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, Maarit Ahtiainen, Jukka-Pekka Mecklin, Ilmo Kellokumpu, Johanna Laukkarinen, Markku Tammi, Raija Tammi, Juha P. Väyrynen, Jan Böhm
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-9; doi:10.1038/s41598-021-91796-x

Abstract:
Hyaluronan (HA) accumulation has been associated with poor survival in various cancers, but the mechanisms for this phenomenon are still unclear. The aim of this study was to investigate the prognostic significance of stromal HA accumulation and its association with host immune response in pancreatic ductal adenocarcinoma (PDAC). The study material consisted of 101 radically treated patients for PDAC from a single geographical area. HA staining was evaluated using a HA-specific probe, and the patterns of CD3, CD8, CD73 and PD-L1 expression were evaluated using immunohistochemistry. HA staining intensity of tumour stromal areas was assessed digitally using QuPath. CD3- and CD8-based immune cell score (ICS) was determined. High-level stromal HA expression was significantly associated with poor disease-specific survival (p = 0.037) and overall survival (p = 0.013) In multivariate analysis, high-level stromal HA expression was an independent negative prognostic factor together with histopathological grade, TNM stage, CD73 positivity in tumour cells and low ICS. Moreover, high-level stromal HA expression was associated with low ICS (p = 0.017). In conclusion, stromal HA accumulation is associated with poor survival and low immune response in PDAC.
Hwa-Seub Lee, Gyu-Weon Hwang, Tae-Yeon Seong, Jongkil Park, Jae Wook Kim, Won Mok Kim, Inho Kim,
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-10; doi:10.1038/s41598-021-91762-7

Abstract:
Mid-infrared wavelengths are called the molecular fingerprint region because it contains the fundamental vibrational modes inherent to the substances of interest. Since the mid-infrared spectrum can provide non-destructive identification and quantitative analysis of unknown substances, miniaturized mid-infrared spectrometers for on-site diagnosis have attained great concern. Filter-array based on-chip spectrometer has been regarded as a promising alternative. In this study, we explore a way of applying a pillar-type plasmonic nanodiscs array, which is advantageous not only for excellent tunability of resonance wavelength but also for 2-dimensional integration through a single layer process, to the multispectral filter array for the on-chip spectrometer. We theoretically and experimentally investigated the optical properties of multi-periodic triangular lattices of metal nanodiscs array that act as stopband filters in the mid-infrared region. Soft-mold reverse nanoimprint lithography with a subsequent lift-off process was employed to fabricate the multispectral filter array and its filter function was successfully extracted using a Fourier transform infrared microscope. With the measured filter function, we tested the feasibility of target spectrum reconstruction using a Tikhonov regularization method for an ill-posed linear problem and evaluated its applicability to the infrared spectroscopic sensor that monitors an oil condition. These results not only verify that the multispectral filter array composed of stopband filters based on the metal nanodiscs array when combined with the spectrum reconstruction technique, has great potential for use to a miniaturized mid-infrared on-chip spectrometer, but also provide effective guidance for the filter design.
Hongxing Lei
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-12; doi:10.1038/s41598-021-91754-7

Abstract:
With many countries strapped for medical resources due to the COVID-19 pandemic, it is highly desirable to allocate the precious resources to those who need them the most. Several markers have been found to be associated with the disease severity in COVID-19 patients. However, the established markers only display modest prognostic power individually and better markers are urgently needed. The aim of this study is to investigate the potential of S100A12, a prominent marker gene for bacterial infection, in the prognosis of disease severity in COVID-19 patients. To ensure the robustness of the association, a total of 1695 samples from 14 independent transcriptome datasets on sepsis, influenza infection and COVID-19 infection were examined. First, it was demonstrated that S100A12 was a marker for sepsis and severity of sepsis. Then, S100A12 was found to be a marker for severe influenza infection, and there was an upward trend of S100A12 expression as the severity level of influenza infection increased. As for COVID-19 infection, it was found that S100A12 expression was elevated in patients with severe and critical COVID-19 infection. More importantly, S100A12 expression at hospital admission was robustly correlated with future quantitative indexes of disease severity and outcome in COVID-19 patients, superior to established prognostic markers including CRP, PCT, d-dimer, ferritin, LDH and fibrinogen. Thus, S100A12 is a valuable novel prognostic marker for COVID-19 severity and deserves more attention.
Correction
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-1; doi:10.1038/s41598-021-92113-2

Linlin Yin, Si Zhao, Hanlong Zhu, Guozhong Ji, Xiuhua Zhang
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-12; doi:10.1038/s41598-021-91823-x

Abstract:
The purpose of our study was to evaluate the effect of surgery on the survival and prognosis of patients with multifocal intrahepatic cholangiocarcinoma (ICCA). Patients with multifocal ICCA were selected from the SEER (Surveillance, Epidemiology, and End Results) database between 2010 and 2016. Kaplan–Meier analyses and log-rank tests were used to evaluate the difference in survival between the surgery group and the non-surgery group. We applied the Cox proportional hazards regression model to identify prognostic factors of overall survival (OS) and cancer-specific survival (CSS). In total, 580 patients were enrolled in our study, including 151 patients who underwent surgery and 429 patients who did not. The median survival time of surgical patients was longer than non-surgical patients (OS: 25 months vs. 8 months, p < 0.001; CSS: 40 months vs. 25 months, p < 0.001). Similarly, the 5-year survival rate in the surgery group was significantly higher than those in the non-surgery group (5-year OS rate: 12.91% vs. 0%; p < 0.001; 5-year CSS rate:26.91% vs. 0%; p < 0.001). Multivariate Cox analysis showed that the OS (HR:0.299, 95% CI: 0.229–0.390, p < 0.001) and CSS (HR:0.305, 95% CI:0.222–0.419, p < 0.001) of patients undergoing surgical resection were significantly improved. Meanwhile, after propensity score matching (PSM) of the original data, we come to the same conclusion.
, Rainer Dumke, Tomasz Paterek
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-10; doi:10.1038/s41598-021-91815-x

Abstract:
Many animals display sensitivity to external magnetic field, but it is only in the simplest organisms that the sensing mechanism is understood. Here we report on behavioural experiments where American cockroaches (Periplaneta americana) were subjected to periodically rotated external magnetic fields with a period of 10 min. The insects show increased activity when placed in a periodically rotated Earth-strength field, whereas this effect is diminished in a twelve times stronger periodically rotated field. We analyse established models of magnetoreception, the magnetite model and the radical pair model, in light of this adaptation result. A broad class of magnetite models, based on single-domain particles found in insects and assumption that better alignment of magnetic grains towards the external field yields better sensing and higher insect activity, is shown to be excluded by the measured data. The radical-pair model explains the data if we assume that contrast in the chemical yield on the order of one in a thousand is perceivable by the animal, and that there also exists a threshold value for detection, attained in an Earth-strength field but not in the stronger field.
Hongyun Wang, , Yongju Zhang, Axiang Ji, Pengyuan Qiu
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-12; doi:10.1038/s41598-021-91836-6

Abstract:
Transient behavior of a magnetorheological brake excited by step currents under compression-shear mode has been experimentally studied. The results show that the amplitude of the applied current had little effect on the rising time of transient torque, while the rising time was significantly affected by the rotational speed, the compressive speed and the compressive strain position. The falling time of transient torque was independent of the amplitude of the applied current, the compressive speed and the compressive strain position, and it was affected by the rotational speed. The falling time of the transient torque was much shorter than the rising time by a step current. The transient process of MR brake applied as a step current was different from a stable process pre-applied at constant current in different particle chain structure forming processes. In addition, the compressive processes applied in one step current and randomly on/off current were compared and experimentally verified: the particle chains in two processes both experienced the same evolutionary of transient torque. The results achieved in this study should be properly considered in the design and control of magnetorheological brake under compression-shear mode.
Yoon Ji Chung, Eun Young Kim
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-10; doi:10.1038/s41598-021-91819-7

Abstract:
We determined the relationship between changes in bioelectrical impedance analysis (BIA) parameters and response of critically ill patients to fluid therapy during early postoperative period. Associations between BIA values indicating volume status of postoperative patient and clinical outcomes were also evaluated. From May 2019 to April 2020, patients who were admitted to the surgical intensive care unit (SICU) of our institution at more than 48 h after surgery were enrolled. Volume status was measured with a portable BIA device every morning for five days from SICU admission. Overhydration was defined as the case where extracellular water (ECW) ratio > 0.390 measured by BIA. Participants were daily classified into an overhydration or a normohydration group. The relationship between daily hydration status and postoperative outcome was evaluated. Most of the 190 participants showed the overhydration status in the first 48 h after surgery. The overhydration status on day 3 was significant predictor of postoperative morbidities (OR 1.182) and in-hospital mortality (OR 2.040). SOFA score was significant factor of postoperative morbidities (OR 1.163) and in-hospital mortality (OR 3.151) except for the overhydration status on day 3. Cut-off values of overhydration status by ECW ratio at day 3 for predicting postoperative morbidities and in-hospital mortality were > 0.3985 and > 0.4145, respectively. BIA would be a useful and convenient tool to assess the volume status of patients requiring intensive fluid resuscitation in early postoperative period. Overhydration status by ECW ratio on postoperative day 3 needs careful monitoring and appropriate interventions to improve clinical outcomes.
, Loreta Kuzmiene, Brent Siesky, Alon Harris, Ingrida Januleviciene
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-10; doi:10.1038/s41598-021-91740-z

Abstract:
The purpose of this study was to evaluate intraocular pressure (IOP) pre- and postoperatively, together with anterior chamber angle (ACA) parameters and biometrical results in cataract patients with or without open angle glaucoma (OAG). The prospective observational case–control study included 15 eyes with cataract and OAG in the glaucoma group and 25 eyes with only cataract in control group. Examination included full ophthalmic evaluation, IOP, ocular biometry and anterior segment optical coherence tomography measuring ACA pre- and 6 months postoperatively. OAG patients had a larger absolute IOP reduction compared to control group. Anterior chamber depth (ACD) and ACA width significantly increased in both groups. The OAG group had a tendency of narrower ACA preoperatively, but overall ACA parameters did not differ in either group pre- and postoperatively. The ACD change after surgery correlated with ACA parameters in the control group, but not in OAG group. Axial length was shorter postoperatively in the control group, but remained similar in the OAG group. Absolute IOP reduction was more pronounced in cataract patients with OAG than in cataract patients without glaucoma. ACD and ACA postoperatively increased in both groups and AL shortening was observed in non-OAG in cataract group.
Keisuke Kamada, Atsushi Yoshida, Shigekazu Iguchi, Yuko Arai, Yutaka Uzawa, Satoshi Konno, Masahiro Shimojima,
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-10; doi:10.1038/s41598-021-91757-4

Abstract:
This study aimed to identify effective treatments against rapidly growing mycobacteria (RGM) infections by investigating the minimum inhibitory concentrations (MIC) of 24 antimicrobial agents and their molecular mechanisms of resistance. In total, 509 clinical RGM isolates were identified by analyzing the sequences of three housekeeping genes (hsp65, rpoB, and sodA), and their susceptibilities to 24 antimicrobial agents were tested. We also performed sequencing analysis of antimicrobial resistance genes (rrl, rrs, gyrA, and gyrB). To identify Mycobacteroides abscessus group subspecies, we performed PCR-based typing and determined the sequevar of erm(41). We identified 15 RGM species, most of which were susceptible to amikacin and linezolid. Among these species, arbekacin and sitafloxacin had the lowest MIC among the same class of antimicrobials. The MIC of rifabutin for M. abscessus subsp. abscessus (MAB) was lower than that for M. abscessus subsp. massiliense (MMA). The proportion of MAB isolates with MIC ≤ 2 mg/L for rifabutin was significantly higher than that of MMA [MAB: 50/178 (28.1%) vs. MMA: 23/130 (17.7%); p = 0.041]. In summary, our study revealed the antimicrobial susceptibility profile of 15 RGM species isolated in Japan and indicated that arbekacin, sitafloxacin, and rifabutin may be possible therapeutic options for RGM infections.
Szu-Chun Yang, , Shi-Yi Wang
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-10; doi:10.1038/s41598-021-91852-6

Abstract:
Low-dose computed tomography screening can be used to diagnose lung cancer at a younger age compared to no screening. Real-world studies observing mortality after lung cancer diagnosis are subject to lead-time bias. This study developed a method using a nationwide cancer registry and stage shift from trial for the adjustment of lead-time bias. 78,897 Taiwanese nationwide lung cancer patients aged 55–82 were matched with 788,820 referents randomly selected from the general population at a ratio of 1:10 by age, sex, calendar year, and comorbidities, to estimate the pathology- and stage-specific life expectancy (LE). Loss-of-LE is the difference between the LE of cancer patients and that of referents. By multiplying LE and loss-of-LE by the pathology and stage shift in the National Lung Screening Trial (NLST), we compared the effectiveness of cancer screening measured by LE gained and loss-of-LE saved. The mean LEs of stage IA and IV adenocarcinoma were 14.5 and 1.9 years, respectively, indicating a LE gain of 12.6 years. However, the mean loss-of-LEs of stage IA and IV adenocarcinoma were 3.7 and 15.1 years, respectively, with a saving of only 11.4 years, implying an adjustment of different distributions of age, sex, and calendar year of diagnosis from stage shift and a reduction in lead-time bias. Applying such estimations on the results of 10,000 participants with the same pathology and stage shift in the NLST, the benefit of screening using LE gained would be 410.3 (95% prediction interval: 328.4 to 503.3) years. It became 297.1 (95% prediction interval: 187.8 to 396.4) years when using loss-of-LE saved, indicating the former approach would overestimate the effectiveness by 38%. Our approach of multiplying loss-of-LE by pathology and stage shift to estimate loss-of-LE saved could adjust for different distributions of age, sex, and calendar year at early diagnosis and reduce lead-time bias.
Kazutoshi Yoshitake, Gaku Kimura, Tomoko Sakami, Tsuyoshi Watanabe, Yukiko Taniuchi, Shigeho Kakehi, Akira Kuwata, Haruyo Yamaguchi, Takafumi Kataoka, Masanobu Kawachi, et al.
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-13; doi:10.1038/s41598-021-91615-3

Abstract:
Although numerous metagenome, amplicon sequencing-based studies have been conducted to date to characterize marine microbial communities, relatively few have employed full metagenome shotgun sequencing to obtain a broader picture of the functional features of these marine microbial communities. Moreover, most of these studies only performed sporadic sampling, which is insufficient to understand an ecosystem comprehensively. In this study, we regularly conducted seawater sampling along the northeastern Pacific coast of Japan between March 2012 and May 2016. We collected 213 seawater samples and prepared size-based fractions to generate 454 subsets of samples for shotgun metagenome sequencing and analysis. We also determined the sequences of 16S rRNA (n = 111) and 18S rRNA (n = 47) gene amplicons from smaller sample subsets. We thereafter developed the Ocean Monitoring Database for time-series metagenomic data (http://marine-meta.healthscience.sci.waseda.ac.jp/omd/), which provides a three-dimensional bird’s-eye view of the data. This database includes results of digital DNA chip analysis, a novel method for estimating ocean characteristics such as water temperature from metagenomic data. Furthermore, we developed a novel classification method that includes more information about viruses than that acquired using BLAST. We further report the discovery of a large number of previously overlooked (TAG)n repeat sequences in the genomes of marine microbes. We predict that the availability of this time-series database will lead to major discoveries in marine microbiome research.
Yutaka Murata, Eriko Kusudo, Shuji Kawamoto, Kazuhiko Fukuda
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-8; doi:10.1038/s41598-021-91725-y

Abstract:
Acute normovolemic hemodilution (ANH) is a potential transfusion method for platelets, as well as for red blood cells. However, previous studies have shown that whole blood storage in ANH decreases platelet aggregability by 14.7–76.3% and that this decrease is not recovered by reinfusion. We investigated whether a new whole blood storage method for 6 h using a polyolefin bag, based on the platelet concentrates storage method, would maintain platelet function better than the conventional method using a polyvinyl chloride bag. We demonstrated that storage of whole blood in a polyolefin bag maintained ADP-induced aggregation rates at more than twofold higher than those in a polyvinyl chloride bag, and also significantly suppressed P-selectin expression, a platelet activation marker (ADP-induced aggregation rates: 24.6 ± 5.1% vs. 51.7 ± 11.5%, p = 0.002; P-selectin expression; 50.3 ± 8.4MFI vs. 31.6 ± 9.3MFI, p = 0.018). These results could be attributed to the high gas permeability of polyolefin, which lowered PCO2 and maintained a high pH with or without agitation. There were no significant changes in platelet count and red blood cell parameters due to the storage methods. Our results suggest that ANH using polyolefin bags is advantageous in improving hemostatic function compared to the conventional method.
Sepideh Yazdian Kashani, ,
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-17; doi:10.1038/s41598-021-91616-2

Abstract:
It has been proved that cell-imprinted substrates molded from template cells can be used for the re-culture of that cell while preserving its normal behavior or to differentiate the cultured stem cells into the template cell. In this study, a microfluidic device was presented to modify the previous irregular cell-imprinted substrate and increase imprinting efficiency by regular and objective cell culture. First, a cell-imprinted substrate from template cells was prepared using a microfluidic chip in a regular pattern. Another microfluidic chip with the same pattern was then aligned on the cell-imprinted substrate to create a chondrocyte-imprinted-based integrated microfluidic device. Computational fluid dynamics (CFD) simulations were used to obtain suitable conditions for injecting cells into the microfluidic chip before performing experimental evaluations. In this simulation, the effect of input flow rate, number per unit volume, and size of injected cells in two different chip sizes were examined on exerted shear stress and cell trajectories. This numerical simulation was first validated with experiments with cell lines. Finally, chondrocyte was used as template cell to evaluate the chondrogenic differentiation of adipose-derived mesenchymal stem cells (ADSCs) in the chondrocyte-imprinted-based integrated microfluidic device. ADSCs were positioned precisely on the chondrocyte patterns, and without using any chemical growth factor, their fibroblast-like morphology was modified to the spherical morphology of chondrocytes after 14 days of culture. Both immunostaining and gene expression analysis showed improvement in chondrogenic differentiation compared to traditional imprinting methods. This study demonstrated the effectiveness of cell-imprinted-based integrated microfluidic devices for biomedical applications.
Nutnicha Neti, Anchisa Pimsri, Sutasinee Boonsopon, Nattaporn Tesavibul,
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-6; doi:10.1038/s41598-021-91701-6

Abstract:
To identify triggering factors for the next inflammatory episode of recurrent acute anterior uveitis (RAAU), a 1:1 case–control study was conducted. We interviewed RAAU patients with recent acute anterior uveitis attack and quiescent controls for their information during a previous month using Srithanya Stress Test (ST-5) and questionnaires about potential triggering factors. Asymptomatic controls were matched for age (± 5 years), sex, and HLA-B27. There were 39 pairs of cases and controls. Patients who recently experienced a uveitis attack demonstrated higher mean ST-5 scores (3.7 ± 2.9 vs 0.7 ± 1.1) and shorter sleep time (6.3 ± 1.4 vs 7.4 ± 0.7 h per day) compared with their controls. In the multivariate conditional logistic regression analysis, ST-5 score ≥ 3 (OR 9.07, 95% CI 1.14–72.16, p = 0.037) and sleep time < 7 h per day (OR 12.12, 95% CI 1.37–107.17, p = 0.025) were more likely to trigger a uveitis attack in RAAU accounted for patients’ age, sex, HLA- B27 positivity, and presence of concurrent anti-inflammatory drugs for co-existing diseases. Other suspected triggering factors were not found to have any significant association. In short, stress and inadequate sleep may lead to the future episode of acute anterior uveitis in RAAU. Both physical and emotional stress management should be advised to RAAU patients to minimize recurrences and further complications.
Qi Li, Peng Li
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-16; doi:10.1038/s41598-021-91639-9

Abstract:
The arbitrary order Hilbert spectral analyses are applied to study the intermittency and multifractality of Global Horizonal Irradiation (GHI) based on one available high sampling rate of 1-year GHI records located at Saint-Denis (Moufia) over Reunion Island. The scaling exponents $$\xi \left( q \right)$$ ξ q is estimated through the arbitrary order Hilbert spectral analyses, and three parameters: Hurst exponent (H), the fractal co-dimension (C 1), and Lévy parameter ( $$\alpha$$ α ) are taken to study the multifractal process of the GHI in the sub-daily, daily fluctuations and also in seasonal variations. A power law behaviour with a spectral exponent β = 1.68 close to the Kolmogorov spectrum is detected through Fourier spectrum analysis, which indicates that the sub-daily fluctuations of GHI are nonstationary. The scaling exponent ζ(q) is then estimated by the arbitrary order Hilbert spectral analysis and the multifractal properties is detected. The log-stable model parameters $$H,{ }C_{1}$$ H , C 1 and $$\alpha$$ α characterize the concavity of the scaling exponent ζ(q) for analysing the intermittency of GHI. The classification method is applied to the daily GHI for analysing the distribution of the daily intermittency process and five classes with GHI and K b are obtained.
Yifan Zhang, , Fengliu Feng, Bowen Cheng, Hang Wang, Jiahui Shen, Haoran Jiao
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-10; doi:10.1038/s41598-021-91637-x

Abstract:
Particulate matter (PM) has been proved to be a risk factor for the development of circulatory system diseases (CSDs) around the world. In this study, we collected daily air pollutants, emergency room (ER) visits for CSDs, and meteorological data from 2009 to 2012 in Beijing, China. After controlling for the long-term trend and eliminating the influence of confounding factors, the generalized additive model (GAM) was used to evaluate the short-term effects of PM10 on CSDs and cause-specific diseases. The results showed that for every 10 μg/m3 increase in PM10, the largest effect estimates in ER visits of total CSDs, arrhythmia, cerebrovascular diseases, high blood pressure, ischemic heart disease and other related diseases were 0.14% (95% CI: 0.06–0.23%), 0.37% (95% CI: − 0.23 to 0.97%), 0.20% (95% CI: 0.00–0.40%), 0.15% (95% CI: 0.02–0.27%), 0.18% (95% CI: 0.02–0.35%) and 0.35% (95% CI: − 0.04 to 0.79%), respectively. When NO2 or SO2 was added into the model, the effect estimates of PM10 were mostly attenuated, while in those models with PM2.5 added, the effect estimates of PM10 were mostly increased. Stratified analysis indicated that PM10 had a greater effect on males and the elderly.
Van-Trung Pham,
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-14; doi:10.1038/s41598-021-91705-2

Abstract:
Evaluating the effect of porosity and ambient temperature on mechanical characteristics and thermal conductivity is vital for practical application and fundamental material property. Here we report that ambient temperature and porosity greatly influence fracture behavior and material properties. With the existence of the pore, the most significant stresses will be concentrated around the pore position during the uniaxial and biaxial processes, making fracture easier to occur than when tensing the perfect sheet. Ultimate strength and Young’s modulus degrade as porosity increases. The ultimate strength and Young's modulus in the zigzag direction is lower than the armchair one, proving that the borophene membrane has anisotropy characteristics. The deformation behavior of borophene sheets when stretching biaxial is more complicated and rough than that of uniaxial tension. In addition, the results show that the ultimate strength, failure strain, and Young’s modulus degrade with growing temperature. Besides the tensile test, this paper also uses the non-equilibrium molecular dynamics (NEMD) approach to investigate the effects of length size, porosity, and temperature on the thermal conductivity (κ) of borophene membranes. The result points out that κ increases as the length increases. As the ambient temperature increases, κ decreases. Interestingly, the more porosity increases, the more κ decreases. Moreover, the results also show that the borophene membrane is anisotropic in heat transfer.
, Gilbert J. Price, Vera Weisbecker, Steven W. Salisbury
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-14; doi:10.1038/s41598-021-91717-y

Abstract:
Based on the known fossil record, the majority of crocodylians from the Cenozoic Era of Australia are referred to the extinct clade Mekosuchinae. The only extant crocodylians in Australia are two species of Crocodylus. Hence, the viewpoint that Crocodylus and mekosuchines have been the only crocodylians inhabiting Australia during the Cenozoic has remained largely undisputed. Herein we describe Australia’s first tomistomine crocodylian, Gunggamarandu maunala gen. et sp. nov., thus challenging the notion of mekosuchine dominance during most of the Cenozoic. The holotype specimen of Gunggamarandu maunala derives from the Pliocene or Pleistocene of south-eastern Queensland, marking the southern-most global record for Tomistominae. Gunggamarandu maunala is known from a large, incomplete cranium that possesses a unique combination of features that distinguishes it from other crocodylians. Phylogenetic analyses place Gunggamarandu in a basal position within Tomistominae, specifically as a sister taxon to Dollosuchoides from the Eocene of Europe. These results hint at a potential ghost lineage between European and Australian tomistomines going back more than 50 million years. The cranial proportions of the Gunggamarandu maunala holotype specimen indicate it is the largest crocodyliform yet discovered from Australia.
Melike Pekmezci, Ramin A. Morshed, Pranathi Chunduru, Balaji Pandian, Jacob Young, Javier E. Villanueva-Meyer, Tarik Tihan, Emily A. Sloan, Manish K. Aghi, Annette M. Molinaro, et al.
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-11; doi:10.1038/s41598-021-91648-8

Abstract:
In the management of diffuse gliomas, the identification and removal of tumor at the infiltrative margin remains a central challenge. Prior work has demonstrated that fluorescence labeling tools and radiographic imaging are useful surgical adjuvants with macroscopic resolution. However, they lose sensitivity at the tumor margin and have limited clinical utility for lower grade histologies. Fiber-laser based stimulated Raman histology (SRH) is an optical imaging technique that provides microscopic tissue characterization of unprocessed tissues. It remains unknown whether SRH of tissues taken from the infiltrative glioma margin will identify microscopic residual disease. Here we acquired glioma margin specimens for SRH, histology, and tumor specific tissue characterization. Generalized linear mixed models were used to evaluate agreement. We find that SRH identified residual tumor in 82 of 167 margin specimens (49%), compared to IHC confirming residual tumor in 72 of 128 samples (56%), and H&E confirming residual tumor in 82 of 169 samples (49%). Intraobserver agreements between all 3 modalities were confirmed. These data demonstrate that SRH detects residual microscopic tumor at the infiltrative glioma margin and may be a promising tool to enhance extent of resection.
, Matteo G. Ziliani, Rasmus Houborg, Trenton E. Franz, Matthew F. McCabe
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-12; doi:10.1038/s41598-021-91646-w

Abstract:
Earth observation has traditionally required a compromise in data collection. That is, one could sense the Earth with high spatial resolution occasionally; or with lower spatial fidelity regularly. For many applications, both frequency and detail are required. Precision agriculture is one such example, with sub-10 m spatial, and daily or sub-daily retrieval representing a key goal. Towards this objective, we produced the first cloud-free 3 m daily evaporation product ever retrieved from space, leveraging recently launched nano-satellite constellations to showcase this emerging potential. Focusing on three agricultural fields located in Nebraska, USA, high-resolution crop water use estimates are delivered via CubeSat-based evaporation modeling. Results indicate good model agreement (r2 of 0.86–0.89; mean absolute error between 0.06 and 0.08 mm/h) when evaluated against corrected flux tower data. CubeSat technologies are revolutionizing Earth observation, delivering novel insights and new agricultural informatics that will enhance food and water security efforts, and enable rapid and informed in-field decision making.
Jacqueline Pontes Monteiro, Carlos A. Fuzo, Fábio V. Ued, Jim Kaput
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-15; doi:10.1038/s41598-021-91611-7

Abstract:
Identifying dietary patterns that contribute to zinc (Zn) and fatty acids intake and their biomarkers that may have an impact on health of males and females. The present study was designed to (a) extract dietary patterns with foods that explain the variation of Zn and PUFAs intake in adult men and women; and (b) evaluate the association between the extracted dietary patterns with circulating levels of serum dihomo-γ-linolenic fatty acid (DGLA) or serum linoleic/dihomo-γ-linolenic (LA/DGLA) ratio in males and females. We used reduced rank regression (RRR) to extract the dietary patterns separated by sex in the NHANES 2011–2012 data. A dietary pattern with foods rich in Zn (1st quintile = 8.67 mg/day; 5th quintile = 11.11 mg/day) and poor in PUFAs (5th quintile = 15.28 g/day; 1st quintile = 18.03 g/day) was found in females (S-FDP2) and the same pattern, with foods poor in PUFAs (5th quintile = 17.6 g/day; 1st quintile = 20.7 g/day) and rich in Zn (1st quintile = 10.4 mg/day; 5th quintile = 12.9 mg/day) (S-MDP2), was found in males. The dietary patterns with foods rich in Zn and poor in PUFAs were negatively associated with serum LA/DGLA ratio. This is the first study to associate the LA/DGLA ratio with Zn and PUFAs related dietary patterns in males and females.
Erkihun Tadesse Amsalu, Bereket Kefale, Amare Muche, Zinabu Fentaw, Reta Dewau, Muluken Genetu Chanie, Mequannent Sharew Melaku, Melaku Yalew, Mastewal Arefayine, Gedamnesh Bitew, et al.
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-10; doi:10.1038/s41598-021-91821-z

Abstract:
Iman Kalani, Davood Toghraie
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-31; doi:10.1038/s41598-021-91699-x

Abstract:
In this study, the numerical simulation of heat transfer of Al2O3-water nanofluid in a pipe equipped with helically twisted tapes is investigated. The volume fraction of nanoparticles in this study is equal to 0, 1, 2, and 3%, and a two-phase mixture method has been used to simulate the nanofluids. The flow regime is laminar in the present study, and Reynolds numbers are Re = 250, 500, 750, and 1000. The helical twisted tapes are in three different types, single, double, and triple. The same heat flux 5000Wm-2 is applied to the walls. The simulation results showed that increasing the Re increases the Nusselt number and decreasing the friction factor. Nusselt number in case 1 and volume fraction of nanoparticles 0% for Re = 250, 500, 750 and 1000 are equal to 95.8, 57.11, 56.13 and 22.15, respectively. The average friction factor is equal to 0.18, 0.09, 0.07, and 0.05. The presence of helical twisted tapes increases the $${\text{Nu}}_{ave}$$ Nu ave . The friction factor due to secondary flows and increases the contact of the fluid and the solid surface, so that the Nusselt number in volume fraction of nanoparticles 0%, Re = 250 for case 1, case 2, case 3, and case 4 are 95.8, 46.10, 58.11, and 51.12, respectively, and the friction factor are 18.0, 29.0, 0.38 and 0.48, respectively.
Xianglian Zhou, Yuting Pan, Yue Wang, Bojun Wang, Yu Yan, ,
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-11; doi:10.1038/s41598-021-91708-z

Abstract:
The liposoluble tanshinones are bioactive components in Salvia miltiorrhiza and are widely investigated as anti-cancer agents, while the molecular mechanism is to be clarified. In the present study, we identified that the human fragile histidine triad (FHIT) protein is a direct binding protein of sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of Tanshinone IIA (TSA), with a Kd value of 268.4 ± 42.59 nM. We also found that STS inhibited the diadenosine triphosphate (Ap3A) hydrolase activity of FHIT through competing for the substrate-binding site with an IC50 value of 2.2 ± 0.05 µM. Notably, near 100 times lower binding affinities were determined between STS and other HIT proteins, including GALT, DCPS, and phosphodiesterase ENPP1, while no direct binding was detected with HINT1. Moreover, TSA, Tanshinone I (TanI), and Cryptotanshinone (CST) exhibited similar inhibitory activity as STS. Finally, we demonstrated that depletion of FHIT significantly blocked TSA’s pro-apoptotic function in colorectal cancer HCT116 cells. Taken together, our study sheds new light on the molecular basis of the anti-cancer effects of the tanshinone compounds.
Shailesh Kumar Samal, Ole Fröbert, Jonas Kindberg, Peter Stenvinkel,
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-9; doi:10.1038/s41598-021-91679-1

Abstract:
Brown bears (Ursus arctos) hibernate for 5–6 months during winter, but despite kidney insufficiency, dyslipidemia and inactivity they do not seem to develop atherosclerosis or cardiovascular disease (CVD). IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) are associated with less atherosclerosis, CVD and mortality in uremia in humans and have anti-inflammatory and other potentially protective properties. PC but not MDA is exposed on different types of microorganisms. We determine anti-PC and anti-MDA in brown bears in summer and winter. Paired serum samples from 12 free ranging Swedish brown bears were collected during hibernation in winter and during active state in summer and analyzed for IgM, IgG, IgG1/2 and IgA anti-PC and anti-MDA by enzyme linked immunosorbent assay (ELISA). When determined as arbitrary units (median set at 100 for summer samples), significantly raised levels were observed in winter for anti-PC subclasses and isotypes, and for IgA anti-PC the difference was striking; 100 IQR (85.9–107.9) vs 782.3, IQR (422.8–1586.0; p < 0.001). In contrast, subclasses and isotypes of anti-MDA were significantly lower in winter except IgA anti-MDA, which was not detectable. Anti-PCs are significantly raised during hibernation in brown bears; especially IgA anti-PC was strikingly high. In contrast, anti-MDA titers was decreased during hibernation. Our observation may represent natural immunization with microorganisms during a vulnerable period and could have therapeutic implications for prevention of atherosclerosis.
, K. Kesper, G. Kräling, C. Birk, P. Mross, N. Hofeditz, J. Höchst, P. Lampe, A. Penning, B. Leutenecker-Twelsiek, et al.
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-9; doi:10.1038/s41598-021-91673-7

Abstract:
The worldwide shortage of medical-grade ventilators is a well-known issue, that has become one of the central topics during the COVID-19 pandemic. Given that these machines are expensive and have long lead times, one approach is to vacate them for patients in critical conditions while patients with mild to moderate symptoms are treated with stripped-down ventilators. We propose a mass-producible solution that can create such ventilators with minimum effort. The central part is a module that can be attached to CPAP machines and repurpose them as low-pressure ventilators. Here, we describe the concept and first measurements which underline the potential of our solution. Our approach may serve as a starting point for open-access ventilator technologies.
Masahiro Yamashita, Yuh Utsumi, Hiromi Nagashima, Hiroo Nitanai, Kohei Yamauchi
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-8; doi:10.1038/s41598-021-91407-9

Abstract:
Circulating monocytes have pathogenic relevance in idiopathic pulmonary fibrosis (IPF). Here, we determined whether the cell surface levels of two markers, pro-inflammatory-related S100A9 and anti-inflammatory-related CD163, expressed on CD14strongCD16− classical monocytes by flow cytometry could discriminate IPF from idiopathic nonspecific interstitial pneumonia (iNSIP). Twenty-five patients with IPF, 25 with iNSIP, and 20 healthy volunteers were prospectively enrolled in this study. The S100A9+CD163− cell percentages in classical monocytes showed a pronounced decrease on monocytes in iNSIP compared to that in IPF. In contrast, the percentages of S100A9−CD163+ cells were significantly higher in iNSIP patients than in IPF patients and healthy volunteers. In IPF patients, there was a trend toward a correlation between the percentage of S100A9+CD163− monocytes and the surfactant protein-D (SP-D) serum levels (r = 0.4158, [95% confidence interval (CI) − 0.02042–0.7191], p = 0.051). The individual percentages of S100A9+CD163− and S100A9−CD163+ cells were also independently associated with IPF through multivariate regression analysis. The unadjusted area under the receiver operating characteristic curve (ROC-AUC) to discriminate IPF from iNSIP was (ROC-AUC 0.802, 95% CI [0.687–0.928]), suggesting that these are better biomarkers than serum SP-D (p < 0.05). This preliminary study reports the first comparative characterization of monocyte phenotypes between IPF and iNSIP.
Toon Ruang-Areerate, Charanyarut Sukphattanaudomchoke, Thanyapit Thita, Saovanee Leelayoova, Phunlerd Piyaraj, Mathirut Mungthin, Patcharapan Suwannin, Duangporn Polpanich, Tienrat Tangchaikeeree, Kulachart Jangpatarapongsa, et al.
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-11; doi:10.1038/s41598-021-91540-5

Abstract:
Asymptomatic leishmaniasis cases have continuously increased, especially among patients with HIV who are at risk to develop further symptoms of cutaneous and visceral leishmaniasis. Thus, early diagnosis using a simple, sensitive and reliable diagnostic assay is important because populations at risk mostly reside in rural communities where laboratory equipment is limited. In this study, the highly sensitive and selective determination of Leishmania infection in asymptomatic HIV patients was achieved using dual indicators (SYBR safe and gold-nanoparticle probe; AuNP-probe) in one-step LAMP method based on basic instruments. The assay can be simply evaluated under the naked eye due to clear interpretation of fluorescent emission of LAMP-SYBR safe dye-complex and colorimetric precipitate of specific AuNP-probes. The sensitivities and specificities of fluorescent SYBR safe dye and AuNP-probe indicators were equal, which were as high as 94.1 and 97.1%, respectively. Additionally, detection limits were 102 parasites/mL (0.0147 ng/µL), ten times more sensitivity than other related studies. To empower leishmaniasis surveillance, this inexpensive one-step SYBR safe and AuNP-LAMP assay is reliably fast and simple for field diagnostics to point-of-care settings, which can be set up in all levels of health care facilities including resource limited areas, especially in low to middle income countries.
, Richard L. Palmer, Gareth S. Baynam, Oliver W. Quarrell, Ophir D. Klein, Richard A. Spritz, Raoul C. Hennekam, Susan Walsh, Mark Shriver, Seth M. Weinberg, et al.
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-12; doi:10.1038/s41598-021-91465-z

Abstract:
Craniofacial dysmorphism is associated with thousands of genetic and environmental disorders. Delineation of salient facial characteristics can guide clinicians towards a correct clinical diagnosis and understanding the pathogenesis of the disorder. Abnormal facial shape might require craniofacial surgical intervention, with the restoration of normal shape an important surgical outcome. Facial anthropometric growth curves or standards of single inter-landmark measurements have traditionally supported assessments of normal and abnormal facial shape, for both clinical and research applications. However, these fail to capture the full complexity of facial shape. With the increasing availability of 3D photographs, methods of assessment that take advantage of the rich information contained in such images are needed. In this article we derive and present open-source three-dimensional (3D) growth curves of the human face. These are sequences of age and sex-specific expected 3D facial shapes and statistical models of the variation around the expected shape, derived from 5443 3D images. We demonstrate the use of these growth curves for assessing patients and show that they identify normal and abnormal facial morphology independent from age-specific facial features. 3D growth curves can facilitate use of state-of-the-art 3D facial shape assessment by the broader clinical and biomedical research community. This advance in phenotype description will support clinical diagnosis and the understanding of disease pathogenesis including genotype–phenotype relations.
, Kei Shibata, Hiromi Wada, Hiroshi Kakehi, Kazuo Hokkirigawa
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-11; doi:10.1038/s41598-021-91683-5

Abstract:
Herein, we investigated the effect of friction between foot sole and floor on the external forward moment about the body center of mass (COM) in normal and shuffling gaits. Five young male adults walked with normal and shuffling gaits, under low- and high-friction surface conditions. The maximum external forward moment about the COM (MEFM-COM) in a normal gait appeared approximately at initial foot contact and was unaffected by floor condition. However, MEFM-COM in a shuffling gait under high-friction conditions exceeded that under low-friction conditions (p < 0.001). Therein, MEFM-COM increased with an increasing utilized coefficient of friction at initial foot contact; this effect was weaker during a normal gait. These findings indicate that increased friction between foot sole and floor might increase tripping risk during a shuffling gait, even in the absence of discrete physical obstacles.
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-13; doi:10.1038/s41598-021-91498-4

Abstract:
In grazing systems, urine patches deposited by livestock are hotspots of nutrient cycling and the most important source of nitrous oxide (N2O) emissions. Studies of the effects of urine deposition, including, for example, the determination of country-specific N2O emission factors, require natural urine for use in experiments and face challenges obtaining urine of the same composition, but of differing concentrations. Yet, few studies have explored the importance of storage conditions and processing of ruminant urine for use in subsequent gaseous emission experiments. We conducted three experiments with sheep urine to determine optimal storage conditions and whether partial freeze-drying could be used to concentrate the urine, while maintaining the constituent profile and the subsequent urine-derived gaseous emission response once applied to soil. We concluded that filtering of urine prior to storage, and storage at − 20 °C best maintains the nitrogen-containing constituent profile of sheep urine samples. In addition, based on the 14 urine chemical components determined in this study, partial lyophilisation of sheep urine to a concentrate represents a suitable approach to maintain the constituent profile at a higher overall concentration and does not alter sheep urine-derived soil gaseous emissions.
, Christoph Simon
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-10; doi:10.1038/s41598-021-91388-9

Abstract:
It is known that bipolar disorder and its lithium treatment involve the modulation of oxidative stress. Moreover, it has been observed that lithium’s effects are isotope-dependent. Based on these findings, here we propose that lithium exerts its effects by influencing the recombination dynamics of a naturally occurring radical pair involving oxygen. We develop a simple model inspired by the radical-pair mechanism in cryptochrome in the context of avian magnetoreception and xenon-induced anesthesia. Our model reproduces the observed isotopic dependence in the lithium treatment of hyperactivity in rats. It predicts a magnetic-field dependence of the effectiveness of lithium, which provides one potential experimental test of our hypothesis. Our findings show that Nature might harness quantum entanglement for the brain’s cognitive processes.
Rong Liu, Jing Lu, Jiayi Xing, Mei Du, Mingxiu Wang, Lei Zhang, Yunfang Li, Chihong Zhang,
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-12; doi:10.1038/s41598-021-91598-1

Abstract:
Polygonatum cyrtonema Hua (Huangjing, HJ) has medicinal and edible value in China. However, the seeds of this plant are naturally difficult to germinate. Therefore, to elucidate the mechanism underlying the germination of this plant in order to meet the market demand, the metabolomic and transcriptomic analyses were performed in this study. We observed that plant hormones and α-amylase activity were differentially regulated when comparing germinated and un-germinated seeds. In addition, the metabolites related to phenylpropanoid and flavonoid biosynthesis were significantly up-accumulated in germinated seeds. Hydroxycinnamoyl derivatives and organic acids were observed to be significantly decreased during germination. The results of this study suggested that compared to un-germinated seeds, germinated seeds promote flavonoid synthesis and inhibit lignin synthesis which could be beneficial to the germination of HJ seeds. Furthermore, these results suggested that starch if hydrolyzed into glucose, which could provide the necessary energy for germination. Our results may help to establish a foundation for further research investigating the regulatory networks of seed germination and may facilitate the propagation of HJ seeds.
, Emma G. Piligrimova,
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-18; doi:10.1038/s41598-021-91289-x

Abstract:
One of the serious public health concerns is food contaminated with pathogens and their vital activity products such as toxins. Bacillus cereus group of bacteria includes well-known pathogenic species such as B. anthracis, B. cereus sensu stricto (ss), B. cytotoxicus and B. thuringiensis. In this report, we describe the Bacillus phages vB_BcM_Sam46 and vB_BcM_Sam112 infecting species of this group. Electron microscopic analyses indicated that phages Sam46 and Sam112 have the myovirus morphotype. The genomes of Sam46 and Sam112 comprise double-stranded DNA of 45,419 bp and 45,037 bp in length, respectively, and have the same GC-content. The genome identity of Sam46 and Sam112 is 96.0%, indicating that they belong to the same phage species. According to the phylogenetic analysis, these phages form a distinct clade and may be members of a new phage genus, for which we propose the name ‘Samaravirus’. In addition, an interesting feature of the Sam46 and Sam112 phages is the unusual structure of their small terminase subunit containing N-terminal FtsK_gamma domain.
Correction
, , Eakpor Piv, Elise J. Farley, Sophy Chy, Saorin Kim, Anneli G. Corbett, Rachel L. Fehrman, Anais Pepey, , et al.
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-2; doi:10.1038/s41598-021-91552-1

Abstract:
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
, Piotr Lech, Mariusz Majewski, Andrzej Rychlik, Slawomir Gonkowski
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-9; doi:10.1038/s41598-021-91529-0

Abstract:
Bisphenol A (BPA) is used in the production of plastics approved for contact with feed and food. Upon entering living organisms, BPA, as a potent endocrine disruptor, negatively affects various internal organs and regulatory systems, especially in young individuals. Although previous studies have described the neurotoxic effects of BPA on various tissues, it should be underlined that the putative influence of this substance on the chemical architecture of the urinary bladder intrinsic innervation has not yet been studied. One of the most important neuronal substances involved in the regulation of urinary bladder functions is vasoactive intestinal polypeptide (VIP), which primarily participates in the regulation of muscular activity and blood flow. Therefore, this study aimed to determine the influence of various doses of BPA on the distribution pattern of VIP-positive neural structures located in the wall of the porcine urinary bladder trigone using the double-immunofluorescence method. The obtained results show that BPA influence leads to an increase in the number of both neurons and nerve fibres containing VIP in the porcine urinary bladder trigone. This may indicate that VIP participates in adaptive processes of the urinary bladder evoked by BPA.
Shintaro Shirahama, Kenzui Taniue, Shuhei Mitsutomi, Rie Tanaka, Toshikatsu Kaburaki, Tomohito Sato, Masaru Takeuchi, Hidetoshi Kawashima, Yoshihiro Urade, Makoto Aihara, et al.
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-6; doi:10.1038/s41598-021-91340-x

Abstract:
Acute retinal necrosis (ARN) is a form of infectious uveitis caused by alpha herpesviruses, including herpes simplex virus type 1 (HSV-1). We previously found that the long non-coding RNA (lncRNA) U90926 is upregulated in murine retinal photoreceptor cells following HSV-1 infection, leading to host cell death. However, to date, an orthologous transcript has not been identified in humans. We investigated U90926 orthologous transcript in humans and examined its utility as a prognostic marker for visual acuity in patients with ARN. We identified two human orthologous transcripts (1955 and 592 bases) of lncRNA U90926. The amount of the longer human U90926 transcript was approximately 30- and 40-fold higher in the vitreous fluid of patients with ARN than in those with sarcoidosis and intraocular lymphoma, respectively. Furthermore, the expression of the longer human U90926 transcript in the vitreous fluid was highly correlated with the final best-corrected logarithm of the minimum angle of resolution visual acuity in patients with ARN (r = 0.7671, p = 0.0079). This suggests higher expression of the longer human U90926 transcript in the vitreous fluid results in worse visual prognosis; therefore, expression of the longer human U90926 transcript is a potential negative prognostic marker for visual acuity in patients with ARN.
Eric Haines, Yuki Nishida, Michael I. Carr, Rafael Heinz Montoya, Lauren B. Ostermann, Weiguo Zhang, Frank T. Zenke, , Michael Andreeff,
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-14; doi:10.1038/s41598-021-90500-3

Abstract:
Peposertib (M3814) is a potent and selective DNA-PK inhibitor in early clinical development. It effectively blocks non-homologous end-joining repair of DNA double-strand breaks (DSB) and strongly potentiates the antitumor effect of ionizing radiation (IR) and topoisomerase II inhibitors. By suppressing DNA-PK catalytic activity in the presence of DNA DSB, M3814 potentiates ATM/p53 signaling leading to enhanced p53-dependent antitumor activity in tumor cells. Here, we investigated the therapeutic potential of M3814 in combination with DSB-inducing agents in leukemia cells and a patient-derived tumor. We show that in the presence of IR or topoisomerase II inhibitors, M3814 boosts the ATM/p53 response in acute leukemia cells leading to the elevation of p53 protein levels as well as its transcriptional activity. M3814 synergistically sensitized p53 wild-type, but not p53-deficient, AML cells to killing by DSB-inducing agents via p53-dependent apoptosis involving both intrinsic and extrinsic effector pathways. The antileukemic effect was further potentiated by enhancing daunorubicin-induced myeloid cell differentiation. Further, combined with the fixed-ratio liposomal formulation of daunorubicin and cytarabine, CPX-351, M3814 enhanced the efficacy against leukemia cells in vitro and in vivo without increasing hematopoietic toxicity, suggesting that DNA-PK inhibition could offer a novel clinical strategy for harnessing the anticancer potential of p53 in AML therapy.
, Daniela Laurino, Riccardo Maggiora, Daniele Milanesio, Maurice Saccani, Peter J. Mazzoglio, Aulo Manino, Marco Porporato
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-10; doi:10.1038/s41598-021-91541-4

Abstract:
An innovative scanning harmonic radar has been recently developed for tracking insects in complex landscapes. This movable technology has been tested on an invasive hornet species (Vespa velutina) for detecting the position of their nests in the environment, in the framework of an early detection strategy. The new model of harmonic radar proved to be effective in tracking hornets either in open landscapes, hilly environments and areas characterised by the presence of more obstacles, such as woodlands and urban areas. Hornets were effectively tracked in complex landscapes for a mean tracking length of 96 ± 62 m with maximum values of ~ 300 m. The effectiveness of locating nests was 75% in new invasive outbreaks and 60% in highly density colonised areas. Furthermore, this technology could provide information on several aspects of insect’s ecology and biology. In this case, new insights were obtained about the mean foraging range of V. velutina (395 ± 208 m with a maximum value of 786 m) and flying features (ground speed), which was 6.66 ± 2.31 m s−1 for foraging individuals (hornets that are not carrying prey’s pellet) and 4.06 ± 1.34 m s−1 for homing individuals.
Meihui Li, Younghoon Kim, Tae-Shin Kim, Nam-Yun Cho, Jeong Mo Bae, Woo Ho Kim,
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-10; doi:10.1038/s41598-021-91652-y

Abstract:
The copy number (CN) gain of protooncogenes is a frequent finding in gastric carcinoma (GC), but its prognostic implication remains elusive. The study aimed to characterize the clinicopathological features, including prognosis, of GCs with copy number gains in multiple protooncogenes. Three hundred thirty-three patients with advanced GC were analyzed for their gene ratios in EGFR, GATA6, IGF2, and SETDB1 using droplet dPCR (ddPCR) for an accurate assessment of CN changes in target genes. The number of GC patients with 3 or more genes with CN gain was 16 (4.8%). Compared with the GCs with 2 or less genes with CN gain, the GCs with 3 or more CN gains displayed more frequent venous invasion, a lower density of tumor-infiltrating lymphocytes, and lower methylation levels of L1 or SAT-alpha. Microsatellite instability-high tumors or Epstein–Barr virus-positive tumors were not found in the GCs with 3 or more genes with CN gain. Patients of this groups also showed the worst clinical outcomes for both overall survival and recurrence-free survival, which was persistent in the multivariate survival analyses. Our findings suggest that the ddPCR-based detection of multiple CN gain of protooncogenes might help to identify a subset of patients with poor prognosis.
, Dean E. Beyer, Zachary Farley, Nicholas L. Fowler, Kenneth F. Kellner, Ashley L. Lutto, Tyler R. Petroelje, Jerrold L. Belant
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-10; doi:10.1038/s41598-021-91587-4

Abstract:
Where two sympatric species compete for the same resource and one species is dominant, there is potential for the subordinate species to be affected through interference competition or energetic costs of avoiding predation. Fishers (Pekania pennanti) and American martens (Martes americana) often have high niche overlap, but fishers are considered dominant and potentially limiting to martens. We observed presence and vigilance of fishers and martens at winter carcass sites using remote cameras in Michigan, USA, to test the hypothesis that interference competition from fishers creates a landscape of fear for martens. Within winters, fishers co-occupied 78–88% of sites occupied by martens, and martens co-occupied 79–88% of sites occupied by fishers. Fishers displaced martens from carcasses during 21 of 6117 marten visits, while martens displaced fishers during 0 of 1359 fisher visits. Martens did not alter diel activity in response to fisher use of sites. Martens allocated 37% of time to vigilance compared to 23% for fishers, and martens increased vigilance up to 8% at sites previously visited by fishers. Fishers increased vigilance by up to 8% at sites previously visited by martens. Our results indicate that fishers were dominant over martens, and martens had greater baseline perception of risk than fishers. However, fishers appeared to be also affected as the dominant competitor by putting effort into scanning for martens. Both species appeared widespread and common in our study area, but there was no evidence that fishers spatially or temporally excluded martens from scavenging at carcasses other than occasional short-term displacement when a fisher was present. Instead, martens appeared to mitigate risk from fishers by using vigilance and short-term avoidance. Multiple short-term anti-predator behaviors within a landscape of fear may facilitate coexistence among carnivore species.
, Pilar Garcés, Emanuele Paracone, Alessandro Cristini, Mario Salerno, Fernando Maestú, Ernesto Pereda
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-17; doi:10.1038/s41598-021-91513-8

Abstract:
Neural modelling tools are increasingly employed to describe, explain, and predict the human brain’s behavior. Among them, spiking neural networks (SNNs) make possible the simulation of neural activity at the level of single neurons, but their use is often threatened by the resources needed in terms of processing capabilities and memory. Emerging applications where a low energy burden is required (e.g. implanted neuroprostheses) motivate the exploration of new strategies able to capture the relevant principles of neuronal dynamics in reduced and efficient models. The recent Leaky Integrate-and-Fire with Latency (LIFL) spiking neuron model shows some realistic neuronal features and efficiency at the same time, a combination of characteristics that may result appealing for SNN-based brain modelling. In this paper we introduce FNS, the first LIFL-based SNN framework, which combines spiking/synaptic modelling with the event-driven approach, allowing us to define heterogeneous neuron groups and multi-scale connectivity, with delayed connections and plastic synapses. FNS allows multi-thread, precise simulations, integrating a novel parallelization strategy and a mechanism of periodic dumping. We evaluate the performance of FNS in terms of simulation time and used memory, and compare it with those obtained with neuronal models having a similar neurocomputational profile, implemented in NEST, showing that FNS performs better in both scenarios. FNS can be advantageously used to explore the interaction within and between populations of spiking neurons, even for long time-scales and with a limited hardware configuration.
Hyewon Kim, Dong Jun Kim, Won Ho Chung, Kyung-Ah Park, James D. K. Kim, Dowan Kim, Kiwon Kim, Hong Jin Jeon
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-11; doi:10.1038/s41598-021-91573-w

Abstract:
The use of virtual reality (VR) in the treatment of psychiatric disorders is increasing, and cybersickness has emerged as an important obstacle to overcome. However, the clinical factors affecting cybersickness are still not well understood. In this study, we investigated clinical predictors and adaptation effect of cybersickness during VR application in highly stressed people. Eighty-three healthy adult participants with high stress level were recruited. At baseline, we conducted psychiatric, ophthalmologic, and otologic evaluations and extracted physiological parameters. We divided the participants into two groups according to the order of exposure to VR videos with different degrees of shaking and repetitively administered the Simulator Sickness Questionnaire (SSQ) and the Fast Motion sickness Scale (FMS). There was no significant difference in changes in the SSQ or the FMS between groups. The 40–59 years age group showed a greater increase in FMS compared to the 19–39 years age group. Smoking was negatively associated with cybersickness, and a high Positive Affect and Negative Affect Schedule score was positively associated with cybersickness. In conclusion, changing the intensity of shaking in VR did not affect cybersickness. While smoking was a protective factor, more expression of affect was a risk factor for cybersickness.
, Yu Fu, Eliezer Masliah, Celine Lefebvre,
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-14; doi:10.1038/s41598-021-88052-7

Abstract:
To generate new mechanistic hypotheses on the pathogenesis and disease progression of neuroHIV and identify novel therapeutic targets to improve neuropsychological function in people with HIV, we investigated host genes and pathway dysregulations associated with brain HIV RNA load in gene expression profiles of the frontal cortex, basal ganglia, and white matter of HIV+ patients. Pathway analyses showed that host genes correlated with HIV expression in all three brain regions were predominantly related to inflammation, neurodegeneration, and bioenergetics. HIV RNA load directly correlated particularly with inflammation genesets representative of cytokine signaling, and this was more prominent in white matter and the basal ganglia. Increases in interferon signaling were correlated with high brain HIV RNA load in the basal ganglia and the white matter although not in the frontal cortex. Brain HIV RNA load was inversely correlated with genesets that are indicative of neuronal and synaptic genes, particularly in the cortex, indicative of synaptic injury and neurodegeneration. Brain HIV RNA load was inversely correlated with genesets that are representative of oxidative phosphorylation, electron transfer, and the tricarboxylic acid cycle in all three brain regions. Mitochondrial dysfunction has been implicated in the toxicity of some antiretrovirals, and these results indicate that mitochondrial dysfunction is also associated with productive HIV infection. Genes and pathways correlated with brain HIV RNA load suggest potential therapeutic targets to ameliorate neuropsychological functioning in people living with HIV.
Hannah von Mersi, Thomas Benkö, Heidrun Boztug, Michael Dworzak, Gernot Engstler, Waltraud Friesenbichler, Caroline Hutter, Karoly Lakatos, Georg Mann, Martin Metzelder, et al.
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-6; doi:10.1038/s41598-021-90206-6

Abstract:
Acute appendicitis is a rare gastrointestinal complication of anti-cancer chemotherapy and hematopoietic stem cell transplantation. Among a cohort of 2341 hemato-oncologic patients at a pediatric tertiary care cancer center, we identified 21 patients (0.9%) with 23 episodes of acute appendicitis, based on pathological imaging of the appendix and clinical findings. Median age at diagnosis was 10.21 years. Types of underlying disease included acute leukemias (n = 15), solid tumors (n = 4), and aplastic anemia (n = 2). Clinical symptoms seen in > 1 case were recorded for all 23 episodes as follows: abdominal pain, n = 22; abdominal tenderness, n = 4; fever, n = 7; nausea, n = 2; emesis; n = 2; diarrhea, n = 5; and constipation, n = 2. Median leukocyte count at diagnosis was 0.5 × 109/L, with a median of 0.1 × 109/L for the absolute neutrophil count (ANC). All patients received broad-spectrum antibiotics and 18/23 (78%) patients underwent uneventful appendectomy after a median of 5 days and with a median ANC of 0.7 × 109/L. Median duration until continuation of chemotherapy was 17 days for the 20 cases of appendicitis occurring during the patients’ disease course. Overall, 5/21 (19%) patients died including one related to the appendicitis itself which progressed to a typhlitis and was due to a fungal infection. The other fatalities were transplant- (n = 2) and leukemia-related (n = 2). Acute appendicitis is a rare and usually not life-threatening event in pediatric hemato-oncologic patients, which, if managed by prompt administration of broad-spectrum antibiotics (and antimycotics), can be safely followed by an elective (delayed) appendectomy, even before complete recovery of the neutrophils is achieved.
Lisa Mosconi, Valentina Berti, Jonathan Dyke, Eva Schelbaum, Steven Jett, Lacey Loughlin, Grace Jang, Aneela Rahman, Hollie Hristov, Silky Pahlajani, et al.
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-16; doi:10.1038/s41598-021-90084-y

Abstract:
All women undergo the menopause transition (MT), a neuro-endocrinological process that impacts aging trajectories of multiple organ systems including brain. The MT occurs over time and is characterized by clinically defined stages with specific neurological symptoms. Yet, little is known of how this process impacts the human brain. This multi-modality neuroimaging study indicates substantial differences in brain structure, connectivity, and energy metabolism across MT stages (pre-menopause, peri-menopause, and post-menopause). These effects involved brain regions subserving higher-order cognitive processes and were specific to menopausal endocrine aging rather than chronological aging, as determined by comparison to age-matched males. Brain biomarkers largely stabilized post-menopause, and gray matter volume (GMV) recovered in key brain regions for cognitive aging. Notably, GMV recovery and in vivo brain mitochondria ATP production correlated with preservation of cognitive performance post-menopause, suggesting adaptive compensatory processes. In parallel to the adaptive process, amyloid-β deposition was more pronounced in peri-menopausal and post-menopausal women carrying apolipoprotein E-4 (APOE-4) genotype, the major genetic risk factor for late-onset Alzheimer’s disease, relative to genotype-matched males. These data show that human menopause is a dynamic neurological transition that significantly impacts brain structure, connectivity, and metabolic profile during midlife endocrine aging of the female brain.
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-11; doi:10.1038/s41598-021-91024-6

Abstract:
The stochastic model for epidemic spreading of the novel coronavirus disease based on the data set supply by the public health agencies in countries as Brazil, United States and India is investigated. We perform a numerical analysis using the stochastic differential equation in Itô’s calculus for the estimating of novel cases daily, as well as analytical calculations solving the correspondent Fokker–Planck equation for the probability density distribution of novel cases, P(N(t), t). Our results display that the model based in the Itô’s diffusion fits well to the results due to uncertainty in the official data and to the number of tests realized in populations of each country.
Xiaoguang Shi, Shuanglai Ren, Bingying Zhang, Shanshan Guo, Wenxin He, Chengmin Yuan, Xiaofan Yang, Kevin Ig-Lzevbekhai, Tao Sun, , et al.
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-12; doi:10.1038/s41598-021-90982-1

Abstract:
Purine rich element binding protein A (Purα), encoded by the Purα gene, is an important transcriptional regulator that binds to DNA and RNA and is involved in processes such as DNA replication and RNA translation. Purα also plays an important role in the nervous system. To identify the function of Pura, we performed RNA sequence (RNA-seq) analysis of Purɑ-KO mouse hippocampal neuron cell line (HT22) to analyze the effect of Purα deletion on neuronal expression profiles. And combined with ChIP-seq analysis to explore the mechanism of Purα on gene regulation. In the end, totaly 656 differentially expressed genes between HT22 and Purα-KO HT22 cells have been found, which include 7 Alzheimer’s disease (AD)-related genes and 5 Aβ clearance related genes. 47 genes were regulated by Purα directly, the evidence based on CHIP-seq, which include Insr, Mapt, Vldlr, Jag1, etc. Our study provides the important informations of Purα in neuro-development. The possible regulative effects of Purα on AD-related genes consist inthe direct and indirect pathways of Purα in the pathogenesis of AD.
Naren Vikram Raj Masna, Junjun Huan, Soumyajit Mandal,
Published: 9 June 2021
Scientific Reports, Volume 11, pp 1-12; doi:10.1038/s41598-021-91531-6

Abstract:
Automatic recognition of unique characteristics of an object can provide a powerful solution to verify its authenticity and safety. It can mitigate the growth of one of the largest underground industries—that of counterfeit goods–flowing through the global supply chain. In this article, we propose the novel concept of material biometrics, in which the intrinsic chemical properties of structural materials are used to generate unique identifiers for authenticating individual products. For this purpose, the objects to be protected are modified via programmable additive manufacturing of built-in chemical “tags” that generate signatures depending on their chemical composition, quantity, and location. We report a material biometrics-enabled manufacturing flow in which plastic objects are protected using spatially-distributed tags that are optically invisible and difficult to clone. The resulting multi-bit signatures have high entropy and can be non-invasively detected for product authentication using $$^{35}$$ 35 Cl nuclear quadrupole resonance (NQR) spectroscopy.
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