bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of different combined regimens of cisplatin, metformin, and quercetin on nasopharyngeal carcinoma cells and subcutaneous xenografts
Authors: Chen Zhongwei , Zeng Zhen , Zhu Shanshan , Zeng Ying , Lin Qihuang , Luo Lianzhong , Hong Xuan
Published: January 2021

Cisplatin, metformin, and quercetin are all reliable anticancer drugs. However, it is unclear how effective their different combination regimens are on the growth of nasopharyngeal carcinoma cell line Sune-1 and subcutaneous xenograft in nude mice. This study evaluated the effects of single-drug, two-drug, and three-drug simultaneous or sequential combined application of these drugs on the growth of Sune-1 cells and subcutaneous xenograft tumors in nude mice. The results showed that the different combination regimens of cisplatin, metformin and quercetin all had significant inhibitory effects on the proliferation of Sune-1 cells and the growth of subcutaneous xenografts in nude mice (P < 0.01), and the inhibition rate of the three drugs simultaneous combined application was significant Higher than the two-drug combination or single-drug application (P < 0.05), the contribution level of each drug in the three-drug combination application from high to low were cisplatin > metformin > quercetin. In summary, our results indicate that the simultaneous combination of cisplatin, metformin, and quercetin may synergistically inhibit the growth of Sune-1 cells and subcutaneous xenografts in nude mice through their different anticancer mechanisms, which may be clinically refractory and provide reference for chemotherapy of patients with recurrent nasopharyngeal carcinoma.
High performance ozone based advanced oxidation processes catalyzed with novel argon plasma treated iron oxyhydroxide hydrate for phenazopyridine degradation
Authors: Pelalak Rasool , Heidari Zahra , Forouzesh Mojtaba , Ghareshabani Eslam , Alizadeh Reza , Marjani Azam , Shirazian Saeed
Published: January 2021

The present study has focused on the degradation of phenazopyridine (PhP) as an emerging contaminant through catalytic ozonation by novel plasma treated natural limonite (FeOOH·xH2O, NL) under argon atmosphere (PTL/Ar). The physical and chemical characteristics of samples were evaluated with different analyses. The obtained results demonstrated higher surface area for PTL/Ar and negligible change in crystal structure, compared to NL. It was found that the synergistic effect between ozone and PTL/Ar nanocatalyst was led to highest PhP degradation efficiency. The kinetic study confirmed the pseudo-first-order reaction for the PhP degradation processes included adsorption, peroxone and ozonation, catalytic ozonation with NL and PTL/Ar. Long term application (6 cycles) confirmed the high stability of the PTL/Ar. Moreover, different organic and inorganic salts as well as the dissolved ozone concentration demonstrated the predominant role of hydroxyl radicals and superoxide radicals in PhP degradation by catalytic Ozonation using PTL/Ar. The main produced intermediates during PhP oxidation by PTL/Ar catalytic ozonation were identified using LC–(+ESI)–MS technique. Finally, the negligible iron leaching, higher mineralization rate, lower electrical energy consumption and excellent catalytic activity of PTL/Ar samples demonstrate the superior application of non-thermal plasma for treatment of NL.
Angiotensin II type 1a receptor loss ameliorates chronic tubulointerstitial damage after renal ischemia reperfusion
Authors: Fujita Yoko , Ichikawa Daisuke , Sugaya Takeshi , Ohata Keiichi , Tanabe Jun , Inoue Kazuho , Hoshino Seiko , Togo Tatsuru , Watanabe Minoru , Kimura Kenjiro , Shibagaki Yugo , Kamijo-Ikemori Atsuko
Published: January 2021

We investigate whether suppressing the activation of the angiotensin II type 1a receptor (AT1a) can ameliorate severe chronic tubulointerstitial damage (TID) after renal ischemia reperfusion (IR) using AT1a knockout homozygous (AT1a−/−) male mice. To induce severe chronic TID after renal IR, unilateral renal ischemia was performed via clamping of the right renal pedicle in both AT1a−/− and wild-type (AT1a+/+) mice for 45 min. While marked renal atrophy and severe TID at 70 days postischemia was induced in the AT1a+/+ mice, such a development was not provoked in the AT1a−/− mice. Although the AT1a+/+ mice were administered hydralazine to maintain the same systolic blood pressure (SBP) levels as the AT1a−/− mice with lower SBP levels, hydralazine did not reproduce the renoprotective effects observed in the AT1a−/− mice. Acute tubular injury at 3 days postischemia was similar between the AT1a−/− mice and the AT1a+/+ mice. From our investigations using IR kidneys at 3, 14, and 28 days postischemia, the multiple molecular mechanisms may be related to prevention of severe chronic TID postischemia in the AT1a−/− mice. In conclusion, inactivation of the AT1 receptor may be useful in preventing the transition of acute kidney injury to chronic kidney disease.
Encountering shoaling internal waves on the dispersal pathway of the pearl river plume in summer
Authors: Lee Jay , Liu James T. , Lee I-Huan , Fu Ke-Hsien , Yang Rick J. , Gong Wenping , Gan Jianping
Published: January 2021

Fundamentally, river plume dynamics are controlled by the buoyancy due to river effluent and mixing induced by local forcing such as winds and tides. Rarely the influence of far-field internal waves on the river plume dynamics is documented. Our 5-day fix-point measurements and underway acoustic profiling identified hydrodynamic processes on the dispersal pathway of the Pearl River plume. The river plume dispersal was driven by the SW monsoon winds that induced the intrusion of cold water near the bottom. The river effluent occupied the surface water, creating strong stratification and showing on-offshore variability due to tidal fluctuations. However, intermittent disruptions weakened stratification due to wind mixing and perturbations by nonlinear internal waves (NIWs) from the northern South China Sea (NSCS). During events of NIW encounter, significant drawdowns of the river plume up to 20 m occurred. The EOF deciphers and ranks the contributions of abovementioned processes: (1) the stratification/mixing coupled by wind-driven plume water and NIWs disruptions (81.7%); (2) the variation caused by tidal modulation (6.9%); and (3) the cold water intrusion induced by summer monsoon winds (5.1%). Our findings further improve the understanding of the Pearl River plume dynamics influenced by the NIWs from the NSCS.
The use of individual, social, and animated cue information by capuchin monkeys and children in a touchscreen task
Authors: Renner Elizabeth , Kean Donna , Atkinson Mark , Caldwell Christine A.
Published: January 2021

The distinctiveness of human cumulative culture raises the question of whether humans respond differently to information originating from social sources, compared with information from other sources. Further, does any such differential responding set humans apart from other species? We studied how capuchin monkeys and 2- to 5-year-old children used information originating from their own actions, those of a human demonstrator, or an animated cue. This information, presented via a touchscreen, always revealed in the first trial (T1) the reward value (rewarded or unrewarded) of one stimulus from a 2- or 3-item array, and could be used in a follow-up trial (T2) involving the same stimulus array. Two monkeys achieved a level of proficiency indicating their appreciation of the T1–T2 relationship, i.e., reliably repeating rewarded (“win”) selections and actively avoiding repetition of unrewarded (“lose”) selections well above chance levels. Neither the two task-proficient monkeys nor the children showed overall performance differences between the three source conditions. Non-task-proficient monkeys, by contrast, did show effects of source, performing best with individually-acquired information. The overall pattern of results hints at an alternative perspective on evidence typically interpreted as showing a human advantage for social information use.
Detection of urban hidden faults using group-velocity ambient noise tomography beneath Zhenjiang area, China
Authors: Zheng Leiming , Fan Xiaoping , Zhang Peng , Hao Jingrun , Qian Hao , Zheng Tuo
Published: January 2021

The Mufushan-Jiaoshan fault (MJF) is a hidden active fault located on the north side of the Ningzhen Mountain Range and developed along the Yangtze River in Zhenjiang area, China. In this paper, the structure of MJF is detected and studied using group-velocity ambient noise tomography. In the study area (18 km × 25 km), 47 short-period seismic stations were deployed with the average station spacing of about 3 km and 24 days (from 27 February to 22 March 2019) of continuous ambient-noise recordings were collected. And 510 group velocity dispersion curves in the period band 0.5–5 s were extracted using the vertical component data. And then the three-dimensional shear-wave velocity structure was inverted using group dispersion data by the direct surface-wave tomographic method. Our results are consistent with the geological background of the study area, showing that in the depth range of 0.6–1.5 km, the north side of MJF presents a relatively high velocity, and the south side presents a distribution pattern of high and low velocity. While in the depth range of 1.5–2.0 km, the shear-wave velocity (Vs) model is relatively simple with relatively low velocity on the north side and relatively high velocity on the south side. And the gradient zone of Vs may be the location of the main fracture surface of MJF. The good correspondence between the Vs model and the fault structure indicates that the ambient noise tomography method can be used as an effective method for detecting hidden faults in urban environments.
Tick saliva-induced programmed death-1 and PD-ligand 1 and its related host immunosuppression
Authors: Sajiki Yamato , Konnai Satoru , Ikenaka Yoshinori , Gulay Kevin Christian Montecillo , Kobayashi Atsushi , Parizi Luís Fernando , João Benvindo Capela , Watari Kei , Fujisawa Sotaro , Okagawa Tomohiro , Maekawa Naoya , Logullo Carlos , da Silva Vaz Itabajara , Murata Shiro , Ohashi Kazuhiko
Published: January 2021

The tick Rhipicephalus microplus is a harmful parasite of cattle that causes considerable economic losses to the cattle breeding industry. Although R. microplus saliva (Rm-saliva) contains several immunosuppressants, any association between Rm-saliva and the expression of immunoinhibitory molecules, such as programmed death (PD)-1 and PD-ligand 1 (PD-L1), has not been described. In this study, flow cytometric analyses revealed that Rm-saliva upregulated PD-1 expression in T cells and PD-L1 expression in CD14+ and CD11c+ cells in cattle. Additionally, Rm-saliva decreased CD69 expression in T cells and Th1 cytokine production from peripheral blood mononuclear cells. Furthermore, PD-L1 blockade increased IFN-γ production in the presence of Rm-saliva, suggesting that Rm-saliva suppresses Th1 responses via the PD-1/PD-L1 pathway. To reveal the upregulation mechanism of PD-1/PD-L1 by Rm-saliva, we analyzed the function of prostaglandin E2 (PGE2), which is known as an inducer of PD-L1 expression, in Rm-saliva. We found that Rm-saliva contained a high concentration of PGE2, and PGE2 treatment induced PD-L1 expression in CD14+ cells in vitro. Immunohistochemical analyses revealed that PGE2 and PD-L1 expression was upregulated in tick-attached skin in cattle. These data suggest that PGE2 in Rm-saliva has the potential to induce the expression of immunoinhibitory molecules in host immune cells.
Design of planar distributed three beam electron gun with narrow beam separation for W band staggered double vane TWT
Authors: Ruan Cunjun , Wang Pengpeng , Zhang Huafeng , Su Yiyang , Dai Jun , Ding Yikun , Zhang Zheng
Published: January 2021

A novel planar distributed three-beam electron gun with narrow beam separations is designed based on grids loaded sheet beam method. The dimensions of the three-beam gun in the y–O-z plane are determined using our basic theoretical design method developed for sheet beam gun. The results show that the profile of focusing electrode in the y–O-z plane is related to the beam width in the x-O-z plane. Then, the characteristics and parameters of three-beam array formation with their stability are analyzed thoroughly by adjustment of control grids in the x-O-z plane. Each of the beamlet obtained is with a small axial deviation of the two transverse waists. Based on the theoretical analysis and simulations, the planar three-beam electron gun is constructed with the beam voltage of 22 kV and the current of 3 $$\times$$
×
0.15 A. The average radius of 0.08 mm at each beam waist is obtained with the compression factor of 4 for the 0.18 mm beam tunnel radius. The beam waist can be achieved at about 4.4 mm away from the cathode with the axis separation about 0.46 mm for each of beamlet. Thus, the design method can be generally used to construct such type of narrow beam separation and planar distributed multiple beam electron gun for the miniaturization and integrated vacuum electron devices in millimeter wave and terahertz band.
Mild systemic inflammation enhances response to OnabotulinumtoxinA in chronic migraineurs
Authors: Leira Yago , Domínguez Clara , Ameijeira Pablo , López-Arias Esteban , Ávila-Gómez Paulo , Pérez-Mato María , Sobrino Tomás , Campos Francisco , Blanco Juan , Leira Rogelio
Published: January 2021

The anti-inflammatory effect of OnabotulinumtoxinA (OnabotA) has been a matter of discussion for many years. In chronic migraine, however, increased pro-inflammatory state is associated with good response to OnabotA. We aimed to investigate whether a mild systemic inflammatory state elicited by a common oral infection (periodontitis) could enhance treatment response to OnabotA. In this study, we included 61 chronic migraineurs otherwise healthy treated with OnabotA of which 7 were poor responders and 54 good responders. Before receiving OnabotA therapy, all participants underwent a full-mouth periodontal examination and blood samples were collected to determine serum levels of calcitonin gene-related peptide (CGRP), interleukin 6 (IL-6), IL-10 and high sensitivity C-reactive protein (hs-CRP). Periodontitis was present in 70.4% of responders and 28.6% of non-responders (P = 0.042). Responders showed greater levels of inflammation than non-responders (IL-6: 15.3 ± 8.7 vs. 9.2 ± 4.7 ng/mL, P = 0.016; CGRP: 18.8 ± 7.6 vs. 13.0 ± 3.1 pg/mL, P = 0.002; and hs-CRP: 3.9 ± 6.6 vs. 0.9 ± 0.8 mg/L, P = 0.003). A linear positive correlation was found between the amount of periodontal tissue inflamed in the oral cavity and markers of inflammation (IL-6: r = 0.270, P = 0.035; CGRP: r = 0.325, P = 0.011; and hs-CRP: r = 0.370, P = 0.003). This report shows that in presence of elevated systemic inflammatory markers related to periodontitis, OnabotA seems to reduce migraine attacks. The changes of scheduled inflammatory parameters after treatment and subsequent assessment during an adequate period still need to be done.
Effect of storage and preconditioning of healing rat Achilles tendon on structural and mechanical properties
Authors: Dietrich-Zagonel Franciele , Hammerman Malin , Bernhardsson Magnus , Eliasson Pernilla
Published: January 2021

Tendon tissue storage and preconditioning are often used in biomechanical experiments and whether this generates alterations in tissue properties is essential to know. The effect of storage and preconditioning on dense connective tissues, like tendons, is fairly understood. However, healing tendons are unlike and contain a loose connective tissue. Therefore, we investigated if storage of healing tendons in the fridge or freezer changed the mechanical properties compared to fresh tendons, using a pull-to-failure or a creep test. Tissue morphology and cell viability were also evaluated. Additionally, two preconditioning levels were tested. Rats underwent Achilles tendon transection and were euthanized 12 days postoperatively. Statistical analyzes were done with one-way ANOVA or Student’s t-test. Tissue force and stress were unaltered by storage and preconditioning compared to fresh samples, while high preconditioning increased the stiffness and modulus (p ≤ 0.007). Furthermore, both storage conditions did not modify the viscoelastic properties of the healing tendon, but altered transverse area, gap length, and water content. Cell viability was reduced after freezing. In conclusion, preconditioning on healing tissues can introduce mechanical data bias when having extensive tissue strength diversity. Storage can be used before biomechanical testing if structural properties are measured on the day of testing.
The alga Euglena gracilis stimulates Faecalibacterium in the gut and contributes to increased defecation
Authors: Nakashima Ayaka , Sasaki Kengo , Sasaki Daisuke , Yasuda Kosuke , Suzuki Kengo , Kondo Akihiko
Published: January 2021

The alga Euglena gracilis (E. gracilis) has recently gained attention as a health food, but its effects on human gut microbiota remain unknown. This study aimed to determine the effect of E. gracilis on gut microbiota and defecation due to modulation of microbiota composition in vitro and in vivo. The in vitro model simulating human colonic microbiota revealed that E. gracilis addition stimulated the growth of commensal Faecalibacterium. Further, E. gracilis addition enhanced butyrate production by Faecalibacterium prausnitzii. Paramylon, an insoluble dietary fibre that accumulates in E. gracilis and is the main component of E. gracilis, did not stimulate Faecalibacterium growth in vitro. Daily ingestion of 2 g of E. gracilis for 30 days increased bowel movement frequency as well as stool volume in 28 human participants. Collectively, these findings indicate that E. gracilis components other than paramylon, stimulate the growth of Faecalibacterium to improve digestive health as well as promote defecation by increasing butyrate production.
Simultaneously performed combined 24-2 and 10-2 visual field tests in glaucoma
Authors: Jung Kyoung In , Ryu Hee Kyung , Hong Ki Hoon , Kim Yong Chan , Park Chan Kee
Published: January 2021

Using either 24-2 or 10-2 visual field (VF) testing only is not enough to cover all the various types of glaucomatous VF defects. We investigated the performance of the combined 24-2 and 10-2 perimetry when conducted together and separately using the structure–function relationship. A total of 30 glaucoma patients with isolated peripheral nasal step, 37 patients with isolated paracentral scotoma, and 38 patients with both paracentral and nasal scotoma were included. To create the combined Humphrey VF test, a custom test pattern was established using the built-in custom point options, an example of the X, Y coordinate system. In glaucoma patients with peripheral nasal step, the superotemporal topographic structure–function relationship with peripapillary retinal nerve fiber layer (RNFL) thickness was superior in relation to the combined or 24-2 perimetry relative to the 10-2 perimetry (both P < 0.05). The combined VF test showed more favorable inferotemporal or inferonasal structure–function correlation with the corresponding ganglion cell–inner plexiform layer (GCIPL) thickness when compared with results gleaned using the 24-2 VF test (P < 0.05). Simultaneously performed 24-2 and 10-2 VF tests demonstrated a superior topographic structure–function relationship when compared with them separately performed in some sectors.
Circulating tumor DNA is detectable in canine histiocytic sarcoma, oral malignant melanoma, and multicentric lymphoma
Authors: Prouteau Anaïs , Denis Jérôme Alexandre , De Fornel Pauline , Cadieu Edouard , Derrien Thomas , Kergal Camille , Botherel Nadine , Ulvé Ronan , Rault Mélanie , Bouzidi Amira , François Romain , Dorso Laetitia , Lespagnol Alexandra , Devauchelle Patrick , Abadie Jérôme , André Catherine , Hédan Benoît
Published: January 2021

Circulating tumor DNA (ctDNA) has become an attractive biomarker in human oncology, and its use may be informative in canine cancer. Thus, we used droplet digital PCR or PCR for antigen receptor rearrangement, to explore tumor-specific point mutations, copy number alterations, and chromosomal rearrangements in the plasma of cancer-affected dogs. We detected ctDNA in 21/23 (91.3%) of histiocytic sarcoma (HS), 2/8 (25%) of oral melanoma, and 12/13 (92.3%) of lymphoma cases. The utility of ctDNA in diagnosing HS was explored in 133 dogs, including 49 with HS, and the screening of recurrent PTPN11 mutations in plasma had a specificity of 98.8% and a sensitivity between 42.8 and 77% according to the clinical presentation of HS. Sensitivity was greater in visceral forms and especially related to pulmonary location. Follow-up of four dogs by targeting lymphoma-specific antigen receptor rearrangement in plasma showed that minimal residual disease detection was concordant with clinical evaluation and treatment response. Thus, our study shows that ctDNA is detectable in the plasma of cancer-affected dogs and is a promising biomarker for diagnosis and clinical follow-up. ctDNA detection appears to be useful in comparative oncology research due to growing interest in the study of natural canine tumors and exploration of new therapies.
Transcript levels of keratin 1/5/6/14/15/16/17 as potential prognostic indicators in melanoma patients
Authors: Han Wei , Hu Chan , Fan Zhao-Jun , Shen Guo-Liang
Published: January 2021

Keratins (KRTs), the intermediate filament-forming proteins of epithelial cells, are extensively used as diagnostic biomarkers in cancers and associated with tumorigenesis and metastasis in multiple cancers. However, the diverse expression patterns and prognostic values of KRTs in melanoma have yet to be elucidated. In the current study, we examined the transcriptional and clinical data of KRTs in patients with melanoma from GEO, TCGA, ONCOMINE, GEPIA, cBioPortal, TIMER and TISIDB databases. We found that the mRNA levels of KRT1/2/5/6/8/10/14/15/16/17 were significantly differential expressed between primary melanoma and metastatic melanoma. The expression levels of KRT1/2/5/6/10/14/15/16/17 were correlated with advanced tumor stage. Survival analysis revealed that the high transcription levels of KRT1/5/6/14/15/16/17 were associated with low overall survival in melanoma patients. GSEA analysis indicated that the most involved hallmarks pathways were P53 pathway, KRAS signaling, estrogen response early and estrogen response late. Furthermore, we found some correlations among the expression of KRTs and the infiltration of immune cells. Our study may provide novel insights for the selection of prognostic biomarkers for melanoma.
Parameters optimization method for the time-delayed reservoir computing with a nonlinear duffing mechanical oscillator
Authors: Zheng T. Y. , Yang W. H. , Sun J. , Xiong X. Y. , Li Z. T. , Zou X. D.
Published: January 2021

Reservoir computing (RC) is a recently introduced bio-inspired computational framework capable of excellent performances in the temporal data processing, owing to its derivation from the recurrent neural network (RNN). It is well-known for the fast and effective training scheme, as well as the ease of the hardware implementation, but also the problematic sensitivity of its performance to the optimizable architecture parameters. In this article, a particular time-delayed RC with a single clamped–clamped silicon beam resonator that exhibits a classical Duffing nonlinearity is presented and its optimization problem is studied. Specifically, we numerically analyze the nonlinear response of the resonator and find a quasi-linear bifurcation point shift of the driving voltage with the driving frequency sweeping, which is called Bifurcation Point Frequency Modulation (BPFM). Furthermore, we first proposed that this method can be used to find the optimal driving frequency of RC with a Duffing mechanical resonator for a given task, and then put forward a comprehensive optimization process. The high performance of RC presented on four typical tasks proves the feasibility of this optimization method. Finally, we envision the potential application of the method based on the BPFM in our future work to implement the RC with other mechanical oscillators.
Carryover effects of long-distance avian migration are weaker than effects of breeding environment in a partially migratory bird
Authors: Buchan Claire , Gilroy James J. , Catry Inês , Bustamante Javier , Marca Alina D. , Atkinson Philip W. , González Juan Miguel , Franco Aldina M. A.
Published: January 2021

Migration may expose individuals to a wide range of increasing anthropogenic threats. In addition to direct mortality effects, this exposure may influence post-migratory reproductive fitness. Partial migration—where a population comprises migrants and residents—represents a powerful opportunity to explore carryover effects of migration. Studies of partial migration in birds typically examine short-distance systems; here we studied an unusual system where residents breed in mixed colonies alongside long-distance trans-Saharan migrants (lesser kestrels (Falco naumanni) in Spain). Combining geolocator data, stable isotope analysis and resighting data, we examined the effects of this stark difference in migratory strategy on body condition, breeding phenology and breeding success. We monitored four colonies in two regions of southern Spain for five consecutive years (2014–2018), yielding 1962 captures, determining migratory strategy for 141 adult bird-years. Despite a 3000-km difference in distance travelled, we find no effect of strategy on breeding parameters. We find weak evidence for a short-term negative carryover effect of migration on body condition, but this was only apparent in the breeding region with lower primary productivity. Our results indicate that carryover effects of even highly divergent migratory strategies may be minimal relative to effects of conditions experienced on breeding grounds.
Aircraft events correspond with vocal behavior in a passerine
Authors: Injaian Allison S. , Lane Ethan D. , Klinck Holger
Published: January 2021

Airports can affect birds by hindering acoustic communication. Here, we investigated the impacts of aircraft events on vocal behavior in wood thrush (Hylocichla mustelina) breeding one mile from an airport in Ithaca, NY, USA. We identified the number of wood thrush songs between 0500 and 0800 h at various distances from the airport and on days with various morning flight schedules. We also analyzed the number of sites from which birds sang during the peak of aircraft events (proxy of number of wood thrush). We found that birds sang more from 0600 to 0640 h when there were aircraft events during this period. This increased vocal behavior is likely explained by increased song output per individual wood thrush, rather than more wood thrush vocalizing. Increased song rate may negatively affect wood thrush fitness through increased energetic demands and/or time tradeoffs with other important behaviors, such as foraging. Identifying the noise thresholds associated with fitness costs (if any) and how different behavioral strategies (i.e. changing the pattern of vocalizations) may allow individuals to evade these costs would be useful for establishing conservation policy in breeding habitats used by passerines, such as the wood thrush.
Sex differences in the effects of prenatal bisphenol A exposure on autism-related genes and their relationships with the hippocampus functions
Authors: Thongkorn Surangrat , Kanlayaprasit Songphon , Panjabud Pawinee , Saeliw Thanit , Jantheang Thanawin , Kasitipradit Kasidit , Sarobol Suthathip , Jindatip Depicha , Hu Valerie W. , Tencomnao Tewin , Kikkawa Takako , Sato Tatsuya , Osumi Noriko , Sarachana Tewarit
Published: January 2021

Our recent study has shown that prenatal exposure to bisphenol A (BPA) altered the expression of genes associated with autism spectrum disorder (ASD). In this study, we further investigated the effects of prenatal BPA exposure on ASD-related genes known to regulate neuronal viability, neuritogenesis, and learning/memory, and assessed these functions in the offspring of exposed pregnant rats. We found that prenatal BPA exposure increased neurite length, the number of primary neurites, and the number of neurite branches, but reduced the size of the hippocampal cell body in both sexes of the offspring. However, in utero exposure to BPA decreased the neuronal viability and the neuronal density in the hippocampus and impaired learning/memory only in the male offspring while the females were not affected. Interestingly, the expression of several ASD-related genes (e.g.Mief2,Eif3h,Cux1, andAtp8a1) in the hippocampus were dysregulated and showed a sex-specific correlation with neuronal viability, neuritogenesis, and/or learning/memory. The findings from this study suggest that prenatal BPA exposure disrupts ASD-related genes involved in neuronal viability, neuritogenesis, and learning/memory in a sex-dependent manner, and these genes may play an important role in the risk and the higher prevalence of ASD in males subjected to prenatal BPA exposure.
The mitochondrial permeability transition phenomenon elucidated by cryo-EM reveals the genuine impact of calcium overload on mitochondrial structure and function
Authors: Strubbe-Rivera Jasiel O. , Schrad Jason R. , Pavlov Evgeny V. , Conway James F. , Parent Kristin N. , Bazil Jason N.
Published: January 2021

Mitochondria have a remarkable ability to uptake and store massive amounts of calcium. However, the consequences of massive calcium accumulation remain enigmatic. In the present study, we analyzed a series of time-course experiments to identify the sequence of events that occur in a population of guinea pig cardiac mitochondria exposed to excessive calcium overload that cause mitochondrial permeability transition (MPT). By analyzing coincident structural and functional data, we determined that excessive calcium overload is associated with large calcium phosphate granules and inner membrane fragmentation, which explains the extent of mitochondrial dysfunction. This data also reveals a novel mechanism for cyclosporin A, an inhibitor of MPT, in which it preserves cristae despite the presence of massive calcium phosphate granules in the matrix. Overall, these findings establish a mechanism of calcium-induced mitochondrial dysfunction and the impact of calcium regulation on mitochondrial structure and function.
Experimental and thermodynamic modeling decitabine anti cancer drug solubility in supercritical carbon dioxide
Authors: Pishnamazi Mahboubeh , Zabihi Samyar , Jamshidian Sahar , Borousan Fatemeh , Hezave Ali Zeinolabedini , Marjani Azam , Shirazian Saeed
Published: January 2021

Design and development of efficient processes for continuous manufacturing of solid dosage oral formulations is of crucial importance for pharmaceutical industry in order to implement the Quality-by-Design paradigm. Supercritical solvent-based manufacturing can be utilized in pharmaceutical processing owing to its inherent operational advantages. However, in order to evaluate the possibility of supercritical processing for a particular medicine, solubility measurement needs to be carried out prior to process design. The current work reports a systematic solubility analysis on decitabine as an anti-cancer medicine. The solvent is supercritical carbon dioxide at different conditions (temperatures and pressures), while gravimetric technique is used to obtain the solubility data for decitabine. The results indicated that the solubility of decitabine varies between 2.84 × 10–05 and 1.07 × 10–03 mol fraction depending on the temperature and pressure. In the experiments, temperature and pressure varied between 308–338 K and 12–40 MPa, respectively. The solubility of decitabine was plotted against temperature and pressure, and it turned out that the solubility had direct relation with the pressure due to the effect of pressure on solvating power of solvent. The effect of temperature on solubility was shown to be dependent on the cross-over pressure. Below the cross-over pressure, there is a reverse relation between temperature and solubility, while a direct relation was observed above the cross-over pressure (16 MPa). Theoretical study was carried out to correlate the solubility data using several thermodynamic-based models. The fitting and model calibration indicated that the examined models were of linear nature and capable to predict the measured decitabine solubilities with the highest average absolute relative deviation percent (AARD %) of 8.9%.
Dissecting the contribution of O-Antigen and proteins to the immunogenicity of Shigella sonnei generalized modules for membrane antigens (GMMA)
Authors: Mancini Francesca , Gasperini Gianmarco , Rossi Omar , Aruta Maria Grazia , Raso Maria Michelina , Alfini Renzo , Biagini Massimiliano , Necchi Francesca , Micoli Francesca
Published: January 2021

GMMA are exosomes released from engineered Gram-negative bacteria resembling the composition of outer membranes. We applied the GMMA technology for the development of an O-Antigen (OAg) based vaccine against Shigella sonnei, the most epidemiologically relevant cause of shigellosis. S. sonnei OAg has been identified as a key antigen for protective immunity, and GMMA are able to induce anti-OAg-specific IgG response in animal models and healthy adults. The contribution of protein-specific antibodies induced upon vaccination with GMMA has never been fully elucidated. Anti-protein antibodies are induced in mice upon immunization with either OAg-negative and OAg-positive GMMA. Here we demonstrated that OAg chains shield the bacteria from anti-protein antibody binding and therefore anti-OAg antibodies were the main drivers of bactericidal activity against OAg-positive bacteria. Interestingly, antibodies that are not targeting the OAg are functional against OAg-negative bacteria. The immunodominant protein antigens were identified by proteomic analysis. Our study confirms a critical role of the OAg on the immune response induced by S. sonnei GMMA. However, little is known about OAg length and density regulation during infection and, therefore, protein exposure. Hence, the presence of protein antigens on S. sonnei GMMA represents an added value for GMMA vaccines compared to other OAg-based formulations.
The effectiveness of a nonalcoholic disinfectant containing metal ions, with broad antimicrobial activity
Authors: Matsubara Tokuhiro , Maki Shuichi , Toshimori Yukiko
Published: January 2021

Disinfectants have different efficacies depending on their use and the target microorganism. This study aimed to evaluate the efficacy and safety of our new nonalcoholic disinfectant, which consists mainly of metal ions. According to the 17th revised Japanese Pharmacopoeia and ASTM international E1052 method, the bactericidal and virucidal efficacy of this new disinfectant against 13 microorganisms was evaluated by the in vitro quantitative suspension test. Additionally, the disinfectant cytotoxicity against multiple cell lines was examined. Then, a safety test using a human open patch test was performed with 26 healthy volunteers. This disinfectant showed strong bactericidal and virucidal activities: all microorganisms except enterovirus were inactivated very quickly. The infectivity of 12 microbial strains was eliminated within 5 min of disinfectant exposure. Additionally, this disinfectant showed little acute cytotoxicity in vitro. All volunteers were negative in the human open patch test. Our new disinfectant has a broad spectrum of microbial targets, is safe for human skin, and demonstrates no cytotoxicity. This disinfectant could prevent common microbial infections.
Water constraints drive allometric patterns in the body shape of tree frogs
Authors: Castro Kathleen M. S. A. , Amado Talita F. , Olalla-Tárraga Miguel Á. , Gouveia Sidney F. , Navas Carlos A. , Martinez Pablo A.
Published: January 2021

The origin of morphological diversity is a critical question in evolutionary biology. Interactions between the environment and developmental processes have determining roles in morphological diversity, creating patterns through space and over time. Also, the shape of organisms tends to vary with increasing size as a result of those developmental processes, known as allometry. Several studies have demonstrated that the body sizes of anurans are associated with hydric conditions in their environments and that localities with high water stress tend to select for larger individuals. However, how environmental conditions alter those patterns of covariance between size and shape is still elusive. We used 3D geometric morphometric analyses, associated with phylogenetic comparative methods, to determine if the morphological variations and allometric patterns found in Arboranae (Anura) is linked to water conservation mechanisms. We found effects of the hydric stress on the shape of Arboranae species, favouring globular shapes. Also, the allometric patterns varied in intensity according to the water stress gradient, being particularly relevant for smaller frogs, and more intense in environments with higher water deficits. Our study provides empirical evidence that more spherical body shapes, especially among smaller species, reflect an important adaptation of anurans to water conservation in water-constrained environments.
Effect of lipopolysaccharide and polyinosinic:polycytidylic acid in a murine model of nasal polyp
Authors: Wee Jee Hye , Ko Young-Kyung , Khalmuratova Roza , Shin Hyun-Woo , Kim Dae Woo , Rhee Chae-Seo
Published: January 2021

Several factors, including bacterial and viral infections, have been associated with rhinosinusitis and nasal tissue remodelling that may result in nasal polyp formation. However, the potential role of bacterial or viral stimuli triggering polyp development is unclear. Here, we used lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid [poly(I:C)] in a murine model of allergic rhinosinusitis to compare different effects of bacterial- and virus-derived stimuli in the pathogenesis of nasal polyp formation. Briefly, BALB/c mice were sensitised and challenged with ovalbumin and staphylococcal enterotoxin, with or without LPS or poly(I:C), and the consequent histopathological profiles, cytokines, and systemic humoral responses were studied. While no significant differences in polyp formations and epithelial disruptions were observed among the experimental groups, the local cell recruitment patterns slightly differed in animals that received either LPS or poly(I:C). Additionally, the local immune environments generated by LPS or poly(I:C) stimulation varied. LPS stimulation induced a marked Th1/Th17 response and predominantly neutrophilic nasal polyp formations, whereas poly(I:C) induced a Th2-skewed environment in neutrophilic nasal polyp development. Overall, our findings show that both cell recruitment patterns and local immune environments induced by these two stimuli differ, which may have implications in the physiopathology of rhinosinusitis with nasal polyp.
Dynamic blood flow phantom for in vivo liquid biopsy standardization
Authors: Kozlova Anastasiia , Bratashov Daniil , Grishin Oleg , Abdurashitov Arkadii , Prikhozhdenko Ekaterina , Verkhovskii Roman , Shushunova Natalia , Shashkov Evgeny , Zharov Vladimir P. , Inozemtseva Olga
Published: January 2021

In vivo liquid biopsy, especially using the photoacoustic (PA) method, demonstrated high clinical potential for early diagnosis of deadly diseases such as cancer, infections, and cardiovascular disorders through the detection of rare circulating tumor cells (CTCs), bacteria, and clots in the blood background. However, little progress has been made in terms of standardization of these techniques, which is crucial to validate their high sensitivity, accuracy, and reproducibility. In the present study, we addressed this important demand by introducing a dynamic blood vessel phantom with flowing mimic normal and abnormal cells. The light transparent silica microspheres were used as white blood cells and platelets phantoms, while hollow polymeric capsules, filled with hemoglobin and melanin, reproduced red blood cells and melanoma CTCs, respectively. These phantoms were successfully used for calibration of the PA flow cytometry platform with high-speed signal processing. The results suggest that these dynamic cell flow phantoms with appropriate biochemical, optical, thermal, and acoustic properties can be promising for the establishment of standardization tool for calibration of PA, fluorescent, Raman, and other detection methods of in vivo flow cytometry and liquid biopsy.
Quantitative immuno-mass spectrometry imaging of skeletal muscle dystrophin
Authors: Bishop David P. , Westerhausen Mika T. , Barthelemy Florian , Lockwood Thomas , Cole Nerida , Gibbs Elizabeth M. , Crosbie Rachelle H. , Nelson Stanley F. , Miceli M. Carrie , Doble Philip A. , Wanagat Jonathan
Published: January 2021

Emerging and promising therapeutic interventions for Duchenne muscular dystrophy (DMD) are confounded by the challenges of quantifying dystrophin. Current approaches have poor precision, require large amounts of tissue, and are difficult to standardize. This paper presents an immuno-mass spectrometry imaging method using gadolinium (Gd)-labeled anti-dystrophin antibodies and laser ablation-inductively coupled plasma-mass spectrometry to simultaneously quantify and localize dystrophin in muscle sections. Gd is quantified as a proxy for the relative expression of dystrophin and was validated in murine and human skeletal muscle sections following k-means clustering segmentation, before application to DMD patients with different gene mutations where dystrophin expression was measured up to 100 µg kg−1 Gd. These results demonstrate that immuno-mass spectrometry imaging is a viable approach for pre-clinical to clinical research in DMD. It rapidly quantified relative dystrophin in single tissue sections, efficiently used valuable patient resources, and may provide information on drug efficacy for clinical translation.
Regulation of carcinogenesis and mediation through Wnt/β-catenin signaling by 3,3′-diindolylmethane in an enzalutamide-resistant prostate cancer cell line
Authors: Tsao Chih-Wei , Li Jia-Sin , Lin Ya-Wen , Wu Sheng-Tang , Cha Tai-Lung , Liu Chin-Yu
Published: January 2021

Enzalutamide (ENZ) is an important drug used to treat castration-resistant prostate cancer (CRPC), which inhibits androgen receptor (AR) signaling. Previous study showed that 3,3′-diindolylmethane (DIM) is an AR antagonist that also inhibits Wnt signaling and epithelial-mesenchymal transition (EMT). To investigate whether combined treatment with ENZ and DIM can overcome ENZ resistance by regulating Wnt signaling to inhibit AR signaling and EMT in ENZ-resistant prostate cancer cells, 22Rv1 cells were cultured in normal medium and treated with ENZ, DIM, and DIM with ENZ. Exposure of ENZ-resistant cells to both DIM and ENZ significantly inhibited cell proliferation without cytotoxicity and invasion in comparison with the control. DIM significantly increased the E-cadherin expression and inhibited the expressions of Vimentin and Fibronectin, subsequently inhibiting EMT. Co-treatment with ENZ and DIM significantly increased the expressions of GSK3β and APC and decreased the β-catenin protein expression, causing inhibition of Wnt signaling and AR expression, it also significantly decreased the AR-v7 expression and down-regulated AR signaling. Via suppression of Wnt and AR signaling, co-treatment increased the E-cadherin and decreased the Vimentin and Fibronectin RNA and protein expressions, then inhibited EMT. Co-treatment with DIM and ENZ regulated Wnt signaling to reduce not only the AR expression, but also the AR-v7 expression, indicating suppression of EMT that inhibits cancer cell proliferation, invasion and migration to ameliorate ENZ resistance.
Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1
Authors: Dang Mei , Li Yifan , Song Jianxing
Published: January 2021

TDP-43 and hnRNPA1 contain tandemly-tethered RNA-recognition-motif (RRM) domains, which not only functionally bind an array of nucleic acids, but also participate in aggregation/fibrillation, a pathological hallmark of various human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), alzheimer's disease (AD) and Multisystem proteinopathy (MSP). Here, by DSF, NMR and MD simulations we systematically characterized stability, ATP-binding and conformational dynamics of TDP-43 and hnRNPA1 RRM domains in both tethered and isolated forms. The results reveal three key findings: (1) upon tethering TDP-43 RRM domains become dramatically coupled and destabilized with Tm reduced to only 49 °C. (2) ATP specifically binds TDP-43 and hnRNPA1 RRM domains, in which ATP occupies the similar pockets within the conserved nucleic-acid-binding surfaces, with the affinity slightly higher to the tethered than isolated forms. (3) MD simulations indicate that the tethered RRM domains of TDP-43 and hnRNPA1 have higher conformational dynamics than the isolated forms. Two RRM domains become coupled as shown by NMR characterization and analysis of inter-domain correlation motions. The study explains the long-standing puzzle that the tethered TDP-43 RRM1–RRM2 is particularly prone to aggregation/fibrillation, and underscores the general role of ATP in inhibiting aggregation/fibrillation of RRM-containing proteins. The results also rationalize the observation that the risk of aggregation-causing diseases increases with aging.
Gut microbiome is affected by inter-sexual and inter-seasonal variation in diet for thick-billed murres (Uria lomvia)
Authors: Góngora Esteban , Elliott Kyle H. , Whyte Lyle
Published: January 2021

The role of the gut microbiome is increasingly being recognized by health scientists and veterinarians, yet its role in wild animals remains understudied. Variations in the gut microbiome could be the result of differential diets among individuals, such as variation between sexes, across seasons, or across reproductive stages. We evaluated the hypothesis that diet alters the avian gut microbiome using stable isotope analysis (SIA) and 16S rRNA gene sequencing. We present the first description of the thick-billed murre (Uria lomvia) fecal microbiome. The murre microbiome was dominated by bacteria from the genus Catellicoccus, ubiquitous in the guts of many seabirds. Microbiome variation was explained by murre diet in terms of proportion of littoral carbon, trophic position, and sulfur isotopes, especially for the classes Actinobacteria, Bacilli, Bacteroidia, Clostridia, Alphaproteobacteria, and Gammaproteobacteria. We also observed differences in the abundance of bacterial genera such as Catellicoccus and Cetobacterium between sexes and reproductive stages. These results are in accordance with behavioural observations of changes in diet between sexes and across the reproductive season. We concluded that the observed variation in the gut microbiome may be caused by individual prey specialization and may also be reinforced by sexual and reproductive stage differences in diet.