Mijin Dušan Ž.
Published: March 2020

Horseradish peroxidase (HRP) is a highly specific enzyme with great potential for use in the decolorization of synthetic dyes. A comprehensive study of HRP immobilization using various techniques such as adsorption and covalent immobilization on the novel carrier Purolite® A109 with a special focus on enzymatic decolorization and toxicity of artificially colored wastewater. The immobilized preparations with an activity of 156.21 ± 1.41 U g−1 and 85.71 ± 1.62 U g−1 after the HRP adsorption and covalent immobilization, respectively, were obtained. Stability and reusability of the immobilized preparations were also evaluated. A noteworthy decolorization level (~90%) with immobilized HRP was achieved. Phytotoxicity testing using Mung bean seeds and acute toxicity assay with Artemia salina has confirmed the applicability of the obtained immobilized preparation in industrial wastewater plants for the treatment of colored wastewater.
Efficacy and safety of anlotinib, a multikinase angiogenesis inhibitor, in combination with epirubicin in preclinical models of soft tissue sarcoma
Authors: Wang Zhi‐Ming , Zhang Shi‐Long , Yang Hua , Zhuang Rong‐Yuan , Guo Xi , Tong Han‐Xing , Zhang Yong , Lu Wei‐Qi , Zhou Yu‐Hong
Published: March 2020

Background

Anlotinib is a novel, orally administered, multitarget receptor tyrosine kinase inhibitor. It functions by inhibiting tumor angiogenesis and proliferative signaling pathways. In this study, we aimed to investigate the efficacy and safety of anlotinib plus epirubicin in a sarcoma patient‐derived xenografts (PDX) model.

Methods

We firstly established a PDX model using fresh tumor tissues that were surgically removed from a patient diagnosed with malignant fibrous histiocytoma. Thirty‐six PDX models were divided into six groups and treated with anlotinib alone (low‐dose, 1.5 or high‐dose, 3.0 mg/kg/day, oral gavage), or with anlotinib plus epirubicin (3.0 mg/kg/once weekly, i.p.) when the tumors grew to 150‐200 mm3. After 5 weeks of treatment, the mice were sacrificed, and the tumors were measured by weight and processed for IHC and H&E staining. IHC staining was performed to detect CD31, EGFR, MVD, and Ki‐67 on paraffin sections. H&E stainings were performed to examine the microcosmic changes that occurred in the tumor tissues and myocardium, respectively.

Results

After 5 weeks, treatment with anlotinib or epirubicin alone significantly inhibited tumor growth in the sarcoma PDX model compared with the vehicle control. Tumor volume in the high‐dose anlotinib group was significantly smaller than the low‐dose anlotinib group (P < .001). Combined high‐dose anlotinib and epirubicin treatment resulted in the most pronounced tumor inhibition. In the groups treated with the anlotinib‐containing regimen, the expression levels of CD31, EGFR, MVD, and Ki‐67 were significantly low. The weight in each group had no statistical differences; the same applied to the hepatic function, cardiac function, and toxicity.

Conclusions

High‐dose anlotinib combined with epirubicin was an effective and safe therapy for STS.
Identification of aberrantly methylated differentially expressed genes and associated pathways in endometrial cancer using integrated bioinformatic analysis
Authors: Liu JinHui , Wan YiCong , Li Siyue , Qiu HuaiDe , Jiang Yi , Ma Xiaoling , Zhou ShuLin , Cheng WenJun
Published: March 2020

Endometrial cancer (EC) is a fatal female reproductive tumor. Bioinformatic tools are increasingly developed to screen out molecular targets related to EC. In this study, GSE17025 and GSE40032 were obtained from Gene Expression Omnibus (GEO). “limma” package and Venn diagram tool were used to identify hub genes. FunRich was used for functional analysis. Retrieval of Interacting Genes Database (STRING) was used to analyze protein‐protein interaction (PPI) complex. Cancer Genome Atlas (TCGA), GEPIA, immunohistochemistry staining, and ROC curve analysis were carried out for validation. Univariate and multivariate regression analyses were performed to predict the risk score. Compound muscle action potential (CMap) was used to find potential drugs. GSEA was also done. We retrieved seven oncogenes which were upregulated and hypomethylated and 12 tumor suppressor genes (TSGs) which were downregulated and hypermethylated. The upregulated and hypomethylated genes were strikingly enriched in term “immune response” while the downregulated and hypermethylated genes were mainly focused on term “aromatic compound catabolic process.” TCGA and GEPIA were used to screen out EDNRB, CDO1, NDN, PLCD1, ROR2, ESPL1, PRAME, and PTTG1. Among them, ESPL1 and ROR2 were identified by Cox regression analysis and were used to construct prognostic risk model. The result showed that ESPL1 was a negative independent prognostic factor. Cmap identified aminoglutethimide, luteolin, sulfadimethoxine, and maprotiline had correlation with EC. GSEA results showed that “hedgehog signaling pathway” was enriched. This research inferred potential aberrantly methylated DEGs and dysregulated pathways may participate in EC development and firstly reported eight hub genes, including EDNRB, CDO1, NDN, PLCD1, ROR2, ESPL1, PRAME, and PTTG1 that could be used to predict EC prognosis. Aminoglutethimide and luteolin may be used to fight against EC.
DPP‐4 Cleaves α/β‐Peptide Bonds: Substrate Specificity and Half‐Lives
Authors: Turalić Amila , Đeđibegović Jasmina , Hegedüs Zsófia , Martinek Tamás A.
Published: March 2020

The incorporation of β‐amino acids into a peptide sequence has gained particular attention as β‐ and α/β‐peptides have shown remarkable proteolytic stability, even after a single homologation at the scissile bond. Several peptidases have been shown to cleave such bonds with high specificity but at a much slower rate compared to α‐peptide bonds. In this study, a series of analogs of dipeptidyl peptidase‐4 (DPP‐4) substrate inhibitors were synthesized in order to investigate whether β‐amino acid homologation at the scissile bond could be a valid approach to improving peptide stability towards DPP‐4 degradation. DPP‐4 cleaved the α/β‐peptide bond after the N‐terminal penultimate Pro with a broad specificity and retained full activity regardless of the β3‐amino acid side chain and peptide length. Significantly improved half‐lives were observed for β3Ile‐containing peptides. Replacing the penultimate Pro with a conformationally constrained Pro mimetic led to proteolytic resistance. DPP‐4 cleavage of α/β‐peptide bonds with a broad promiscuity represents a new insight into the stability of peptide analogs containing β‐amino acids as such analogs were thought to be stable towards enzymatic degradation.
Bifunctional DNA Duplexes Permit Efficient Incorporation of pH Probes into Liposomes
Authors: Dolder Nicolas , von Ballmoos Christoph
Published: March 2020

Enzyme‐mediated proton transport across biological membranes is critical for many vital cellular processes. pH‐sensitive fluorescent dyes are an indispensable tool for investigating the molecular mechanism of proton‐translocating enzymes. Here, we present a novel strategy to entrap pH‐sensitive probes in the lumen of liposomes that has several advantages over the use of soluble or lipid‐coupled probes. In our approach, the pH sensor is linked to a DNA oligomer with a sequence complementary to a second oligomer modified with a lipophilic moiety that anchors the DNA conjugate to the inner and outer leaflets of the lipid bilayer. The use of DNA as a scaffold allows subsequent selective enzymatic removal of the probe in the outer bilayer leaflet. The method shows a high yield of insertion and is compatible with reconstitution of membrane proteins by different methods. The usefulness of the conjugate for time‐resolved proton pumping measurements was demonstrated by using two large membrane protein complexes.
A rare case of group A streptococcal toxic‐shock syndrome in a postpartum adolescent leading to multi‐organ failure
Authors: Cortez Granados Samuel , Batsch Jonathan , Lui Asona , Hessman Jacob , Gloyeske Nika , Panchal Apurva
Published: March 2020

Teenage pregnancy is not uncommon, but given the age of the patient, experience, and competency among medical providers varies. While toxic‐shock syndrome from group A streptococcus is rare in teenage pregnancy, observed is a gap in care of bridging.
Rh(III)‐Catalyzed Selective ortho‐C−H Amination of Benzoic Acids with Anthranils: A Facile Access to Anthranilic Acid Derivatives (AAs)
Authors: Gao Yang , Nie Jianhong , Li Yibiao , Liao Guilan , Huo Yanping , Hu Xiao‐Qiang
Published: March 2020

An efficient Rh(III)‐catalyzed Csp2‐H amination protocol of benzoic acids with anthranils was developed for the rapid assembly of valuable anthranilic acid derivatives (AAs). The weakly coordinating carboxyl acted as a directing group and was further transformed to an ester group after facilitating the first C−H amination process. This reaction features good functional group tolerance, mild conditions and operational simplicity. The synthetic potential of this methodology was demonstrated by the synthesis of various useful heterocycles and derivatives.
Coupling Photothermal Effect into Efficient Photocatalytic H2 Production by Using a Plate‐like Cu@Ni Core‐shell Cocatalyst
Authors: Guo Xinyang , Xue Fei , Xu Shikai , Shen Shaohua , Huang Hongwen , Liu Maochang
Published: March 2020

The general moderate reaction condition in solar photocatalytic hydrogen production (i. e., near ambient pressure, room temperature) makes interfacial mass and energy transfer extremely slow, even by employing a cocatalytic material (usually in the form of noble metal nanoparticles or their counterparts). Herein, by fabricating well‐defined Cu@Ni core‐shell nanoplate cocatalyst and further incorporating it with a g‐C3N4 photocatalyst, we demonstrate that interfacial processes could be significantly improved by coupling localized photothermal effect into a cocatalyst. Specifically, Cu nanoplate can induce localized strong hot spots on Ni nanoparticles via a visible‐light‐driven surface plasma resonance effect. As a result, photogenerated electrons transferred from g‐C3N4 to Ni, could be elevated to a more energetic state, leading to a substantially improved photocatalytic activity toward H2 evolution from water. The highest hydrogen generation rate reaches 55 μmol h−1 g−1, 110 times of that pristine g‐C3N4. This work indicates that photoelectric and photothermal effects can be effectively coupled by integrating metal hetero‐nanoparticles.
Detailed Kinetic Model for the Reaction of Ethene to Propene on Ni/AlMCM‐41
Authors: Felischak Matthias , Wolff Tanya , Alvarado Perea Leo , Seidel‐Morgenstern Andreas , Hamel Christof
Published: March 2020

The Ni/AlMCM‐41 was prepared and applied as the catalyst for the direct conversion of ethene to propene. Based on the results of the broad experimental study, two reaction networks were compared, one consisting of dimerization, isomerization and metathesis and a modified network suggesting the cracking of long‐chain olefins. To correlate the experimentally obtained data, the classical Langmuir‐Hinshelwood‐Hougen‐Watson model was applied for both reaction networks. The second network involving catalytic cracking offers a satisfying prediction of the observed product distributions.
Investigation of fluidized bed behaviour using electrical capacitance tomography
Authors: Azzi Abdelwahid , Bouyahiaoui Hiba , Berrouk Abdallah S. , Hunt Andrew , Lowndes Ian S.
Published: March 2020

The temporal and cross‐sectional distributions of particles in a 127 mm diameter fluidized bed have been obtained using a new generation, high‐speed electrical capacitance tomography. Two planes of eight electrodes were used and mounted at 160 and 660 mm from the gas distributor which was a 3 mm thick porous plastic plate (maximum pore size of 50‐70
μm). 3 mm diameter, nearly‐spherical polyethylene granules made up the bed. Experiments at sampling frequencies of 200‐2000 cross‐sections per second and gas superficial velocities from just below the minimum fluidization to 83% above minimum fluidization velocities were used. The time series of the cross‐sectional average void fractions have been examined both directly and in amplitude and frequency space. The last two used probability density functions and power spectral densities. The information gathered shows that the fluidized bed was operating in the slugging mode, which is not surprising given the size of the particles. It has been found that an increase in the excess gas velocity above the minimum fluidization velocity resulted in an increase in the mean void fraction, an increase in the length and velocity of the slug bubbles as well as the bed height, and a slight decrease in the slug frequency. The results are presented in a level of detail suitable for comparison with later numerical simulation.
Sequential Ir‐Catalyzed Allylation/2‐aza‐Cope Rearrangement Strategy for the Construction of Chiral Homoallylic Amines†
Authors: Wang Ruo‐Qing , Shen Chong , Cheng Xiang , Wang Zuo‐Fei , Tao Hai‐Yan , Dong Xiu‐Qin , Wang Chun‐Jiang
Published: March 2020

Summary of main observation and conclusion

Sequential Ir‐catalyzed asymmetric allylation/2‐aza‐Cope rearrangement of arylidene aminomalonates with allylic carbonates was successfully developed, and a variety of enantioenriched homoallylic amine derivatives were obtained in high yields with good chirality transfer and excellent E/Z‐geometry control (up to 99% yield, 96% ee). Compared with previous dual catalytic system established for this transformation, the current mono metal catalytic system provides a simpler and more practical protocol employing the readily available starting materials.
Radical Heteroarylalkylation of Alkenes via Three‐Component Docking‐Migration Thioetherification Cascade
Authors: Niu Tao , Liu Jige , Wu Xinxin , Zhu Chen
Published: March 2020

Summary of main observation and conclusion

A novel, rational‐designed approach to access various heteroaryl‐substituted alkyl thioethers was developed via docking‐migration cascade process. By utilizing three components involving alkene, dual‐function reagent, and thioetherificating reagent, radical heteroarylalkylation of alkenes followed by thiolation of the alkyl radical intermediates proceeded smoothly, manifesting well compatibility of substrates and cascade transformations. Furthermore, this protocol also features mild conditions, broad substrate scope, and wide product diversity.