bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Localized Heat on the Hallmarks of Cancer
Authors: Hannon Gary , Tansi Felista L. , Hilger Ingrid , Prina‐Mello Adriele
Published: May 2021

Heat has been used to treat tumors for thousands of years. There are reports of the Egyptians and Greek philosophers using such treatments as far back as 3000 BC and 500 BC respectively for various solid tumors. Albeit, in these cases, the treatment was not very controlled and consisted of hot sticks or blades placed against tissue in order to thermally ablate the tumor. It was not until recent times that the application of heat through various mediums enabled a more controlled, localized, and consistent method of treating tumors. While the therapeutic potential of this treatment has become more apparent, the mechanisms related to its efficacy are only recently beginning to surface. This review discusses the evidence associated with the effects of localized heat on the hallmarks of cancer. Key literature describing modulations to vasculature, cell viability, DNA damage and repair, metabolism, immune system, and tumor metastasis in response to heat will be reviewed along with considerations for its optimal implementation in the clinic to enhance the efficacy of conventional treatments.
Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration
Authors: Arnold Frank , Mahaddalkar Pallavi U , Kraus Johann M. , Zhong Xiaowei , Bergmann Wendy , Srinivasan Dharini , Gout Johann , Roger Elodie , Beutel Alica K. , Zizer Eugen , Tharehalli Umesh , Daiss Nora , Russell Ronan , Perkhofer Lukas , Oellinger Rupert , Lin Qiong , Azoitei Ninel , Weiss Frank‐Ulrich , Lerch Markus M. , Liebau Stefan , Katz Sarah‐Fee , Lechel André , Rad Roland , Seufferlein Thomas , Kestler Hans A. , Ott Michael , Sharma Amar Deep , Hermann Patrick C. , Kleger Alexander
Published: May 2021

Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf‐3 (DKK3) is identified as novel factor for organ regeneration using combined transcription‐factor‐induced reprogramming and RNA‐interference techniques. Loss of Dkk3 enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three‐germ‐layer differentiation or colony formation capacity of liver and pancreatic organoids. However, DKK3 expression levels in wildtype animals and serum levels in human patients are elevated upon injury. Accordingly, Dkk3‐null mice display less liver damage upon acute and chronic failure mediated by increased proliferation in hepatocytes and LGR5+ liver progenitor cell population, respectively. Similarly, recovery from experimental pancreatitis is accelerated. Regeneration onset occurs in the acinar compartment accompanied by virtually abolished canonical‐Wnt‐signaling in Dkk3‐null animals. This results in reduced expression of the Hedgehog repressor Gli3 and increased Hedgehog‐signaling activity upon Dkk3 loss. Collectively, these data reveal Dkk3 as a key regulator of organ regeneration via a direct, previously unacknowledged link between DKK3, canonical‐Wnt‐, and Hedgehog‐signaling.
Inkjet Printed Circuits with 2D Semiconductor Inks for High‐Performance Electronics
Authors: Carey Tian , Arbab Adrees , Anzi Luca , Bristow Helen , Hui Fei , Bohm Sivasambu , Wyatt‐Moon Gwenhivir , Flewitt Andrew , Wadsworth Andrew , Gasparini Nicola , Kim Jong M. , Lanza Mario , McCulloch Iain , Sordan Roman , Torrisi Felice
Published: May 2021

Air‐stable semiconducting inks suitable for complementary logic are key to create low‐power printed integrated circuits (ICs). High‐performance printable electronic inks with 2D materials have the potential to enable the next generation of high performance low‐cost printed digital electronics. Here, the authors demonstrate air‐stable, low voltage (<5 V) operation of inkjet‐printed n‐type molybdenum disulfide (MoS2), and p‐type indacenodithiophene‐co‐benzothiadiazole (IDT‐BT) field‐effect transistors (FETs), estimating an average switching time of τMoS2 ≈ 4.1 μs for the MoS2 FETs. They achieve this by engineering high‐quality MoS2 and air‐stable IDT‐BT inks suitable for inkjet‐printing complementary pairs of n‐type MoS2 and p‐type IDT‐BT FETs. They then integrate MoS2 and IDT‐BT FETs to realize inkjet‐printed complementary logic inverters with a voltage gain |Av| ≈ 4 when in resistive load configuration and |Av| ≈ 1.4 in complementary configuration. These results represent a key enabling step towards ubiquitous long‐term stable, low‐cost printed digital ICs.
Simultaneous Enhancement of Actuation Strain and Mechanical Strength of Nanoporous Ni–Mn Actuators
Authors: Cheng Chuan , Lührs Lukas , Krekeler Tobias
Published: May 2021

Metallic electrochemical actuators convert electrical energy into mechanical energy via charge‐induced strain at the nanoporous metal/electrolyte interface. To enhance the actuation amplitude, a general choice is to increase the electrode surface area to elevate the charge capacity. However, a large surface area is detrimental to the actuation stability and mechanical strength of the actuator, such as irreversible volume shrinkage due to surface coarsening. Here, this critical issue can be mitigated by introducing a secondary actuation metal (Mn) into the network of a primary actuation metal (Ni). A nanoporous Ni–Mn actuator is synthesized by chemical dealloying with a controllable Mn content by adjusting dealloying conditions. Mn enriched nanowires are entangled with much larger sized Ni nanoligaments throughout the whole nanoporous network. Mn contributes a two‐electron‐transfer redox of Mn(OH)2/MnOOH/MnO2, which induces reversible volume change via H+ intercalation/deintercalation. It is more efficient for strain generation than a one‐electron‐transfer redox of Ni(OH)2/NiOOH in the host. A recorded high reversible strain of 1.94% is obtained. Simultaneously, the mechanical strength of the actuator exponentially increases with the relative density due to the introduction of the secondary actuation metal.
Nitrogen management of furrow‐irrigated rice on clayey soils
Authors: Chlapecka Justin L. , Hardke Jarrod T. , Roberts Trenton L. , Gbur Edward E.
Published: May 2021

Furrow‐irrigated rice (Oryza sativa L.) (FIR) has garnered increasing attention in Arkansas and across the Mid‐South, as more than 15% of Arkansas’ rice crop now utilizes furrow irrigation water management. Because of this recent interest, little data exists on FIR production management. Studies were conducted from 2018 to 2020 to determine the optimum nitrogen (N) management program for FIR production on clayey soils. Nine N management strategies were studied in 2018 and 2019, including one‐ to four‐way applications and several rates, with one additional approach in 2020. Five site‐years were utilized where grain yield, milling yield, and total nitrogen uptake (TNU) were examined. Grain and milling yield were consistently maximized with a three‐way split consisting of 84 kg N ha–1 at V5–V6 (pre‐irrigation), 84 kg N ha–1 2 wk later, and 52 kg N ha–1 1 wk after the second application. Grain yield averaged 10,307–12,585 kg ha–1 while head rice yield averaged 52.2–62.1% under the 84/0/84/52 kg N ha–1 split. Total N uptake was greatest where three to four applications and/or a higher total N rate were utilized across all years, while a two‐way split or greater maximized TNU in 2020 alone. Recovery efficiency of nitrogen (REn) and agronomic efficiency of nitrogen (AEn) were generally higher with a greater number of split applications. Average REn for the 84/0/84/52 kg N ha–1 split was 34.4–50.6%. Results suggest that an additional 52–67 kg N ha–1 and/or additional N applications are warranted to maximize FIR production on clayey soils compared to recommendations in a traditional flooded system.
A multi‐environment analysis of winter faba bean germplasm for cover crop traits
Authors: Brasier Kyle , Smither‐Kopperl Margaret , Bullard Valerie , Young‐Matthews Anna , Bartow Amy , Friddle Mara , Bernau Christopher , Humphrey Mathew , Dial Heather , Wolf Mary , Hu Jinguo , Zakeri Hossein
Published: May 2021

Faba bean (Vicia faba L.) cultivars for cover cropping have remained unchanged in the western United States over the past century. Although breeding efforts have improved grain production across much of the world, improvement of the crop for cover crop applications (e.g., biomass production at the flowering stage) remains understudied. Therefore, a trial of nine newly developed faba bean lines from the USDA‐ARS and four commercial checks (‘Bell Bean’, ‘V4’, ‘V5’, and ‘Windsor’) was established to evaluate cover crop traits across six diverse testing environments. The experiment revealed significant genotype × environment interactions for winter vigor, nitrogen (N) concentration, and aboveground N yield. Significant genotypic variation was observed for important cover crop traits including winter vigor, spring vigor, aboveground biomass, and aboveground N yield, whereas variation for percentage of N derived from the atmosphere was primarily determined by the testing environment. The study also identified a strong association between early plant vigor and aboveground biomass (r = .71), which offers potential increases in breeding efficiencies. In addition, advanced faba bean lines from the USDA‐ARS were shown to produce twice the biomass of Bell Bean across testing environments, and faba bean line PS18301 produced at least 20% more aboveground N yield in five out of the six environments than the conventionally used cover crop cultivars Windsor and Bell Bean. Faba bean lines in this study may be used by cover crop breeders as parent materials.
The influence and countermeasure of obesity in laparoscopic colorectal resection
Authors: Kashihara Hideya , Shimada Mitsuo , Yoshikawa Kozo , Higashijima Jun , Tokunaga Takuya , Nishi Masaaki , Takasu Chie , Yoshimoto Toshiaki
Published: May 2021

Background

The aim of this study was to investigate the influence of obesity and the usefulness of a preoperative weight loss program (PWLP) for obese patients undergoing laparoscopic colorectal resection (LCR).

Methods

Study 1: 392 patients who underwent LCR for colorectal cancer were divided into two groups: those with a body mass index (BMI) ≥25 kg/m2 (n = 113) and those with a BMI <25 kg/m2 (n = 279). The influence of BMI on LCR was investigated. Study 2: Patients with a BMI ≥28 kg/m2 who were scheduled to undergo LCR (n = 7, mean body weight 87.0 kg, mean BMI 33.9 kg/m2) undertook a PWLP including caloric restriction and exercise for 29.6 (15–70) days. The effects of this program were evaluated.

Results

Study 1: The BMI ≥25 kg/m2 group had a prolongation of operation time and hospital stay than the BMI <25 kg/m2 group. Study 2: The patients achieved a mean weight loss of 6.9% (−6.0 kg). The mean visceral fat area was significantly decreased by 18.0%, whereas the skeletal muscle mass was unaffected. The PWLP group had a significantly lower prevalence of postoperative complications compared with the BMI ≥25 kg/m2 group.

Conclusion

Obesity affected the surgical outcomes in LCR. A PWLP may be useful for obese patients undergoing LCR.
Rejecting Gargoylism: Reflections on the term and its relationship to Hurler syndrome
Authors: Abbott Mary‐Alice , Diebold William J. , Rosengren Sally S.
Published: May 2021

Just over a century ago, Dr. Gertrud Hurler described what is now commonly called Hurler syndrome. This rare inherited condition became known by terms describing its cardinal physical signs; the eponymous name was not proposed. In 1936, Ellis et al. coined the term “gargoylism” to name the syndrome. We propose that the film The Hunchback of Notre Dame played a key role in the original association of Hurler syndrome with the architectural figures known as gargoyles and with the persistence of the term. Over time, due in large part to its extremely negative connotations and lack of accuracy, “gargoylism” was abandoned. It has been supplanted by a sophisticated clinical understanding of mucopolysaccharidosis type 1 (MPS1), the underlying enzymatic defect, and dramatic advances in early diagnosis and treatment.
The portrayal of people with dwarfism in Chinese art
Authors: Wu Liuyin , Zhou Ying , Zhang Dan , Shen Yiping , Liu Aixia
Published: May 2021

Dwarfism has been depicted in various Chinese art forms including literature, sculpture, and painting. This article examines several representative Chinese works of art from different ages of Chinese history, in order to glimpse the living situations of people with dwarfism, their professions and social status, as well as the social attitude toward them in China. We highlight “山海经” (Shan Hai Jing, translated as the Classic of Mountains and Seas), a remarkable collection of myths and illustrations which documented the existence of dwarf communities where the residents were capable of producing high‐quality grains. Representations from sculptures and paintings frequently captured the images of individuals with dwarfism in royal courts, which showed their remarkable performance skills and social ability. There are also works of art associating dwarfism with rituals. In addition to portraying ordinary individuals with humble social status, there was one particular individual with dwarfism named Yan Zi (晏子) who was highly regarded as a figure of wisdom. Throughout the long Chinese history, dwarfism had been portrayed in art as either positive, neutral or derogatory, which reflected the fact that people with dwarfism, while short in stature, are usually intellectually normal, generally skillful, and often talented, in short, like the general population.
Teaching healthcare professionals to see
Authors: Ganske Ingrid , Khoshbin Shahram , Katz Joel T.
Published: May 2021

Prerequisite to establishing a diagnosis, healthcare providers must detect and appreciate subtle cues to dysfunction, disease and dysmorphology. A medical school course designed to connect art observation and diagnosis addresses the ongoing erosion of careful looking, which is at the core of detecting malformations and dysmorphologies, among other medical conditions. We present an example from within the field of medical genetics of how the skill of deep looking can be taught.
Acute Toxicity, Biodistribution, and Pharmacokinetics Studies of Pegylated Platinum Nanoparticles in Mouse Model
Authors: Mukherjee Sudip , Bollu Vishnu Sravan , Roy Arpita , Nethi Susheel Kumar , Madhusudana Kuncha , Kumar Jerald Mahesh , Sistla Ramakrishna , Patra Chitta Ranjan
Published: May 2021

Pegylated colloidal platinum nanoparticles (PEG‐PtNPs) are widely used as a potential agent for diagnosis and therapy of various diseases including cancer. Prior to any preclinical applications, detailed investigations of toxicity, biodistribution, clearance, and pharmacokinetics (PKs) of new nanomaterials are essential. Extensive toxicological studies of PEG‐PtNPs are not reported in a systematic manner elsewhere. Herein, acute toxicity of PEG‐PtNPs is thoroughly investigated in mouse model. Prior to study in mice, a hemolytic analysis is performed with PtNPs that displays biocompatible nature. Administration of a single intraperitoneal dose of PEG‐PtNPs (10 and 50 mg kg−1 body weight) in mice does not induce any gross pathological changes. The data obtained from hematology, serum biochemistry, and histopathological analysis indicate no significant changes except for moderate nephrotoxicity at the higher dose. In addition, a PK analysis displays a maximum retention time and elimination half‐life at 10 mg kg−1 b.w. dose. Biodistribution studies demonstrate maximum accumulation of platinum in spleen tissue and tail of mice. Finally, detection of platinum in feces and urine confirms their excretion through a hepatobiliary system. Altogether, this study indicates that 10 mg kg−1 b.w. therapeutic dose of PEG‐PtNPs is safe for their potential future application in cancer theranostics.
Manipulation of Polarizations with Crystalline Orientation for an Elliptically Polarized Passively Q‐Switched Raman Laser
Authors: An Yinming , Yang Haolin , Lin Bohan , Bi Jiaxiang , Dong Jun
Published: May 2021

Polarization control of dual‐wavelength high peak power Raman lasers based on passively Q‐switched technology and yttrium vanadate (YVO4) crystal are widely used for generating novel laser sources, terahertz wave, material processing, and manipulating microparticles. However, the Raman lasers are usually linear polarization. Here, elliptical polarizations with controllable ellipticity and azimuthal angle are manipulated by adjusting the crystalline orientation of a‐cut YVO4 crystal in a passively Q‐switched Raman laser constructed with a Cr4+,Nd3+:Y3Al5O12 (Cr,Nd:YAG) crystal and a a‐cut YVO4 crystal. The ellipticity of the elliptically polarized dual‐wavelength Raman laser varies in a sinusoid modulation as a‐cut YVO4 crystal rotates with respect to the major axis of the intracavity fundamental laser and increases with applied pump power. The azimuthal angle varies in the same speed as a‐cut YVO4 crystal rotates. Anisotropic behavior of sinusoidal modulation of output power, pulse energy, and peak power is observed as a‐cut YVO4 crystal rotates. There are four peaks and four troughs for ellipticity, output power, pulse energy, and peak power within a 360° rotation of a‐cut YVO4 crystal. This work provides a solid and simple method for developing elliptical polarization controllable dual‐wavelength passively Q‐switched Raman laser with high peak power for various potential applications.
Chemical Identification of Catalytically Active Sites on Oxygen‐doped Carbon Nanosheet to Decipher the High Activity for Electro‐synthesis Hydrogen Peroxide
Authors: Chen Shanyong , Luo Tao , Chen Kejun , Lin Yiyang , Fu Junwei , Liu Kang , Cai Chao , Wang Qiyou , Li Huangjingwei , Li Xiaoqing , Hu Junhua , Li Hongmei , Zhu Mingshan , Liu Min
Published: May 2021

Electrochemical production of hydrogen peroxide (H2O2) through two‐electron (2 e−) oxygen reduction reaction (ORR) is an on‐site and clean route. Oxygen‐doped carbon materials with high ORR activity and H2O2 selectivity have been considered as the promising catalysts, however, there is still a lack of direct experimental evidence to identify true active sites at the complex carbon surface. Herein, we propose a chemical titration strategy to decipher the oxygen‐doped carbon nanosheet (OCNS900) catalyst for 2 e− ORR. The OCNS900 exhibits outstanding 2 e− ORR performances with onset potential of 0.825 V (vs. RHE), mass activity of 14.5 A g−1 at 0.75 V (vs. RHE) and H2O2 production rate of 770 mmol g−1 h−1 in flow cell, surpassing most reported carbon catalysts. Through selective chemical titration of C=O, C−OH, and COOH groups, we found that C=O species contributed to the most electrocatalytic activity and were the most active sites for 2 e− ORR, which were corroborated by theoretical calculations.
Effect of long‐chain branching molar fraction on scratch behavior of polypropylene
Authors: Tsai Chia‐Ying , Chang Chao‐Shun , Zhao Mingzhen , Sue Hung‐Jue
Published: May 2021

Polymers containing a certain amount of long‐chain‐branching (LCB) structure are expected to possess improved mechanical properties over those of the linear structure counterpart. However, fundamental knowledge on the structure–property relationship in LCB containing polypropylene (PP) is still illusive. In the present study, a set of model PP systems containing an increasing molar fraction of LCB (5–19 mol%) were prepared by reactive extrusion to determine how LCB content may influence the scratch behavior of PP. It is shown that with only 5 mol% of LCB content in PP can improve resistance against scratch‐induced fish‐scale formation by over 25%. The improvement of scratch resistance is attributed to the increases in entanglement density in LCB‐containing PPs, which is evidenced by their creep‐recovery behavior. The present study demonstrates that the incorporation of LCB in PP leads to higher viscoelastic recovery and increased tensile strength, which account for the observed improvement in scratch performance. The usefulness of LCB in polymers for improving scratch performance is discussed.
Dynamic evaluation of swallowing in pediatric patients with dysphagia: The Brazilian perspective
Authors: Gonçalves Maria Ines R. , Lederman Henrique M.
Published: May 2021

Dynamic Evaluation of Swallowing (DES) is an exam which provides invaluable information on the swallowing function. This review describes the requirements, protocols and processes for DES in regions of Brazil. Dysphagia is a swallowing abnormality, in one or more swallowing phases, with risk and/or occurrence of aspiration, damage regarding nutrition and/or hydration and possible need of nonoral feeding methods. DES is performed in an armored room, using fluoroscopy, with the patient in lateral and anteroposterior views, in an orthostatic position. Different consistencies and volumes are tested, depending on the patient's age, complaint and clinical conditions. Its main objective is to determine if the patient can safely eat orally, is able to meet his basic nutritional and hydration needs, or if alternative means of feeding are necessary. It allows anatomical observation of structures, and the dynamics of swallowing during oral, pharyngeal and esophageal phases, in real time. The DES is used worldwide for pediatric patients, from newborns to adolescents, for a complete assessment. In Brazil, the exam is the state of the art in the functional evaluation of swallowing, however it is only available to a fraction of the population, mostly in the largest, and economically developed cities, and usually restricted to major health centers and teaching hospitals. Implementing DES in healthcare units requires radiological equipment, infrastructure standards, availability and training of personnel, as well as specialized physicians, and speech‐language pathologists. For these reasons, our services face daily challenges while managing long scheduling waiting lists.
Augmentation of Stimulator of Interferon Genes–Induced Type I Interferon Production in COPA Syndrome
Authors: Kato Takashi , Yamamoto Masaki , Honda Yoshitaka , Orimo Takashi , Sasaki Izumi , Murakami Kohei , Hemmi Hiroaki , Fukuda‐Ohta Yuri , Isono Kyoichi , Takayama Saki , Nakamura Hidenori , Otsuki Yoshiro , Miyamoto Toshiaki , Takita Junko , Yasumi Takahiro , Nishikomori Ryuta , Matsubayashi Tadashi , Izawa Kazushi , Kaisho Tsuneyasu
Published: May 2021

Objective

Coatomer subunit alpha (COPA) syndrome, also known as autoinflammatory interstitial lung, joint, and kidney disease, is caused by heterozygous mutations in COPA. We identified a novel COPA variant in 4 patients in one family. We undertook this study to elucidate whether and how the variant causes manifestations of COPA syndrome by studying these 4 patients and by analyzing results from a gene‐targeted mouse model.

Methods

We performed whole‐exome sequencing in 7 family members and measured the type I interferon (IFN) signature of the peripheral blood cells. We analyzed the effects of COPA variants in in vitro experiments and in Copa mutant mice that were generated.

Results

We identified a heterozygous variant of COPA (c.725T>G, p.Val242Gly) in the 4 affected members of the family. The IFN score was high in the members carrying the variant. In vitro analysis revealed that COPA V242G, as well as the previously reported disease‐causing variants, augmented stimulator of interferon genes (STING)–induced type I IFN promoter activities. CopaV242G/+ mice manifested interstitial lung disease and STING‐dependent elevation of IFN‐stimulated gene expression. In CopaV242G/+ dendritic cells, the STING pathway was not constitutively activated but was hyperactivated upon stimulation, leading to increased type I IFN production.

Conclusion

V242G, a novel COPA variant, was found in 4 patients from one family. In gene‐targeted mice with the V242G variant, interstitial lung disease was recapitulated and augmented responses of the STING pathway, leading to an increase in type I IFN production, were demonstrated.
Amelioration of Posttraumatic Osteoarthritis in Mice Using Intraarticular Silencing of Periostin via Nanoparticle‐Based Small Interfering RNA
Authors: Duan Xin , Cai Lei , Pham Christine T. N. , Abu‐Amer Yousef , Pan Hua , Brophy Robert H. , Wickline Samuel A. , Rai Muhammad Farooq
Published: May 2021

Objective

Recent evidence delineates an emerging role of periostin in osteoarthritis (OA), since its expression after knee injury is detrimental to the articular cartilage. We undertook this study to examine whether intraarticular (IA) knockdown of periostin would ameliorate posttraumatic OA in a murine model.

Methods

Posttraumatic OA was induced in 10‐week‐old male C57BL/6J mice (n = 24) by destabilization of the medial meniscus (DMM), and mice were analyzed 8 weeks after surgery. Periostin expression was inhibited by small interfering RNA (siRNA) delivered IA using a novel peptide–nucleotide polyplex. Following histologic assessment of the mouse knee cartilage, the extent of cartilage degeneration was determined using Osteoarthritis Research Society International (OARSI) cartilage damage score, and severity of synovitis was also assessed. Bone changes were measured using micro–computed tomography. The effect and mechanism of periostin silencing were investigated in human chondrocytes that had been stimulated with interleukin‐1β (IL‐1β) with or without the IκB kinase 2 inhibitor SC‐514.

Results

Periostin expression in mice with posttraumatic OA was significantly abolished using IA delivery of a peptide–siRNA nanoplatform. OARSI cartilage damage scores were significantly lower in mice receiving periostin siRNA (mean ± SEM 10.94 ± 0.66) compared to untreated mice (22.38 ± 1.30) and mice treated with scrambled siRNA (22.69 ± 0.87) (each P = 0.002). No differences in the severity of synovitis were observed. Subchondral bone sclerosis, bone volume/total volume, volumetric bone mineral density, and heterotopic ossification were significantly lower in mice that had received periostin siRNA treatment. Immunostaining of cartilage revealed that periostin knockdown reduced the intensity of DMM‐induced matrix metalloproteinase 13 (MMP‐13) expression and also diminished the phosphorylation of p65 and immunoreactivity of the aggrecan neoepitope DIPEN. Periostin knockdown also suppressed IL‐1β–induced MMP‐13 and ADAMTS‐4 expression in chondrocytes. Mechanistically, periostin‐induced MMP‐13 expression was abrogated by SC‐514, demonstrating a link between periostin and NF‐κB.

Conclusion

IA delivery of the periostin–siRNA nanocomplex represents a promising clinical approach to mitigate the severity of joint degeneration in OA. Our findings may thus provide an unequivocal scientific rationale for longitudinal studies of this approach. Utilizing a cartilage‐specific gene‐knockout strategy will further illuminate the functional role of periostin in OA.
Lupus Susceptibility Region Containing CDKN1B rs34330 Mechanistically Influences Expression and Function of Multiple Target Genes, Also Linked to Proliferation and Apoptosis
Authors: Singh Bhupinder , Maiti Guru P. , Zhou Xujie , Fazel‐Najafabadi Mehdi , Bae Sang‐Cheol , Sun Celi , Terao Chikashi , Okada Yukinori , Heng Chua Kek , Kochi Yuta , Guthridge Joel M. , Zhang Hong , Weirauch Matthew , James Judith A. , Harley John B. , Varshney Gaurav K. , Looger Loren L. , Nath Swapan K.
Published: May 2021

Objective

In a recent genome‐wide association study, a significant genetic association between rs34330 of CDKN1B and risk of systemic lupus erythematosus (SLE) in Han Chinese was identified. This study was undertaken to validate the reported association and elucidate the biochemical mechanisms underlying the effect of the variant.

Methods

We performed an allelic association analysis in patients with SLE, followed by a meta‐analysis assessing genome‐wide association data across 11 independent cohorts (n = 28,872). In silico bioinformatics analysis and experimental validation in SLE‐relevant cell lines were applied to determine the functional consequences of rs34330.

Results

We replicated a genetic association between SLE and rs34330 (meta‐analysis P = 5.29 × 10−22, odds ratio 0.84 [95% confidence interval 0.81–0.87]). Follow‐up bioinformatics and expression quantitative trait locus analysis suggested that rs34330 is located in active chromatin and potentially regulates several target genes. Using luciferase and chromatin immunoprecipitation–real‐time quantitative polymerase chain reaction, we demonstrated substantial allele‐specific promoter and enhancer activity, and allele‐specific binding of 3 histone marks (H3K27ac, H3K4me3, and H3K4me1), RNA polymerase II (Pol II), CCCTC‐binding factor, and a critical immune transcription factor (interferon regulatory factor 1 [IRF‐1]). Chromosome conformation capture revealed long‐range chromatin interactions between rs34330 and the promoters of neighboring genes APOLD1 and DDX47, and effects on CDKN1B and the other target genes were directly validated by clustered regularly interspaced short palindromic repeat (CRISPR)–based genome editing. Finally, CRISPR/dead CRISPR‐associated protein 9–based epigenetic activation/silencing confirmed these results. Gene‐edited cell lines also showed higher levels of proliferation and apoptosis.

Conclusion

Collectively, these findings suggest a mechanism whereby the rs34330 risk allele (C) influences the presence of histone marks, RNA Pol II, and IRF‐1 transcription factor to regulate expression of several target genes linked to proliferation and apoptosis. This process could potentially underlie the association of rs34330 with SLE.
Cancer progression as a sequence of atavistic reversions
Authors: Lineweaver Charles H. , Bussey Kimberly J. , Blackburn Anneke C. , Davies Paul C. W.
Published: May 2021

It has long been recognized that cancer onset and progression represent a type of reversion to an ancestral quasi‐unicellular phenotype. This general concept has been refined into the atavistic model of cancer that attempts to provide a quantitative analysis and testable predictions based on genomic data. Over the past decade, support for the multicellular‐to‐unicellular reversion predicted by the atavism model has come from phylostratigraphy. Here, we propose that cancer onset and progression involve more than a one‐off multicellular‐to‐unicellular reversion, and are better described as a series of reversionary transitions. We make new predictions based on the chronology of the unicellular‐eukaryote‐to‐multicellular‐eukaryote transition. We also make new predictions based on three other evolutionary transitions that occurred in our lineage: eukaryogenesis, oxidative phosphorylation and the transition to adaptive immunity. We propose several modifications to current phylostratigraphy to improve age resolution to test these predictions. Also see the video abstract here: https://youtu.be/3unEu5JYJrQ
Neuronal circuits on a chip for biological network monitoring
Authors: Herreros Pedro , Ballesteros‐Esteban Luis M. , Laguna María Fe , Leyva Inmaculada , Sendiña‐Nadal Irene , Holgado Miguel
Published: May 2021

Cultured neuronal networks (CNNs) are a robust model to closely investigate neuronal circuits’ formation and monitor their structural properties evolution. Typically, neurons are cultured in plastic plates or, more recently, in microfluidic platforms with potentially a wide variety of neuroscience applications. As a biological protocol, cell culture integration with a microfluidic system provides benefits such as accurate control of cell seeding area, culture medium renewal, or lower exposure to contamination. The objective of this report is to present a novel neuronal network on a chip device, including a chamber, fabricated from PDMS, vinyl and glass connected to a microfluidic platform to perfuse the continuous flow of culture medium. Network growth is compared in chips and traditional Petri dishes to validate the microfluidic chip performance. The network assessment is performed by computing relevant topological measures like the number of connected neurons, the clustering coefficient, and the shortest path between any pair of neurons throughout the culture's life. The results demonstrate that neuronal circuits on a chip have a more stable network structure and lifespan than developing in conventional settings, and therefore this setup is an advantageous alternative to current culture methods. This technology could lead to challenging applications such as batch drug testing of in vitro cell culture models. From the engineering perspective, a device's advantage is the chance to develop custom designs more efficiently than other microfluidic systems.
Microfluidic encapsulation of nanoparticles in alginate microgels gelled via competitive ligand exchange crosslinking
Authors: Cinel Victor Dal Posolo , Taketa Thiago Bezerra , de Carvalho Bruna Gregatti , de la Torre Lucimara Gaziola , de Mello Lucas Rodrigues , da Silva Emerson Rodrigo , Han Sang Won
Published: May 2021

Efficient delivery of nanometric vectors complexed with nanoparticles at a target tissue without spreading to other tissues is one of the main challenges in gene therapy. One means to overcome this problem is to confine such vectors within microgels that can be placed in a target tissue to be released slowly and locally. Herein, a conventional optical microscope coupled to a common smartphone was employed to monitor the microfluidic production of monodisperse alginate microgels containing nanoparticles as a model for the encapsulation of vectors. Alginate microgels (1.2%) exhibited an average diameter of 125 ± 3 μm, which decreased to 106 ± 5 μm after encapsulating 30 nm fluorescent nanoparticles. The encapsulation efficiency was 70.9 ± 18.9%. In a 0.1 M NaCl solution, 55 ± 5% and 92 ± 4.7% of nanoparticles were released in 30 minutes and 48 hours, respectively. Microgel topography assessment by atomic force microscopy revealed that incorporation of nanoparticles into the alginate matrix changes the scaffold's interfacial morphology and induces crystallization with the appearance of oriented domains. The high encapsulation rate of nanoparticles, alongside their continuous release of nanoparticles over time, makes these microgels and the production unit a valuable system for vector encapsulation for gene therapy research.
Development of an HPLC–MS method for the determination of four terpene trilactones in Ginkgo biloba leaf extract via quality by design
Authors: Zhang Sijie , Wu Linlin , Wang Xiaoping , Gong Xingchu , Qu Haibin
Published: May 2021

Previously reported HPLC–evaporative light scattering detection methods for terpene trilactone determination in Ginkgo biloba leaf extract (EGBL) have complicated sample preparation steps and are time‐consuming. Thus, in this work, an HPLC–MS method for the determination of terpene trilactones in EGBL was developed with a novel analytical quality by design approach to provide robust and simple measurements. For this purpose, analytical target profiles and systematic risk analyses were performed to identify potential critical method attributes and critical method parameters. After screening experiments, a Box–Behnken design approach was utilized to investigate the relationships between critical method attributes and critical method parameters. A hypercube design space obtained by a Monte Carlo method was used for choosing the analytical control strategy. Then, verification experiments were performed within the design space, and the models were found to be accurate. After that, the optimized method was verified and successfully used for quality control analysis of EGBL from different manufacturers, and the results were almost the same as those determined by HPLC–evaporative light scattering detection. To our knowledge, this is the first study to establish a robust HPLC–MS method for determination of terpene trilactones in EGBL based on a novel analytical quality by design concept, which can improve the quality control of commercial EGBL.
Pharmacokinetics and tissue distribution of cantharidin after oral administration of aqueous extracts from Mylabris in rats
Authors: Duan Cancan , Cheng Weina , Chen Qihong , Li Xiaofei , Zhang Jianyong
Published: May 2021

A sensitive gas chromatography–mass spectroscopy method was established for the determination of cantharidin (CTD) in rat plasma and liver homogenates. During the experiment, rats were randomly divided into two groups (low, high) and were administered aqueous extract of Mylabris compound for 7 days. Then, plasma and tissue samples were taken at different time points to study the pharmacokinetics and tissue distribution of CTD in rats. The selected reaction monitoring transitions for CTD and clofibrate (internal standard) were m/z 128 → 85 and m/z 169 → 141, respectively. The calibration curve ranged from 10.26 to 3,078 ng/ml for plasma and from 10.26 to 246.24 ng/ml for liver homogenates. The lower limits of quantification were 10.26 ng/ml for both plasma and liver. The intra‐ and inter‐day precision and accuracy were <20% for both plasma and liver homogenates. Extraction recovery ranged from 89.21 to 103.61% for CTD in rat plasma and liver and from 83.79 to 102.74% for IS in rat plasma and liver. Matrix effects ranged from 93.06 to 110.44% for CTD and from 91.65 to 110.80% for IS.
Emplacing linked lives: A qualitative approach to understanding the co‐evolution of residential mobility and place attachment formation over time
Authors: Bailey Etienne , Devine‐Wright Patrick , Batel Susana
Published: May 2021

Despite growing interest in issues of residential mobility and place attachment in a globalised world, research within Environmental and Community psychology has tended to overlook the ways that interpersonal relations, and wider socio‐political and economic structural factors inform place attachment formation amongst residentially mobile individuals. We address this gap drawing on the Human Geography concept of ‘Linked Lives’ (Coulter et al., Progress in Human Geography, 2016, 40(3), 352–374), to conceive the relocation decisions of residentially mobile individuals, and their place (non)attachment to the current residence place, as deeply intertwined with formative place experiences, interpersonal relations, and the structural contexts within which people live (Coulter et al., Progress in Human Geography, 2016, 40(3), 352–374). With the aim of deepening understanding of the co‐evolution of residential mobility and place attachment, this paper presents narrative case studies of residents living in a town in Southwest England, with each resident indicating a different variety of people–place relations to their current residence place. Findings indicate that moving intentions and consequent residential place attachment result from complex interactions over time between (a) formative place experiences and settlement identities, leading to preferred types of residence place; (b) interpersonal relations with significant others including family and community members that vary according to life stage events; and (c) structural forces, comprising cultural, economic, and political factors shaping people's lives. Future research could examine how structural changes arising from the COVID‐19 pandemic are influencing residential mobilities and attachments to place.
Dual‐Knockout of Mutant Isocitrate Dehydrogenase 1 and 2 Subtypes Towards Glioma Therapy: Structural Mechanistic Insights on the Role of Vorasidenib
Authors: Poonan Preantha , Agoni Clement , Soliman Mahmoud E. S.
Published: May 2021

Recently, Vorasidenib (AG‐881) has been reported as a therapeutic alternative that exerts potent dual inhibitory activity against mIDH1/2 towards the treatment of low‐grade glioma. However, structural and dynamic events associated with its dual inhibition mechanism remain unclear. As such, we employ integrative computer‐assisted atomistic techniques to provide thorough structural and dynamic insights. Our analysis proved that the dual‐targeting ability of AG‐881 is mediated by Val255/Val294 within the binding pockets of both mIDH1 and mIDH2 which are shown to elicit a strong intermolecular interaction, thus favoring binding affinity. The structural orientations of AG‐881 within the respective hydrophobic pockets allowed favorable interactions with binding site residues which accounted for its high binding free energy of −28.69 kcal/mol and −19.89 kcal/mol towards mIDH1 and mIDH2, respectively. Interestingly, upon binding, AG‐881 was found to trigger systemic alterations of mIDH1 and mIDH2 characterized by restricted residue flexibility and a reduction in exposure of residues to the solvent surface area. As a result of these structural alterations, crucial interactions of the mutant enzymes were inhibited, a phenomenon that results in a suppression of the production of oncogenic stimulator 2‐HG. Findings therefore provide thorough structural and dynamic insights associated with the dual inhibitory activity of AG‐881 towards glioma therapy.
Bewertung von Energieeffizienztechnologien mit der Methodik EDUAR&D an zwei Beispielen
Authors: Schäfer Bernhard , Toro Chacón Felipe Andrés , Brinkmann Thorsten , Drews Anja , Jochem Eberhard , Sauer Jörg
Published: May 2021

Die Methodik EDUAR&D, kurz für Energiedaten und ‐analyse R&D, wird zur Bewertung von Energieeffizienztechniken genutzt. Es handelt sich um einen strukturierten Such‐ und Analyseprozess, der verschiedene methodische Ansätze zur Darstellung, Analyse und Bewertung der Techniken miteinander verbindet. Ziel ist es, Handlungsempfehlungen, z. B. bzgl. thematischer Schwerpunktsetzung, für die zukünftige Energieforschung im Rahmen der Forschungsförderung und für die Energiepolitik abzuleiten. Die Methodik wird hier am Beispiel der organophilen Nanofiltration und der Latentwärmespeicher vorgestellt.
A Small Molecule with Bridged Carbonyl and Tri‐fluoro‐aceto‐phenone Groups Impedes Microtubule Dynamics and Subsequently Triggers Cancer Cell Apoptosis
Authors: Mohapatra Saswat , Gupta Varsha , Mondal Prasenjit , Chatterjee Shreyam , Bhunia Debmalya , Ghosh Surajit
Published: May 2021

We identified a new microtubule targeted small molecule, which showed significant anticancer activity and induced apoptotic death of cancer cells. Precisely the central bridged carbonyl group and trifluoro‐acetophenone group of a bis‐benzothiazole molecule (BBT) interacts with tubulin close to the curcumin site and perturbs microtubule dynamics as well as causes microtubule depolymerization. We observed a significant enhancement of fluorescence while BBT interacts with the tubulin through bridged carbonyl moiety, a similar phenomenon to colchicine. Further, BBT activates tumor‐suppressing bim and p53‐puma axes to inhibit cancer survival. It also shows promising results against a tumor spheroid model. BBT is also capable of tumor regression, which shows that this molecule can serve as a potential template for the design of next‐generation microtubule targeted anticancer drugs.
On the undetectability of payloads generated through automatic tools: A human‐oriented approach
Authors: Carpentieri Bruno , Castiglione Arcangelo , Palmieri Francesco , Pizzolante Raffaele
Published: May 2021

Nowadays, several tools have been proposed to support the operations performed during a security assessment process. In particular, it is a common practice to rely on automated tools to carry out some phases of this process in an automatic or semiautomatic way. In this article, we focus on tools for the automatic generation of custom executable payloads. Then, we will show how these tools can be transformed, through some human‐oriented modifications on the generated payloads, into threats for a given asset's security. The danger of such threats lies in the fact that they may not be detected by common antivirus (AVs). More precisely, in this article, we show a general approach to make a payload generated through automated tools run undetected by most AVs. In detail, we first analyze and explain most of the methods used by AVs to recognize malicious payloads and, for each one of them, we outline the relative strengths and flaws, showing how these flaws could be exploited using a general approach to evade AVs controls, by performing simple human‐oriented operations on the payloads. The testing activity we performed shows that our proposal is helpful in evading virtually all the most popular AVs on the market. Therefore, low‐skilled malicious users could easily use our approach.
Stakeholder engagement and firms' innovation: Evidence from LGBT‐supportive policies
Authors: Kyaw Khine , Treepongkaruna Sirimon , Jiraporn Pornsit
Published: May 2021

There is a paucity of research on the effects corporate policies have on fostering innovative activities in firms, while research and development (R&D) investments offer a source of innovations in firms. Using governance data from Kinder, Lyndenberg, and Domini, Research and Analytics, Inc., R&D and financial data from Compustat, and market data from CRSP during the period from 1996 through 2011 this paper investigates whether Lesbian, Gay, Bisexual and Transgender (LGBT) ‐supportive corporate policies promote innovative activities in US firms. To the extent that LGBT–friendly policies allow inclusive working environments and therefore attract and retain talents, corporate can engage more in innovative activities. The findings show that firms with LGBT–supportive policies nurture employees' commitment to the firms and engage more in innovative activities. Heckman selection model, propensity score matching and difference‐in‐difference results all confirm the main findings from instrumental variable (IV) analyses.
NiIII‐rich NiFeBa as an Efficient Catalyst for Water Oxidation
Authors: Zhang Peili , Song Tao , Zheng Dehua , Li Fusheng , Wu Xiujuan , Fan Ke , Sun Licheng
Published: May 2021

Electrocatalytic water oxidation requires efficient catalysts to reduce the overpotential and accelerate the sluggish kinetics of oxygen formation. Here, a promising NiFeBa material was prepared by the co‐electrodeposition of Ba2+, Ni2+, and Fe3+ as an efficient catalyst for electrocatalytic water oxidation. NiFeBa showed enhanced water oxidation performance compared with NiFe layered double hydroxide and NiFe oxide, delivering a current density of 10 mA cm−2 at an overpotential of 180 mV. Doped Ba ions played a key role in stabilizing the electrogenerated Ni3+ species, producing more octahedral Ni−O structures for lattice oxygen‐based water oxidation, adjusting the catalytic mechanism, and finally leading to an enhancement of catalytic efficiency.
Log reduction of leukemic cells and minimal residual disease by flow cytometry represent effective predictors of clinical outcome in elderly patients with acute myeloid leukemia
Authors: Rossi Giovanni , Giambra Vincenzo , de Waure Chiara , Giacchetta Irene , Minervini Maria Marta , Abbenante Maria Chiara , Spadano Raffaele , La Torre Antonella , Scalzulli Potito Rosario , Cascavilla Nicola
Published: May 2021

Background

Nowadays minimal residual disease (MRD) and log‐reduction of leukemic cells are poorly investigated in elderly patients with acute myeloid leukemia (AML) treated with hypometilating agents (HMAs). Studies focusing on MRD in elderly AML patients who received HMAs are scant and devoid of rigorous criteria for both enrollment and monitoring. Log‐reduction has never been investigated in these patients. Thus, the purpose of our study was to compare the prognostic impact of MRD and log‐reduction of leukemic cells at the optimal time of assessment in older AML patients.

Methods

Elderly patients who completed at least six cycles of HMAs and showed suitable leukemia‐associated immunophenotypes (LAIPs) for the MRD and log‐reduction assessment by flow cytometry were enrolled in the study.

Results

After comparing the times of assessment C4 (4‐cycles) and C6 (6‐cycles), C6 has been chosen as optimal. Patients who achieved MRD negativity or 2‐log‐reduction of leukemic cells at C6 had a significantly longer DFS. Particularly, results of 2‐log‐reduction were confirmed a multivariate analysis. Patients with MRD negativity or 2‐log reduction of leukemic cells showed an improvement of their OS, although not significantly.

Conclusions

Our data confirmed the predictive role of MRD and 2‐log reduction also in older AML patients treated with HMAs.