Variations of Major Glucosinolates in Diverse Chinese Cabbage (Brassica rapa ssp. pekinensis) Germplasm as Analyzed by UPLC-ESI-MS/MS.

In this study, the variability of major glucosinolates in the leaf lamina of 134 Chinese cabbage accessions was investigated using Acquity ultra-performance liquid chromatography (UPLC-ESI-MS/MS). A total of twenty glucosinolates were profiled, of which glucobrassicanapin and gluconapin were identified as the predominant glucosinolates within the germplasm. These two glucosinolates had mean concentration levels above 1000.00 µmol/kg DW. Based on the principal component analysis, accessions IT186728, IT120044, IT221789, IT100417, IT278620, IT221754, and IT344740 were separated from the rest in the score plot. These accessions exhibited a higher content of total glucosinolates. Based on the VIP values, 13 compounds were identified as the most influential and responsible for variation in the germplasm. Sinigrin (r = 0.73), gluconapin (r = 0.78), glucobrassicanapin (r = 0.70), epiprogoitrin (r = 0.73), progoitrin (r = 0.74), and gluconasturtiin (r = 0.67) all exhibited a strong positive correlation with total glucosinolate at p < 0.001. This indicates that each of these compounds had a significant influence on the overall glucosinolate content of the various accessions. This study contributes valuable insights into the metabolic diversity of glucosinolates in Chinese cabbage, providing potential for breeding varieties tailored to consumer preferences and nutritional demands.

High-Performance Ferroelectric Thin Film Transistors with Large Memory Window Using Epitaxial Yttrium-Doped Hafnium Zirconium Gate Oxide.

Preventing ferroelectric materials from losing their ferroelectricity over a low thickness of several nanometers is crucial in developing multifunctional nanoelectronics. Epitaxially grown 5 at. % yttrium-doped Hf0.5Zr0.5O2 (YHZO) thin films exhibit an atomically smooth surface, an ability to maintain ferroelectricity even at a thickness of 10 nm, and excellent insulating properties, making them suitable for use as gate oxides in ferroelectric thin film transistors (FeTFTs). Through the epitaxial growth of a YHZO/La0.67Sr0.33MnO3 (LSMO)/SrTiO3 (STO) heterostructure, YHZO effectively retains its ferroelectricity and orthorhombic single phase, leading to enhancing electron mobility (∼19.74 cm2 V-1 s-1) and memory window (3.7 V) in the amorphous InGaZnO4 (a-IGZO)/YHZO/LSMO/STO FeTFTs. These FeTFTs demonstrate a consistent memory function with remarkable endurance (∼106 cycles) and retention (∼104 s). Furthermore, they sustain a constant memory window even under ±6 V bias stress for 104 s and exhibit excellent stability even under ±6 V/1 ms pulse cycling for 107 cycles. For comparison, a transistor with the same structure was fabricated using epitaxial nonferroelectric LaAlO3 (LAO) and epitaxial undoped Hf0.5Zr0.5O2 (HZO) as alternatives to YHZO. This study presents a novel approach to exploit the potential of YHZO in FeTFTs, contributing to the development of next-generation logic-in-memory.

Nanoelectronics Using Metal-Insulator Transition.

Metal-insulator transition (MIT) coupled with an ultrafast, significant, and reversible resistive change in Mott insulators has attracted tremendous interest for investigation into next-generation electronic and optoelectronic devices, as well as a fundamental understanding of condensed matter systems. Although the mechanism of MIT in Mott insulators is still controversial, great efforts have been made to understand and modulate MIT behavior for various electronic and optoelectronic applications. In this review, recent progress in the field of nanoelectronics utilizing MIT is highlighted. A brief introduction to the physics of MIT and its underlying mechanisms is begun. After discussing the MIT behaviors of various Mott insulators, recent advances in the design and fabrication of nanoelectronics devices based on MIT, including memories, gas sensors, photodetectors, logic circuits, and artificial neural networks are described. Finally, an outlook on the development and future applications of nanoelectronics utilizing MIT is provided. This review can serve as an overview and a comprehensive understanding of the design of MIT-based nanoelectronics for future electronic and optoelectronic devices.

Effects of SKCPT on Osteoarthritis in Beagle Meniscectomy and Cranial Cruciate Ligament Transection Models.

Osteoarthritis (OA) affects >500 million people globally, and this number is expected to increase. OA management primarily focuses on symptom alleviation, using non-steroidal anti-inflammatory drugs, including Celecoxib. However, such medication has serious side effects, emphasizing the need for disease-specific treatment. The meniscectomy and cranial cruciate ligament transection (CCLx)-treated beagle dog was used to investigate the efficacy of a modified-release formulation of SKI306X (SKCPT) from Clematis mandshurica, Prunella vulgaris, and Trichosanthes kirilowii in managing arthritis. SKCPT's anti-inflammatory and analgesic properties have been assessed via stifle circumference, gait, incapacitance, histopathology, and ELISA tests. The different SKCPT concentrations and formulations also affected the outcome. SKCPT improved the gait, histopathological, and ELISA OA assessment parameters compared to the control group. Pro-inflammatory cytokines and matrix metalloproteinases were significantly lower in the SKCPT-treated groups than in the control group. This study found that SKCPT reduces arthritic lesions and improves abnormal gait. The 300 mg modified-release formulation was more efficacious than others, suggesting a promising approach for managing OA symptoms and addressing disease pathogenesis. A high active ingredient level and a release pattern make this formulation effective for twice-daily arthritis treatment.

Potential of a bivalent vaccine for broad protection against enterovirus 71 and coxsackie virus 16 infections causing hand, foot, and mouth disease.

Hand, foot, and mouth disease (HFMD) is a highly contagious viral infection that is mainly caused by enterovirus 71 (EV71) and coxsackievirus 16 (CVA16). As there are no specific therapeutics for HFMD, the development of a bivalent vaccine is required to cover a broad range of infections. In this study, the effectiveness of novel monovalent and bivalent vaccines targeting EV71 C4a and CVA16 was investigated for their ability to prevent viral infections in neonatal human scavenger receptor class B member 2 (hSCARB2) transgenic mice. As hSCARB2 serves as a key viral receptor for EV71, these transgenic mice are susceptible to EV71 strains and facilitate viral binding, internalization, and uncoating processes. Antisera prepared by vaccine immunization were transferred to 2-day-old hSCARB2 transgenic mice, which were then infected with EV71 C4a or CVA16 virus. The antisera generated by each monovalent or bivalent vaccine effectively protected against EV71 C4a and CVA16 infections. The examination of tissue damage and viral contents in various organs indicated that both monovalent and bivalent antisera reduced EV71 C4a viral load in the brainstem, and no significant tissue damage was observed. During CVA16 infection, the monovalent and bivalent antisera significantly reduced viral contents in both the brainstem and muscles. These results suggest that passive immunity by monovalent and bivalent antisera can effectively protect against EV71 C4a and CVA16 infections. Thus, the development of a bivalent vaccine that can provide broad protection against both CV and EV infections may be a promising strategy in preventing HFMD.

A Bivalent Inactivated Vaccine Prevents Enterovirus 71 and Coxsackievirus A16 Infections in the Mongolian Gerbil.

Hand-foot-and-mouth disease (HFMD) is a viral infectious disease that occurs in children under 5 years of age. Its main causes are coxsackievirus (CV) and enterovirus (EV). Since there are no efficient therapeutics for HFMD, vaccines are effective in preventing the disease. To develop broad coverage against CV and EV, the development of a bivalent vaccine form is needed. The Mongolian gerbil is an efficient and suitable animal model of EV71 C4a and CVA16 infection used to investigate vaccine efficacy following direct immunization. In this study, Mongolian gerbils were immunized with a bivalent inactivated EV71 C4a and inactivated CVA16 vaccine to test their effectiveness against viral infection. Bivalent vaccine immunization resulted in increased Ag-specific IgG antibody production; specifically, EV71 C4a-specific IgG was increased with medium and high doses and CVA16-specific IgG was increased with all doses of immunization. When gene expression of T cell-biased cytokines was analysed, Th1, Th2, and Th17 responses were found to be highly activated in the high-dose immunization group. Moreover, bivalent vaccine immunization mitigated paralytic signs and increased the survival rate following lethal viral challenges. When the viral RNA content was determined from various organs, all three doses of bivalent vaccine immunization were found to significantly decrease viral amplification. Upon histologic examination, EV71 C4a and CVA16 induced tissue damage to the heart and muscle. However, bivalent vaccine immunization alleviated this in a dose-dependent manner. These results suggest that the bivalent inactivated EV71 C4a/CVA16 vaccine could be a safe and effective candidate HFMD vaccine.

Diffuse Large B-cell Lymphoma Presenting as an "Oops" Lesion in the Nasolabial Fold: A Case Report.

BACKGROUND: Diffuse large B-cell lymphomas are the most common type of non-Hodgkin lymphoma. Because cutaneous lymphomas predominantly originate from the T cells, primary cutaneous diffuse large B-cell lymphomas are considered a rare subtype of extranodal diffuse large B-cell lymphomas that commonly involve the subcutaneous tissues of the trunk and extremities. To date, only a single case of facial primary cutaneous diffuse large B-cell lymphoma has been reported in the literature. CASE REPORT: We present a case of primary cutaneous diffuse large B-cell lymphoma presented with a small painless nodule in the right nasolabial fold that had persisted for 10 days in a 67-year-old man. Ultrasonographic findings of this lesion mimicked the features of a complicated epidermal inclusion cyst. Primary cutaneous diffuse large B-cell lymphoma was confirmed by an excisional biopsy of the mass. CONCLUSION: The diagnosis of primary cutaneous diffuse large B-cell lymphomas presenting as "oops lesions" in daily clinical practice can be challenging due to their rarity and nonspecific clinical and radiological findings. Therefore, clinical suspicion and awareness are critical for the accurate diagnosis and management of patients with palpable soft tissue masses in the head and neck region.

Variability of Glucosinolates in Pak Choy (Brassica rapa subsp. chinensis) Germplasm.

Glucosinolates are sulfur-containing phytochemicals generally abundant in cruciferous vegetables such as pak choy. Glucosinolates participate in a range of biological activities essential for promoting a healthy human body. In this study, we aimed to elucidate glucosinolate variability present in pak choy germplasm that are under conservation at the Rural Development Administration Genebank, Jeonju, Republic of Korea. The Acquity Ultra-Performance Liquid Chromatography (UHPLC) analytical system was used in profiling the glucosinolate content in leaf samples of various accessions. We identified a total of 17 glucosinolates in the germplasm. Based on principal compoment analysis performed, three separate groups of the accessions were obtained. Group 1 contained the cultivar cheongsacholong which recorded high content of glucobrassicin (an indole), glucoerucin (aliphatic), gluconasturtiin (aromatic) and glucoberteroin (aliphatic). Group 2 consisted of six accessions, BRA77/72, Lu ling gaogengbai, 9041, Wuyueman, RP-75 and DH-10, predominatly high in aliphatic compounds including glucoiberin, glucocheirolin, and sinigrin. Group 3 comprised the majority of the accessions which were characterized by high content of glucoraphanin, epiprogoitrin, progoitrin, and glucotropaeolin. These results revealed the presence of variability among the pak choy germplasm based on their glucosinolate content, providing an excellent opprtunity for future breeding for improved glucosinolate content in the crop.

MRI-Based Personalized Transcranial Direct Current Stimulation to Enhance the Upper Limb Function in Patients with Stroke: Study Protocol for a Double-Blind Randomized Controlled Trial.

Transcranial direct current stimulation (tDCS) has been shown to have the potential to improve the motor recovery of the affected upper limbs in patients with stroke, and recently, several optimized tDCS methods have been proposed to magnify its effectiveness. This study aims to determine the effectiveness of personalized tDCS using brain MRI-based electrical field simulation and optimization, to enhance motor recovery of the upper limbs in the patients. This trial is a double-blind, randomized controlled trial in the subacute to chronic rehabilitation phase. Forty-two adult stroke patients with unilateral upper limb involvement will be randomly allocated to three groups: (1) personalized tDCS with MRI-based electrical field simulation and optimized stimulation, (2) conventional tDCS with bihemispheric stimulation of the primary motor cortex, and (3) sham tDCS. All three groups will undergo 10 intervention sessions with 30 min of 2-mA intensity stimulation, during a regular upper limb rehabilitation program over two weeks. The primary outcome measure for the motor recovery of the upper limb impairment is the Fugl-Meyer assessment for the upper extremity score at the end of the intervention, and the secondary measures include changes in the motor evoked potentials, the frequency power and coherence of the electroencephalography, performance in activities of daily living, and adverse events with a 1-month follow-up assessment. The primary outcome will be analyzed on the intention-to-treat principle. There is a paucity of studies regarding the effectiveness of personalized and optimized tDCS that considers individual brain lesions and electrical field characteristics in the real world. No feasibility or pivotal studies have been performed in stroke patients using brain MRI, to determine a lesion-specific tDCS simulation and optimization that considers obstacles in the segmentation and analysis of the affected brain tissue, such as ischemic and hemorrhagic lesions. This trial will contribute to addressing the effectiveness and safety of personalized tDCS, using brain MRI-based electrical field simulation and optimization, to enhance the motor recovery of the upper limbs in patients with stroke.

Genome-Wide Association Study for Agro-Morphological Traits in Eggplant Core Collection.

Eggplant is one of the most economically and nutritionally important vegetables worldwide. The study of the association of phenotypic traits with genetic factors is vital for the rapid and efficient identification and selection of eggplant genetic resources for breeding purposes with desired traits. The eggplant resources (587) collected from different countries, including Korea, were used for establishing the core collection. A total of 288 accessions were selected from 587 Solanum accessions based on 52 single nucleotide polymorphisms (SNPs) markers together with 17 morphological traits. This core collection was further used to analyze the genetic associations of eggplant morphological variations. A large variation was found among the evaluated eggplant accessions for some agro-morphological traits. Stem prickles and leaf prickles showed a significant positive correlation (r = 0.83***), followed by days to flowering and days to maturity (r = 0.64***). A total of 114,981 SNPs were filtered and used for phylogenetic tree analysis, population structure analysis, and genome-wide association study (GWAS). Among the agro-morphological traits, significantly associated SNPs were found for six traits. A total of 377 significantly associated SNPs with six agro-morphological traits were identified. These six traits and the number of SNPs were: days to maturity (51), flower size (121), fruit width (20), harvest fruit color (42), leaf prickles (38), and stem prickles (105). The largest fraction of significant SNPs (11.94%) was obtained on chromosome Ch01, followed by Ch07 and Ch06 with 11.67% and 10.08%, respectively. This study will help to develop markers linked to the most important agro-morphological traits of eggplant genetic resources and support the selection of desirable traits for eggplant breeding programs.

Ambient Stable All Inorganic CsCu2I3 Artificial Synapses for Neurocomputing.

In resistive switching memories or artificial synaptic devices, halide perovskites have attracted attention for their unusual features such as rapid ion migration, adjustable composition, and facile synthesis. Herein, the environmentally friendly and highly air stable CsCu2I3 perovskite films are used as the active layer in the Au/CsCu2I3/ITO/glass artificial synapses. The device shows variable synaptic plasticities such as long-term and short-term synaptic plasticity, paired-pulse facilitation, and spike-timing-dependent plasticity by combining potentiation and depression along the formation of conductive filaments. The performances of the devices are maintained for 160 days under ambient conditions. Additionally, the accuracy evaluation of the CsCu2I3-based artificial synapses performs exceptionally well with the MNIST and Fashion MNIST data sets, demonstrating high learning accuracy in deep neural networks. Using the novel B-site engineered halide perovskite material with extreme air stability, this study paves the way for artificial synaptic devices for next-generation in-memory hardware.

Nonvolatile Control of Metal-Insulator Transition in VO2 by Ferroelectric Gating.

Controlling phase transitions in correlated materials yields emergent functional properties, providing new aspects to future electronics and a fundamental understanding of condensed matter systems. With vanadium dioxide (VO2 ), a representative correlated material, an approach to control a metal-insulator transition (MIT) behavior is developed by employing a heteroepitaxial structure with a ferroelectric BiFeO3 (BFO) layer to modulate the interaction of correlated electrons. Owing to the defect-alleviated interfaces, the enhanced coupling between the correlated electrons and ferroelectric polarization is successfully demonstrated by showing a nonvolatile control of MIT of VO2 at room temperature. The ferroelectrically-tunable MIT can be realized through the Mott transistor (VO2 /BFO/SrRuO3 ) with a remanent polarization of 80 µC cm-2 , leading to a nonvolatile MIT behavior through the reversible electrical conductance with a large on/off ratio (≈102 ), long retention time (≈104 s), and high endurance (≈103 cycles). Furthermore, the structural phase transition of VO2 is corroborated by ferroelectric polarization through in situ Raman mapping analysis. This study provides novel design principles for heteroepitaxial correlated materials and innovative insight to modulate multifunctional properties.

Instant pH sensor based on the functionalized cellulose for detecting strong acid leaks.

Acid spills cause large-scale environmental damage and casualties. To respond to such incidents, a sensor capable of detecting acid leaks is required. Cellulose is a useful substrate material for the fast detection of acid leaks because it has high hydrophilicity and porosity. On the other hand, methods of manufacturing cellulose-based sensors are still complicated or time-consuming. Thus, in this study, a simple and rapid synthesis method for a cellulose-based pH sensor was proposed. The functionalization of α-cellulose was achieved via chloroacetyl chloride, and Congo red was covalently immobilized to the functionalized cellulose for detecting strong acids. The manufacturing process was composed of two steps as above and finished within 8 h. The developed sensor exhibited absorbance changes in the pH range of 0.2 to 3.0, and response time was shorter than 1 s. A prototype system using this sensor was manufactured and tested, and it detected acid leaks easily and quickly.

Implication and Influence of Multigene Panel Testing with Genetic Counseling in Korean Patients with BRCA1/2 Mutation-Negative Breast Cancer.

PURPOSE: The aim of the study was to evaluate the clinical implication of multigene panel testing of beyond BRCA genes in Korean patients with BRCA1/2 mutation-negative breast cancer. MATERIALS AND METHODS: Between 2016 and 2019, a total of 700 BRCA1/2 mutation-negative breast cancer patients received comprehensive multigene panel testing and genetic counseling. Among them, 347 patients completed a questionnaire about cancer worry, genetic knowledge, and preference for the method of genetic tests during pre- and post-genetic test counseling. The frequency of pathogenic and likely pathogenic variants (PV/LPV) were analyzed. RESULTS: At least one PV/LPV of 26 genes was found in 76 out of 700 patients (10.9 %). The rate for PV/LPV was 3.4% for high-risk genes (17 PALB2, 6 TP53, and 1 PTEN). PV/LPVs of clinical actionable genes for breast cancer management, high-risk genes and other moderate-risk genes such as ATM, BARD1, BRIP, CHEK2, NF1, and RAD51D, were observed in 7.4%. Patients who completed the questionnaire showed decreased concerns about the risk of additional cancer development (average score, 4.21 to 3.94; p < 0.001), influence on mood (3.27 to 3.13; p < 0.001), influence on daily functioning (3.03 to 2.94; p=0.006); and increased knowledge about hereditary cancer syndrome (66.9 to 68.8; p=0.025) in post-test genetic counseling. High cancer worry scales (CWSs) were associated with age ≤ 40 years and the identification of PV/LPV. Low CWSs were related to the satisfaction of the counselee. CONCLUSION: Comprehensive multigene panel test with genetic counseling is clinically applicable. It should be based on interpretable genetic information, consideration of potential psychological consequences, and proper preventive strategies.

Long noncoding RNAs associated with nonalcoholic fatty liver disease in a high cholesterol diet adult zebrafish model.

The mechanism of nonalcoholic fatty liver disease (NAFLD) has not been completely revealed. In this study, we investigated the association of liver histological changes and long noncoding RNAs (lncRNAs) in the NAFLD zebrafish model. Forty zebrafish were fed a high-cholesterol diet (1.5 g per day) for 8 weeks. We measured fatty liver changes in the zebrafish liver using oil red O staining and divided them into two groups based on high and low scores. We pooled each group of zebrafish livers and identified lncRNAs, miRNAs, and mRNAs using Next-generation sequencing. Human homologs of lncRNAs were identified using ZFLNC, Ensembl, and NONCODE. We found several significant genes, including 32 lncRNAs, 5 miRNA genes, and 8 protein-coding genes, that were associated with liver metabolism and NAFLD-related functions in zebrafish. In particular, eight conserved human homologs of lncRNAs were found. We discovered the human homologs of eight lncRNA candidates from fatty liver zebrafish for the first time. The spectrum of biological mechanisms by which lncRNAs mediate their functional roles in NAFLD in a high cholesterol diet adult zebrafish model remains to be uncovered.

Phylogeography and Antioxidant Activity of Proso Millet (Panicum miliaceum L.).

Proso millet (Panicum miliaceum L.) or broomcorn millet is among the most important food crops to be domesticated by humans; it is widely distributed in America, Europe, and Asia. In this study, we genotyped 578 accessions of P. miliaceum using 37 single-sequence repeat (SSR) markers, to study the genetic diversity and population structure of each accession. We also investigated total phenolic content (TPC) and superoxide dismutase (SOD) activity and performed association analysis using SSR markers. The results showed that genetic diversity and genetic distance were related to geographic location and the fixation index (Fst). Population structure analysis divided the population into three subpopulations. Based on 3 subpopulations, the population is divided into six clusters in consideration of geographical distribution characteristics and agronomic traits. Based on the genetic diversity, population structure, pairwise Fst, and gene flow analyses, we described the topological structure of the six proso millet subpopulations, and the geographic distribution and migration of each cluster. Comparison of the published cluster (cluster 1) with unique germplasms in Japan and South Korea suggested Turkey as a possible secondary center of origin and domestication (cluster 3) for the cluster. We also discovered a cluster domesticated in Nepal (cluster 6) that is adapted to high-latitude and high-altitude cultivation conditions. Differences in phenotypic characteristics, such as TPC, were observed between the clusters. The association analysis showed that TPC was associated with SSR-31, which explained 7.1% of the total variance, respectively. The development of markers associated with TPC and SOD will provide breeders with new tools to improve the quality of proso millet through marker-assisted selection.

The feasibility and satisfaction of an online global health education course at a single medical school: a retrospective study.

PURPOSE: The aim of this study was to evaluate the feasibility and satisfaction of an online global health education course for medical students in comparison with an in-person of the course and to assess students' preferences regarding online methods of delivery. METHODS: Second-year medical students enrolled in this course in 2019 (in-person) and 2020 (online). The attendance rate, satisfaction in the course evaluation survey, and academic achievement on the written final examination were utilized to compare the two different methods of course delivery. The medical students who took the online course were also asked about their preferences regarding the method of course delivery and the advantages and drawbacks of each method of online lectures. RESULTS: There was no significant difference in the attendance rate and overall satisfaction between the two groups. The mean score on the written examination of the online course (84.1±19.6) showed comparable effects to the in-person course (78.0±18.3). The percentages of students who achieved high performance (55.5%) and the achieved minimum requirement (95.9%) were also maintained compared to the in-person course (14.6% and 93.6%, respectively). Medical students preferred the online course to the in-person course; in particular, they preferred prerecorded videos over live streaming online lectures. CONCLUSION: The participation, satisfaction, and the academic achievement of the online course were comparable to those of the in-person course. However, the greatest drawback of the online course was the lack of interaction between peer learners. Therefore, diverse methods for online education should be considered to increase students' sense of belonging to a learning community.

A phase I, randomized, single-dose pharmacokinetic study comparing sb8 (bevacizumab biosimilar) with reference bevacizumab in healthy volunteers.

PURPOSE: To compare pharmacokinetics, safety, tolerability, and immunogenicity between SB8, a bevacizumab biosimilar, and the European Union (EU) and United States (US) reference products (bevacizumab-EU, bevacizumab-US). METHODS: In this randomized, double-blind, parallel-group, and single-dose study, healthy volunteers were randomized to receive a 3 mg/kg dose of SB8, bevacizumab-EU, or bevacizumab-US via intravenous infusion. Primary endpoints were area under the concentration-time curve from time zero to infinity (AUCinf) and to the last quantifiable concentration (AUClast), and maximum observed serum concentration (Cmax). Bioequivalence was achieved if 90% confidence intervals (CIs) for the ratios of the geometric least squares means (LSMeans) of primary endpoints were within the predefined bioequivalence margins of 80.00-125.00%. Safety and immunogenicity were also investigated. RESULTS: The 90% CIs for the geometric LSMean ratios of AUCinf, AUClast and Cmax were all within the prespecified bioequivalence margins. Geometric LSMean ratios for SB8/bevacizumab-EU, SB8/bevacizumab-US and bevacizumab-EU/bevacizumab-US were 88.01%, 88.48% and 100.54% for AUCinf, 88.65%, 89.08% and 100.49% for AUClast and 99.59%, 101.15% and 101.56% for Cmax, respectively. Incidence of treatment-emergent adverse events (TEAEs) across treatment groups was comparable (SB8: 50.0%, bevacizumab-EU: 37.5%, bevacizumab-US: 53.8%). Most TEAEs were mild and considered as not related to the study drug. No deaths or treatment discontinuations due to adverse events occurred. Incidence of anti-drug antibodies was also comparable between all groups and no neutralizing antibodies were detected. CONCLUSION: This study demonstrated pharmacokinetic bioequivalence and similar safety and immunogenicity profiles of SB8 to both reference products, bevacizumab-EU and bevacizumab-US, and of bevacizumab-EU to bevacizumab-US. CLINICALTRIALS. GOV IDENTIFIER: NCT02453672 (submitted date); EudraCT number: 2015-001,026-41.

Lead-Free Dual-Phase Halide Perovskites for Preconditioned Conducting-Bridge Memory.

Organometallic and all-inorganic halide perovskites (HPs) have recently emerged as promising candidate materials for resistive switching (RS) nonvolatile memory due to their current-voltage hysteresis caused by fast ion migration. Lead-free and all-inorganic HPs have been researched for non-toxic and environmentally friendly RS memory devices. However, only HP-based devices with electrochemically active top electrode (TE) exhibit ultra-low operating voltages and high on/off ratio RS properties. The active TE easily reacts to halide ions in HP films, and the devices have a low device durability. Herein, RS memory devices based on an air-stable lead-free all-inorganic dual-phase HP (AgBi2 I7 -Cs3 Bi2 I9 ) are successfully fabricated with inert metal electrodes. The devices with Au TE show filamentary RS behavior by conducting-bridge involving Ag cations in HPs with ultra-low operating voltages (<0.15 V), high on/off ratio (>107 ), multilevel data storage, and long retention times (>5 × 104 s). The use of a closed-loop pulse switching method improves reversible RS properties up to 103 cycles with high on/off ratio above 106 . With an extremely small bending radius of 1 mm, the devices are operable with reasonable RS characteristics. This work provides a promising material strategy for lead-free all-inorganic HP-based nonvolatile memory devices for practical applications.

p53 regulates mitochondrial dynamics by inhibiting Drp1 translocation into mitochondria during cellular senescence.

Cellular senescence acts as an important barrier to tumorigenesis by eliminating precancerous cells. Previous studies have shown an essential role of the tumor suppressor p53 in cellular senescence, but how p53 induces cellular senescence is not fully understood. We found that p53 promoted the formation of highly interconnected and elongated mitochondria prior to the onset of cellular senescence. The inhibition of mitochondrial elongation upon p53 expression suppressed cellular senescence, suggesting that mitochondrial elongation is required for the induction of p53-dependent senescence. p53-induced mitochondrial elongation resulted in mitochondrial dysfunction and subsequent increases in intracellular reactive oxygen species (ROS) levels, an important mediator of cellular senescence. Mechanistically, the inhibitory phosphorylation of Drp1 Ser637 increased upon p53 expression, suppressing the translocation of Drp1 into mitochondria. The transcriptional function of p53 was crucial for controlling the inhibitory phosphorylation of Drp1, whereas p21 was nonessential. Protein kinase A (PKA) activity was responsible for p53-mediated Drp1 Ser637 phosphorylation and mitochondrial dysfunction. Taken together, these results suggest that p53 regulates mitochondrial dynamics through the PKA-Drp1 pathway to induce cellular senescence.