bluuebunny/crossref_metadata_2025 huggingface dataset:
Ammonium tetrathiomolybdate triggers autophagy-dependent NRF2 activation in vascular endothelial cells
Authors: Zhang Mengling , Qiu Hongmei , Mao Lejiao , Wang Bin , Li Na , Fan Yinzhen , Weng Ping , Hu Siyao , Dong Xiaomei , Qin Xia , Chen Chengzhi , Zou Zhen , Yu Chao , Zhang Jun
Published: August 2022

Ammonium tetrathiomolybdate (TTM) is a copper chelator in clinical trials for treatment of Wilson’s disease, tumors and other diseases. In the current study, we innovatively discovered that TTM is a novel NRF2 activator and illustrated that autophagy contributed to TTM-induced NRF2 activation. We showed that TTM treatment promoted NRF2 nuclear translocation and upregulated transcription level of NRF2 target genes includingHMOX1,GCLM, andSLC7A11in vascular endothelial cells (HUVECs). Moreover, NRF2 deficiency directly hindered TTM-mediated antioxidative effects. Followingly, we revealed that overexpression of KEAP1, a negative regulator of NRF2, significantly repressed NRF2 activation induced by TTM. Further mutation analysis revealed that KEAP1 Cys151 is a major sensor responsible for TTM-initiated NRF2 signaling, suggesting that KEAP1 is involved in TTM-mediated NRF2 activation. Notably, we found that TTM can trigger autophagy as evidenced by accumulation of autophagosomes, elevation of LC3BI-II/I, increase of LC3 puncta and activation of AMPK/mTOR/ULK1 pathway. Autophagic flux assay indicated that TTM significantly enhanced autophagic flux in HUVECs. Inhibition of autophagy with knockout of autophagy key geneATG5resulted in suppression of TTM-induced NRF2 activation. TTM also induced phosphorylation of autophagy receptor SQSTM1 at Ser349, while SQSTM1-deficiency inhibited KEAP1 degradation and blocked NRF2 signaling pathway, suggesting that TTM-induced NRF2 activation is autophagy dependent. As the novel NRF2 activator, TTM protected against sodium arsenite (NaAsO2)-induced oxidative stress and cell death, while NRF2 deficiency weakened TTM antioxidative effects. Finally, we showed that autophagy-dependent NRF2 activation contributed to the protective effects of TTM against NaAsO2-induced oxidative injury, because ofATG5orSQSTM1knockout aggravated NaAsO2-induced elevation of HMOX1, cleaved PARP and γH2AX. Taken together, our findings highlight copper chelator TTM is a novel autophagy-dependent NRF2 activator and shed a new light on the cure for oxidative damage-related diseases.
Zeb1 sustains hematopoietic stem cell functions by suppressing mitofusin-2-mediated mitochondrial fusion
Authors: Zhang Kai , Zhao Huifang , Sheng Yaru , Chen Xinyu , Xu Penghui , Wang Jinming , Ji Zhongzhong , He Yuman , Gao Wei-Qiang , Zhu Helen He
Published: August 2022

Metabolic status is essential in maintaining normal functions of hematopoietic stem cells (HSCs). However, how the dynamic of the mitochondrion, as a central organelle in metabolism, is molecularly regulated to orchestrate metabolism and HSC stemness remains to be elucidated. Here, we focus on the role of Zeb1, a well-characterized epithelial-to-mesenchymal transition (EMT) inducer which has been demonstrated to confer stem-cell-like characteristics in multiple cancer types in stemness regulation of HSCs. Using a Zeb1-tdTomato reporter mouse model, we find that Zeb1+Lin−Sca-1+c-Kit+ cells (Zeb1+-LSKs) represent a subset of functional long-term HSCs. Zeb1+LSKs exhibit a reduced reactive oxygen species (ROS) level, low mitochondrial mass, low mitochondrial membrane potential (MMP), and particularly small, round fragmented mitochondria. Of note, ectopic expression of Zeb1 leads to a fragmented mitochondrial morphology with a low mitochondrial metabolic status in EML cells. In addition, Zeb1-knockout (Zeb1-KO) LSKs from fetal liver display an exhausted stem-cell activity. Zeb1 deficiency results in elongated and tubulated mitochondria with increased mitochondrial mass, elevated MMP, and higher ROS production. Mechanistically, Zeb1 acts as a transcriptional suppressor on the key mitochondrial-fusion protein Mitofusin-2 (encoded by Mfn2). We highlight an important role of Zeb1 in the regulation of mitochondrial morphology in HSC and the metabolic control of HSC stemness by repressing Mfn2-mediated mitochondrial fusion.
Complete classification of steerability under local filters and its relation with measurement incompatibility
Authors: Ku Huan-Yu , Hsieh Chung-Yun , Chen Shin-Liang , Chen Yueh-Nan , Budroni Costantino
Published: August 2022

Quantum steering is a central resource for one-sided device-independent quantum information. It is manipulated via one-way local operations and classical communication, such as local filtering on the trusted party. Here, we provide a necessary and sufficient condition for a steering assemblage to be transformable into another via local filtering. We characterize the equivalence classes with respect to filters in terms of the steering equivalent observables (SEO), first proposed to connect the problem of steerability and measurement incompatibility. We provide an efficient method to compute the extractable steerability that is maximal via local filters and show that it coincides with the incompatibility of the SEO. Moreover, we show that there always exists a bipartite state that provides an assemblage with steerability equal to the incompatibility of the measurements on the untrusted party. Finally, we investigate the optimal success probability and rates for transformation protocols (distillation and dilution) in the single-shot scenario together with examples.
Single-cell analysis of hepatoblastoma identifies tumor signatures that predict chemotherapy susceptibility using patient-specific tumor spheroids
Authors: Song Hanbing , Bucher Simon , Rosenberg Katherine , Tsui Margaret , Burhan Deviana , Hoffman Daniel , Cho Soo-Jin , Rangaswami Arun , Breese Marcus , Leung Stanley , Ventura María V. Pons , Sweet-Cordero E. Alejandro , Huang Franklin W. , Nijagal Amar , Wang Bruce
Published: August 2022

Pediatric hepatoblastoma is the most common primary liver cancer in infants and children. Studies of hepatoblastoma that focus exclusively on tumor cells demonstrate sparse somatic mutations and a common cell of origin, the hepatoblast, across patients. In contrast to the homogeneity these studies would suggest, hepatoblastoma tumors have a high degree of heterogeneity that can portend poor prognosis. In this study, we use single-cell transcriptomic techniques to analyze resected human pediatric hepatoblastoma specimens, and identify five hepatoblastoma tumor signatures that may account for the tumor heterogeneity observed in this disease. Notably, patient-derived hepatoblastoma spheroid cultures predict differential responses to treatment based on the transcriptomic signature of each tumor, suggesting a path forward for precision oncology for these tumors. In this work, we define hepatoblastoma tumor heterogeneity with single-cell resolution and demonstrate that patient-derived spheroids can be used to evaluate responses to chemotherapy.
Experimental demonstration of adversarial examples in learning topological phases
Authors: Zhang Huili , Jiang Si , Wang Xin , Zhang Wengang , Huang Xianzhi , Ouyang Xiaolong , Yu Yefei , Liu Yanqing , Deng Dong-Ling , Duan L.-M.
Published: August 2022

Classification and identification of different phases and the transitions between them is a central task in condensed matter physics. Machine learning, which has achieved dramatic success in a wide range of applications, holds the promise to bring unprecedented perspectives for this challenging task. However, despite the exciting progress made along this direction, the reliability of machine-learning approaches in experimental settings demands further investigation. Here, with the nitrogen-vacancy center platform, we report a proof-of-principle experimental demonstration of adversarial examples in learning topological phases. We show that the experimental noises are more likely to act as adversarial perturbations when a larger percentage of the input data are dropped or unavailable for the neural network-based classifiers. We experimentally implement adversarial examples which can deceive the phase classifier with a high confidence, while keeping the topological properties of the simulated Hopf insulators unchanged. Our results explicitly showcase the crucial vulnerability aspect of applying machine learning techniques in experiments to classify phases of matter, which can benefit future studies in this interdisciplinary field.
Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance
Authors: Tye Mark A. , Payne N. Connor , Johansson Catrine , Singh Kritika , Santos Sofia A. , Fagbami Lọla , Pant Akansha , Sylvester Kayla , Luth Madeline R. , Marques Sofia , Whitman Malcolm , Mota Maria M. , Winzeler Elizabeth A. , Lukens Amanda K. , Derbyshire Emily R. , Oppermann Udo , Wirth Dyann F. , Mazitschek Ralph
Published: August 2022

The development of next-generation antimalarials that are efficacious against the human liver and asexual blood stages is recognized as one of the world’s most pressing public health challenges. In recent years, aminoacyl-tRNA synthetases, including prolyl-tRNA synthetase, have emerged as attractive targets for malaria chemotherapy. We describe the development of a single-step biochemical assay for Plasmodium and human prolyl-tRNA synthetases that overcomes critical limitations of existing technologies and enables quantitative inhibitor profiling with high sensitivity and flexibility. Supported by this assay platform and co-crystal structures of representative inhibitor-target complexes, we develop a set of high-affinity prolyl-tRNA synthetase inhibitors, including previously elusive aminoacyl-tRNA synthetase triple-site ligands that simultaneously engage all three substrate-binding pockets. Several compounds exhibit potent dual-stage activity against Plasmodium parasites and display good cellular host selectivity. Our data inform the inhibitor requirements to overcome existing resistance mechanisms and establish a path for rational development of prolyl-tRNA synthetase-targeted anti-malarial therapies.
Tripterygium wilfordii cytochrome P450s catalyze the methyl shift and epoxidations in the biosynthesis of triptonide
Authors: Hansen Nikolaj Lervad , Kjaerulff Louise , Heck Quinn Kalby , Forman Victor , Staerk Dan , Møller Birger Lindberg , Andersen-Ranberg Johan
Published: August 2022

The diterpenoid triepoxides triptolide and triptonide from Tripterygium wilfordii (thunder god wine) exhibit unique bioactivities with potential uses in disease treatment and as a non-hormonal male contraceptives. Here, we show that cytochrome P450s (CYPs) from the CYP71BE subfamily catalyze an unprecedented 18(4→3) methyl shift required for biosynthesis of the abeo-abietane core structure present in diterpenoid triepoxides and in several other plant diterpenoids. In combination with two CYPs of the CYP82D subfamily, four CYPs from T. wilfordii are shown to constitute the minimal set of biosynthetic genes that enables triptonide biosynthesis using Nicotiana benthamiana and Saccharomyces cerevisiae as heterologous hosts. In addition, co-expression of a specific T. wilfordii cytochrome b5 (Twcytb5-A) increases triptonide output more than 9-fold in S. cerevisiae and affords isolation and structure elucidation by NMR spectroscopic analyses of 18 diterpenoids, providing insights into the biosynthesis of diterpenoid triepoxides. Our findings pave the way for diterpenoid triepoxide production via fermentation.
Catalytic innovation underlies independent recruitment of polyketide synthases in cocaine and hyoscyamine biosynthesis
Authors: Tian Tian , Wang Yong-Jiang , Huang Jian-Ping , Li Jie , Xu Bingyan , Chen Yin , Wang Li , Yang Jing , Yan Yijun , Huang Sheng-Xiong
Published: August 2022

Tropane alkaloids such as hyoscyamine and cocaine are of importance in medicinal uses. Only recently has the hyoscyamine biosynthetic machinery become complete. However, the cocaine biosynthesis pathway remains only partially elucidated. Here we characterize polyketide synthases required for generating 3-oxo-glutaric acid from malonyl-CoA in cocaine biosynthetic route. Structural analysis shows that these two polyketide synthases adopt distinctly different active site architecture to catalyze the same reaction as pyrrolidine ketide synthase in hyoscyamine biosynthesis, revealing an unusual parallel/convergent evolution of biochemical function in homologous enzymes. Further phylogenetic analysis suggests lineage-specific acquisition of polyketide synthases required for tropane alkaloid biosynthesis in Erythroxylaceae and Solanaceae species, respectively. Overall, our work elucidates not only a key unknown step in cocaine biosynthesis pathway but also, more importantly, structural and biochemical basis for independent recruitment of polyketide synthases in tropane alkaloid biosynthesis, thus broadening the understanding of conservation and innovation of biosynthetic catalysts.
Methylation risk scores are associated with a collection of phenotypes within electronic health record systems
Authors: Thompson Mike , Hill Brian L. , Rakocz Nadav , Chiang Jeffrey N. , Geschwind Daniel , Sankararaman Sriram , Hofer Ira , Cannesson Maxime , Zaitlen Noah , Halperin Eran
Published: August 2022

Inference of clinical phenotypes is a fundamental task in precision medicine, and has therefore been heavily investigated in recent years in the context of electronic health records (EHR) using a large arsenal of machine learning techniques, as well as in the context of genetics using polygenic risk scores (PRS). In this work, we considered the epigenetic analog of PRS, methylation risk scores (MRS), a linear combination of methylation states. We measured methylation across a large cohort (n = 831) of diverse samples in the UCLA Health biobank, for which both genetic and complete EHR data are available. We constructed MRS for 607 phenotypes spanning diagnoses, clinical lab tests, and medication prescriptions. When added to a baseline set of predictive features, MRS significantly improved the imputation of 139 outcomes, whereas the PRS improved only 22 (median improvement for methylation 10.74%, 141.52%, and 15.46% in medications, labs, and diagnosis codes, respectively, whereas genotypes only improved the labs at a median increase of 18.42%). We added significant MRS to state-of-the-art EHR imputation methods that leverage the entire set of medical records, and found that including MRS as a medical feature in the algorithm significantly improves EHR imputation in 37% of lab tests examined (median R2 increase 47.6%). Finally, we replicated several MRS in multiple external studies of methylation (minimum p-value of 2.72 × 10−7) and replicated 22 of 30 tested MRS internally in two separate cohorts of different ethnicity. Our publicly available results and weights show promise for methylation risk scores as clinical and scientific tools.
Wildfire-dependent changes in soil microbiome diversity and function
Authors: Nelson Amelia R. , Narrowe Adrienne B. , Rhoades Charles C. , Fegel Timothy S. , Daly Rebecca A. , Roth Holly K. , Chu Rosalie K. , Amundson Kaela K. , Young Robert B. , Steindorff Andrei S. , Mondo Stephen J. , Grigoriev Igor V. , Salamov Asaf , Borch Thomas , Wilkins Michael J.
Published: August 2022

Forest soil microbiomes have crucial roles in carbon storage, biogeochemical cycling and rhizosphere processes. Wildfire season length, and the frequency and size of severe fires have increased owing to climate change. Fires affect ecosystem recovery and modify soil microbiomes and microbially mediated biogeochemical processes. To study wildfire-dependent changes in soil microbiomes, we characterized functional shifts in the soil microbiota (bacteria, fungi and viruses) across burn severity gradients (low, moderate and high severity) 1 yr post fire in coniferous forests in Colorado and Wyoming, USA. We found severity-dependent increases of Actinobacteria encoding genes for heat resistance, fast growth, and pyrogenic carbon utilization that might enhance post-fire survival. We report that increased burn severity led to the loss of ectomycorrhizal fungi and less tolerant microbial taxa. Viruses remained active in post-fire soils and probably influenced carbon cycling and biogeochemistry via turnover of biomass and ecosystem-relevant auxiliary metabolic genes. Our genome-resolved analyses link post-fire soil microbial taxonomy to functions and reveal the complexity of post-fire soil microbiome activity.
Embryo model completes gastrulation to neurulation and organogenesis
Authors: Amadei Gianluca , Handford Charlotte E. , Qiu Chengxiang , De Jonghe Joachim , Greenfeld Hannah , Tran Martin , Martin Beth K. , Chen Dong-Yuan , Aguilera-Castrejon Alejandro , Hanna Jacob H. , Elowitz Michael B. , Hollfelder Florian , Shendure Jay , Glover David M. , Zernicka-Goetz Magdalena
Published: August 2022

Embryonic stem (ES) cells can undergo many aspects of mammalian embryogenesis in vitro1–5, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem (TS) cells, extraembryonic endoderm stem (XEN) cells and inducible XEN (iXEN) cells6–11. Here we assembled stem cell-derived embryos in vitro from mouse ES cells, TS cells and iXEN cells and showed that they recapitulate the development of whole natural mouse embryo in utero up to day 8.5 post-fertilization. Our embryo model displays headfolds with defined forebrain and midbrain regions and develops a beating heart-like structure, a trunk comprising a neural tube and somites, a tail bud containing neuromesodermal progenitors, a gut tube, and primordial germ cells. This complete embryo model develops within an extraembryonic yolk sac that initiates blood island development. Notably, we demonstrate that the neurulating embryo model assembled from Pax6-knockout ES cells aggregated with wild-type TS cells and iXEN cells recapitulates the ventral domain expansion of the neural tube that occurs in natural, ubiquitous Pax6-knockout embryos. Thus, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse cell lineages and genes in development. Our results demonstrate the self-organization ability of ES cells and two types of extraembryonic stem cells to reconstitute mammalian development through and beyond gastrulation to neurulation and early organogenesis.
Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial
Authors: Gogishvili Miranda , Melkadze Tamar , Makharadze Tamta , Giorgadze Davit , Dvorkin Mikhail , Penkov Konstantin , Laktionov Konstantin , Nemsadze Gia , Nechaeva Marina , Rozhkova Irina , Kalinka Ewa , Gessner Christian , Moreno-Jaime Brizio , Passalacqua Rodolfo , Li Siyu , McGuire Kristina , Kaul Manika , Paccaly Anne , Quek Ruben G. W. , Gao Bo , Seebach Frank , Weinreich David M. , Yancopoulos George D. , Lowy Israel , Gullo Giuseppe , Rietschel Petra
Published: August 2022

First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has previously shown significant improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced non-small cell lung cancer (aNSCLC) and PD-ligand 1 (PD-L1) expression ≥50%. EMPOWER-Lung 3 (NCT03409614), a double-blind, placebo-controlled, phase 3 study, examined cemiplimab plus platinum-doublet chemotherapy as first-line treatment for aNSCLC, irrespective of PD-L1 expression or histology. In this study, 466 patients with stage III/IV aNSCLC without EGFR, ALK or ROS1 genomic tumor aberrations were randomized (2:1) to receive cemiplimab 350 mg (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks in combination with four cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as indicated). In total, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2% (397/466 patients) had stage IV disease. The primary endpoint was OS. The trial was stopped early per recommendation of the independent data monitoring committee, based on meeting preset OS efficacy criteria: median OS was 21.9 months (95% confidence interval (CI), 15.5–not evaluable) with cemiplimab plus chemotherapy versus 13.0 months (95% CI, 11.9–16.1) with placebo plus chemotherapy (hazard ratio (HR) = 0.71; 95% CI, 0.53–0.93; P = 0.014). Grade ≥3 adverse events occurred with cemiplimab plus chemotherapy (43.6%, 136/312 patients) and placebo plus chemotherapy (31.4%, 48/153 patients). Cemiplimab is only the second anti-PD-1/PD-L1 agent to show efficacy in aNSCLC as both monotherapy and in combination with chemotherapy for both squamous and non-squamous histologies.
Extended longevity of DNA preservation in Levantine Paleolithic sediments, Sefunim Cave, Israel
Authors: Slon Viviane , Clark Jamie L. , Friesem David E. , Orbach Meir , Porat Naomi , Meyer Matthias , Kandel Andrew W. , Shimelmitz Ron
Published: August 2022

Paleogenomic research can elucidate the evolutionary history of human and faunal populations. Although the Levant is a key land-bridge between Africa and Eurasia, thus far, relatively little ancient DNA data has been generated from this region, since DNA degrades faster in warm climates. As sediments can be a source of ancient DNA, we analyzed 33 sediment samples from different sedimentological contexts in the Paleolithic layers of Sefunim Cave (Israel). Four contained traces of ancient Cervidae and Hyaenidae mitochondrial DNA. Dating by optical luminescence and radiocarbon indicates that the DNA comes from layers between 30,000 and 70,000 years old, surpassing theoretical expectations regarding the longevity of DNA deposited in such a warm environment. Both identified taxa are present in the zooarchaeological record of the site but have since gone extinct from the region, and a geoarchaeological study suggests little movement of the sediments after their deposition, lending further support to our findings. We provide details on the local conditions in the cave, which we hypothesize were particularly conducive to the long-term preservation of DNA—information that will be pertinent for future endeavors aimed at recovering ancient DNA from the Levant and other similarly challenging contexts.
Emergence of sensory attenuation based upon the free-energy principle
Authors: Idei Hayato , Ohata Wataru , Yamashita Yuichi , Ogata Tetsuya , Tani Jun
Published: August 2022

The brain attenuates its responses to self-produced exteroceptions (e.g., we cannot tickle ourselves). Is this phenomenon, known as sensory attenuation, enabled innately, or acquired through learning? Here, our simulation study using a multimodal hierarchical recurrent neural network model, based on variational free-energy minimization, shows that a mechanism for sensory attenuation can develop through learning of two distinct types of sensorimotor experience, involving self-produced or externally produced exteroceptions. For each sensorimotor context, a particular free-energy state emerged through interaction between top-down prediction with precision and bottom-up sensory prediction error from each sensory area. The executive area in the network served as an information hub. Consequently, shifts between the two sensorimotor contexts triggered transitions from one free-energy state to another in the network via executive control, which caused shifts between attenuating and amplifying prediction-error-induced responses in the sensory areas. This study situates emergence of sensory attenuation (or self-other distinction) in development of distinct free-energy states in the dynamic hierarchical neural system.
Electrical resistivity of polycrystalline graphene: effect of grain-boundary-induced strain fields
Authors: Krasavin S. E. , Osipov V. A.
Published: August 2022

We have revealed the decisive role of grain-boundary-induced strain fields in electron scattering in polycrystalline graphene. To this end, we have formulated the model based on Boltzmann transport theory which properly takes into account the microscopic structure of grain boundaries (GB) as a repeated sequence of heptagon–pentagon pairs. We show that at naturally low GB charges the strain field scattering dominates and leads to physically reasonable and, what is important, experimentally observable values of the electrical resistivity. It ranges from 0.1 to 10 k$$\Omega$$
Ω
$$\upmu m$$

μ
m

for different types of symmetric GBs with a size of 1 $$\upmu$$
μ
m and has a strong dependence on misorientation angle. For low-angle highly charged GBs, two scattering mechanisms may compete. The resistivity increases markedly with decreasing GB size and reaches values of 60 k$$\Omega$$
Ω
$$\upmu$$
μ
m and more. It is also very sensitive to the presence of irregularities modeled by embedding of partial disclination dipoles. With significant distortion, we found an increase in resistance by more than an order of magnitude, which is directly related to the destruction of diffraction on the GB. Our findings may be of interest both in the interpretation of experimental data and in the design of electronic devices based on poly- and nanocrystalline graphene.
Survival prediction in triple negative breast cancer using multiple instance learning of histopathological images
Authors: Sandarenu Piumi , Millar Ewan K. A. , Song Yang , Browne Lois , Beretov Julia , Lynch Jodi , Graham Peter H. , Jonnagaddala Jitendra , Hawkins Nicholas , Huang Junzhou , Meijering Erik
Published: August 2022

Computational pathology is a rapidly expanding area for research due to the current global transformation of histopathology through the adoption of digital workflows. Survival prediction of breast cancer patients is an important task that currently depends on histopathology assessment of cancer morphological features, immunohistochemical biomarker expression and patient clinical findings. To facilitate the manual process of survival risk prediction, we developed a computational pathology framework for survival prediction using digitally scanned haematoxylin and eosin-stained tissue microarray images of clinically aggressive triple negative breast cancer. Our results show that the model can produce an average concordance index of 0.616. Our model predictions are analysed for independent prognostic significance in univariate analysis (hazard ratio = 3.12, 95% confidence interval [1.69,5.75], p < 0.005) and multivariate analysis using clinicopathological data (hazard ratio = 2.68, 95% confidence interval [1.44,4.99], p < 0.005). Through qualitative analysis of heatmaps generated from our model, an expert pathologist is able to associate tissue features highlighted in the attention heatmaps of high-risk predictions with morphological features associated with more aggressive behaviour such as low levels of tumour infiltrating lymphocytes, stroma rich tissues and high-grade invasive carcinoma, providing explainability of our method for triple negative breast cancer.
Scraping nasal cytology in the diagnostics of rhinitis and the comorbidities
Authors: Myszkowska Dorota , Bazgier Monika , Brońska Sara , Nowak Karol , Ożga Joanna , Woźniak Aleksandra , Stanisz Andrzej , Szaleniec Joanna
Published: August 2022

Nasal scraping cytology is a non-invasive tool used in the diagnostics of allergic and non-allergic rhinitis. The study aimed to analyze to what extent the cytological picture of the nasal mucosa coincides with the diagnosis of a given disease, taking into account the content of eosinophils. Retrospective analysis of the cytograms performed in 842 patients was carried out in relation to the disease entities and the content of eosinophils. Significant relationship between the Epith:Infl ratio and the four groups of diseases (Chi2 = 9.6488; p = .014) was confirmed. The more intensive inflammation was found, the higher percentage of patients had manifested the increased level of eosinophils (> 1% in the inflammatory cells). The value of 20% of eosinophils in all counted cells corresponds to around 45% of eosinophils in the inflammatory cells in patients with the evident inflammatory picture. Allergic rhinitis presents a different cytological picture regarding the eosinophilic reaction against the background of the inflammation process: the higher degree of inflammation observed, the lower amount of eosinophils detected, with the exception of allergic rhinitis provoked by pollen allergens.
Fire and termite resistance of wood treated with PF6-based ionic liquids
Authors: Miyafuji Hisashi , Minamoto Koji
Published: August 2022

Six PF6-based ionic liquids (ILs) were investigated to evaluate their potential as chemicals for enhancing fire and termite resistance of wood. The ILs used in this study included 1-methyl-1-propylpyrrolidinium hexafluorophosphate ([MPPL]PF6), 1-methyl-1-propylpiperidinium hexafluorophosphate ([MPPR]PF6), 1-ethyl-3-methylimidazolium hexafluorophosphate ([EMIM]PF6), tetrabutylphosphonium hexafluorophosphate ([TBP]PF6), trihexyltetradecylphosphonium hexafluorophosphate ([THP]PF6), and 1-butylpyridinium hexafluorophosphate ([BPYR]PF6). All of the IL-treated wood samples did not undergo any morphological changes, and exhibited enhanced fire- and termite resistance compared with untreated wood. The fire resistance properties of all of the prepared IL-treated wood specimens were comparable. However, the [EMIM]PF6- and [THP]PF6-treated wood showed slightly inferior termite resistance among the tested IL-treated woods. Overall, [TBP]PF6 was the most promising candidate among the evaluated PF6-based ILs because it is stable in wood without leaching after water penetration.
An early prediction model for canine chronic kidney disease based on routine clinical laboratory tests
Authors: Kokkinos Yiannis , Morrison JoAnn , Bradley Richard , Panagiotakos Theodoros , Ogeer Jennifer , Chew Dennis , O’Flynn Ciaran , De Meyer Geert , Watson Phillip , Tagkopoulos Ilias
Published: August 2022

The aim of this study was to derive a model to predict the risk of dogs developing chronic kidney disease (CKD) using data from electronic health records (EHR) collected during routine veterinary practice. Data from 57,402 dogs were included in the study. Two thirds of the EHRs were used to build the model, which included feature selection and identification of the optimal neural network type and architecture. The remaining unseen EHRs were used to evaluate model performance. The final model was a recurrent neural network with 6 features (creatinine, blood urea nitrogen, urine specific gravity, urine protein, weight, age). Identifying CKD at the time of diagnosis, the model displayed a sensitivity of 91.4% and a specificity of 97.2%. When predicting future risk of CKD, model sensitivity was 68.8% at 1 year, and 44.8% 2 years before diagnosis. Positive predictive value (PPV) varied between 15 and 23% and was influenced by the age of the patient, while the negative predictive value remained above 99% under all tested conditions. While the modest PPV limits its use as a stand-alone diagnostic screening tool, high specificity and NPV make the model particularly effective at identifying patients that will not go on to develop CKD.
Airway epithelial immunoproteasome subunit LMP7 protects against rhinovirus infection
Authors: Dimasuay Kris Genelyn , Schaunaman Niccolette , Berg Bruce , Cervantes Diana , Kruger Elke , Heppner Frank L. , Ferrington Deborah A. , Chu Hong Wei
Published: August 2022

Immunoproteasomes (IP) serve as an important modulator of immune responses to pathogens and other pathological factors. LMP7/β5i, one of the IP subunits, plays a critical role in autoimmune diseases by downregulating inflammation. Rhinovirus (RV) infection is a major risk factor in the exacerbations of respiratory inflammatory diseases, but whether LMP7 regulates RV-mediated inflammation in the lung particularly in the airway epithelium, the first line of defense against RV infection, remains unclear. In this study, we determined whether airway epithelial LMP7 promotes the resolution of RV-mediated lung inflammation. Inducible airway epithelial-specific LMP7-deficient (conditional knockout, CKO) mice were generated to reveal the in vivo anti-inflammatory and antiviral functions of LMP7. By using LMP7-deficient primary human airway epithelial cells generated by CRISPR-Cas9, we confirmed that airway epithelial LMP7 decreased pro-inflammatory cytokines and viral load during RV infection. Additionally, airway epithelial LMP7 enhanced the expression of a negative immune regulator A20/TNFAIP3 during viral infection that may contribute to the anti-inflammatory function of LMP7. We also discovered that induction of LMP7 by a low dose of polyinosinic:polycytidylic acid (PI:C) reduced RV-mediated inflammation in our CKO mice infected with RV. Our findings suggest that airway epithelial LMP7 has anti-inflammatory and antiviral functions that is critical to the resolution of RV-mediated lung inflammation. Induction of airway epithelial LMP7 may open a novel avenue for therapeutic intervention against RV infection.
A metasurface composed of orifice-type unit cells for the redirection of acoustic waves
Authors: Park Choon Mahn , Yim Geo-Su , Lee Sang Hun
Published: August 2022

To implement a sound wave redirection system, a two-dimensional (2D) slice of a three-dimensional (3D) metasurface is designed and fabricated using a one-dimensional (1D) face-centred orifice cubic (FCOC) unit cell. The metasurface consists of five identical periodic groups, of which one periodic group consists of eight unit-cell groups with a phase shift of $$\pi /4$$

π
/
4

adjacent to each other. One unit-cell group consists of four 1D FCOC unit cells with the same orifice diameter. From the numerical simulation results of the designed metasurface, we observed the redirections of sound waves and compared them with the expected theoretical results. It was confirmed that the experimental results agree well with the simulated results with respect to the different incident angles and frequencies. The used frequencies that satisfy the homogeneous medium condition of the metamaterial for the redirection of incident waves range between 1500 and 2700 Hz. At the characteristic frequency of 1540 Hz at normal incidence, it is considered that stationary evanescent waves exist at the boundary of the metasurface due to the characteristics of the surface wave and the limited end boundary. The FCOC-based metasurface provides a new method of metasurface fabrication and is expected to expand the applicability of the metasurface because it can be easily applied to a surface with any shape.
An automated deep learning method and novel cardiac index to detect canine cardiomegaly from simple radiography
Authors: Jeong Yeojin , Sung Joohon
Published: August 2022

Since most of degenerative canine heart diseases accompany cardiomegaly, early detection of cardiac enlargement is main priority healthcare issue for dogs. In this study, we developed a new deep learning-based radiographic index quantifying canine heart size using retrospective data. The proposed “adjusted heart volume index” (aHVI) was calculated as the total area of the heart multiplied by the heart’s height and divided by the fourth thoracic vertebral body (T4) length from simple lateral X-rays. The algorithms consist of segmentation and measurements. For semantic segmentation, we used 1000 dogs’ radiographic images taken between Jan 2018 and Aug 2020 at Seoul National University Veterinary Medicine Teaching Hospital. The tversky loss functions with multiple hyperparameters were used to capture the size-unbalanced regions of heart and T4. The aHVI outperformed the current clinical standard in predicting cardiac enlargement, a common but often fatal health condition for small old dogs.
Members of Venezuelan Equine Encephalitis complex entry into host cells by clathrin-mediated endocytosis in a pH-dependent manner
Authors: Ghietto Lucia Maria , Gil Pedro Ignacio , Olmos Quinteros Paloma , Gomez Emiliano , Piris Franco Martin , Kunda Patricia , Contigiani Marta , Paglini Maria Gabriela
Published: August 2022

Pixuna virus (PIXV) and Río Negro virus (RNV) are mosquito-borne alphaviruses belonging to the Venezuelan Equine Encephalitis (VEE) complex, which includes pathogenic epizootic and enzootic subtypes responsible for life-threatening diseases in equines. Considering that the first steps in viral infection are crucial for the efficient production of new progeny, the aim of this study was to elucidate the early events of the replication cycle of these two viruses. To this end, we used chemical inhibitors and the expression of dominant-negative constructs to study the dependence of clathrin and endosomal pH on PIXV and RNV internalization mechanisms. We demonstrated that both viruses are internalized primarily via clathrin-mediated endocytosis, where the low pH in endosomes is crucial for viral replication. Contributing knowledge regarding the entry route of VEE complex members is important to understand the pathogenesis of these viruses and also to develop new antiviral strategies.
Life cycle impact assessment and life cycle cost assessment for centralized and decentralized wastewater treatment plants in Thailand
Authors: Prateep Na Talang Rutjaya , Sirivithayapakorn Sanya , Polruang Sucheela
Published: August 2022

This research investigates the cost-effectiveness of four sludge treatment scenarios for centralized (C) and decentralized (D) wastewater treatment plants (WWTP) using life cycle cost assessment (LCCA). The environmental impacts and costs are quantified by Stepwise2006. The most environmentally and financially viable WWTP construction option for Bangkok, Thailand (2022–2031) is determined in terms of LCCA and net present value (NPV). The environmental costs of D-treatment scenarios are lower than those of C-treatment scenarios. The total environmental costs of C- and D-fertilizer scenarios are lower than those of C- and D-dewatering scenarios. The net cash flow per functional unit of C-WWTPs is higher than that of D-WWTPs. The C-fertilizer scenario is the most environmentally and economically viable treatment scenario due to the lowest LCCA deficit (−5.58 THB2020 per m3 treated effluent). Composting should thus be adopted for treating sludge. The most environmentally and financially viable WWTP construction option is option I (building four C-WWTPs within 10 years) due to the lowest LCCA deficit (−19925 million THB2020) and smallest financial loss (NPV = −6309.96 million THB2020). Essentially, the local administration of the capital should adopt option I as a guideline in formulating the wastewater treatment management policy of 2022–2031.
Qualitative immunoassay for the determination of tetracycline antibiotic residues in milk samples followed by a quantitative improved HPLC-DAD method
Authors: Alnassrallah Moneera N. , Alzoman Nourah Z. , Almomen Aliyah
Published: August 2022

Environmental contaminant is one of several problems harming people and wildlife. An example of current emerging contaminants are antibiotics residues that can present in water and food. Although antibiotics are intended to treat or prevent human and animal infections, antibiotics have also been used as animal food supplements for their ability to promote growth and feed efficiency. This overuse of antibacterial has resulted in the accumulation of antibiotics residues in food products which are eventually consumed by human. The continuous unnecessary exposure of human to antibiotics through the direct animals meet or milk, or indirectly through plants or soil can increase the chance of the emergence of multi drug resistance bacteria and consequently adversely affecting human health. New regulations have been imposed regarding antibiotics utilization. Due to the scarce of data regarding antibiotics residue conditions in different types of food intended for human consumption in Saudi Arabia, this study proposed an optimized chromatographic method (HPLC-DAD) followed by an immunoassay approach for specifically detecting tetracyclines antibiotics in animal milk samples. The method was carried out using an RP-C18 column with a mobile phase consisting of 0.01 M KH2PO4: acetonitrile:methanol (70:20:10, v/v/v) adjusted to pH 4. Improvements were observed in the method in terms of resolution and sensitivity. The protein precipitation method used for extraction demonstrated high percent recoveries of 85–101%. The method was validated according to the guidelines of the International Conference for Harmonization (ICH). It is evidently clear from these findings that the presence of tetracycline and oxytetracycline antibiotics residues in milk products from the Saudi market are below the maximum residual limits (MRLs).
Apolipoprotein C3 and necrotic core volume are correlated but also associated with future cardiovascular events
Authors: Ohwada Takayuki , Sakamoto Takayuki , Suzuki Satoshi , Sugawara Yukiko , Sakamoto Kazuya , Ikeda Ayano , Haga Fumika , Sato Tomoki , Nakazato Kazuhiko , Takeishi Yasuchika , Watanabe Kenichi
Published: August 2022

We aimed to clarify the relationship between apolipoprotein C3 (apo-C3) and the vascular composition of lesion plaque in stable coronary disease (SCD) before percutaneous coronary intervention (PCI), and to investigate major adverse cardiovascular events (MACEs) within 4 years. Data of 98 consecutive patients with SCD who underwent PCI between November 1, 2012, and March 10, 2015, were analyzed. Laboratory and virtual histology-intravascular ultrasound (VH-IVUS) examinations of culprit lesions were conducted before PCI. Patients were divided according to median apo-C3 into low apo-C3 (≤ 8.5 mg/dL) and high apo-C3 (> 8.5 mg/dL) groups. VH-IVUS data indicated that the percentage of necrotic core volume (%NC) was significantly higher in the high apo-C3 group than in the low apo-C3 group. Moreover, the %NC significantly correlated with the apo-C3 level (R = 0.2109, P = 0.037). Kaplan–Meier curve analysis revealed that freedom from MACEs exhibited a greater decrease in the high apo-C3 group than in the low apo-C3 group, and in the high %NC group than in the low %NC group. Multivariate Cox hazards analysis showed that the %NC and high apo-C3 were independent predictors of 4 year MACEs. Apo-C3 may be a useful marker of future MACEs in patients with SCD after PCI and contribute to %NC growth.
Spatial release from masking in crocodilians
Authors: Thévenet Julie , Papet Léo , Campos Zilca , Greenfield Michael , Boyer Nicolas , Grimault Nicolas , Mathevon Nicolas
Published: August 2022

Ambient noise is a major constraint on acoustic communication in both animals and humans. One mechanism to overcome this problem isSpatial Release from Masking(SRM), the ability to distinguish a target sound signal from masking noise when both sources are spatially separated. SRM is well described in humans but has been poorly explored in animals. Although laboratory tests with trained individuals have suggested that SRM may be a widespread ability in vertebrates, it may play a limited role in natural environments. Here we combine field experiments with investigations in captivity to test whether crocodilians experience SRM. We show that 2 species of crocodilians are able to use SRM in their natural habitat and that it quickly becomes effective for small angles between the target signal source and the noise source, becoming maximal when the angle exceeds 15∘. Crocodiles can therefore take advantage of SRM to improve sound scene analysis and the detection of biologically relevant signals.
Developmental depression-to-facilitation shift controls excitation-inhibition balance
Authors: Jia David W. , Vogels Tim P. , Costa Rui Ponte
Published: August 2022

Changes in the short-term dynamics of excitatory synapses over development have been observed throughout cortex, but their purpose and consequences remain unclear. Here, we propose that developmental changes in synaptic dynamics buffer the effect of slow inhibitory long-term plasticity, allowing for continuously stable neural activity. Using computational modeling we demonstrate that early in development excitatory short-term depression quickly stabilises neural activity, even in the face of strong, unbalanced excitation. We introduce a model of the commonly observed developmental shift from depression to facilitation and show that neural activity remains stable throughout development, while inhibitory synaptic plasticity slowly balances excitation, consistent with experimental observations. Our model predicts changes in the input responses from phasic to phasic-and-tonic and more precise spike timings. We also observe a gradual emergence of short-lasting memory traces governed by short-term plasticity development. We conclude that the developmental depression-to-facilitation shift may control excitation-inhibition balance throughout development with important functional consequences.
Analyzing cell-type-specific dynamics of metabolism in kidney repair
Authors: Wang Gangqi , Heijs Bram , Kostidis Sarantos , Mahfouz Ahmed , Rietjens Rosalie G. J. , Bijkerk Roel , Koudijs Angela , van der Pluijm Loïs A. K. , van den Berg Cathelijne W. , Dumas Sébastien J. , Carmeliet Peter , Giera Martin , van den Berg Bernard M. , Rabelink Ton J.
Published: August 2022

A common drawback of metabolic analyses of complex biological samples is the inability to consider cell-to-cell heterogeneity in the context of an organ or tissue. To overcome this limitation, we present an advanced high-spatial-resolution metabolomics approach using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) combined with isotope tracing. This method allows mapping of cell-type-specific dynamic changes in central carbon metabolism in the context of a complex heterogeneous tissue architecture, such as the kidney. Combined with multiplexed immunofluorescence staining, this method can detect metabolic changes and nutrient partitioning in targeted cell types, as demonstrated in a bilateral renal ischemia–reperfusion injury (bIRI) experimental model. Our approach enables us to identify region-specific metabolic perturbations associated with the lesion and throughout recovery, including unexpected metabolic anomalies in cells with an apparently normal phenotype in the recovery phase. These findings may be relevant to an understanding of the homeostatic capacity of the kidney microenvironment. In sum, this method allows us to achieve resolution at the single-cell level in situ and hence to interpret cell-type-specific metabolic dynamics in the context of structure and metabolism of neighboring cells.
Disentangling the electronic structure of an adsorbed graphene nanoring by scanning tunneling microscopy
Authors: Martinez-Castro Jose , Bolat Rustem , Fan Qitang , Werner Simon , Arefi Hadi H. , Esat Taner , Sundermeyer Jörg , Wagner Christian , Michael Gottfried J. , Temirov Ruslan , Ternes Markus , Stefan Tautz F.
Published: August 2022

Graphene nanorings are promising model structures to realize persistent ring currents and Aharonov–Bohm effect at the single molecular level. To investigate such intriguing effects, precise molecular characterization is crucial. Here, we combine low-temperature scanning tunneling imaging and spectroscopy with CO functionalized tips and algorithmic data analysis to investigate the electronic structure of the molecular cycloarene C108 (graphene nanoring) adsorbed on a Au(111) surface. We demonstrate that CO functionalized tips enhance the visibility of molecular resonances, both in differential conductance spectra and in real-space topographic images. Comparing our experimental data with ab-initio density functional theory reveals a remarkably precise agreement of the molecular orbitals and enables us to disentangle close-lying molecular states only separated by 50 meV at an energy of 2 eV below the Fermi level. We propose this combination of techniques as a promising new route for a precise electronic characterization of complex molecules and other physical properties which have electronic resonances in the tip-sample junction.
Fluorescence and electrochemical integrated dual-signal sensor for the detection of iron ions in water based on an ITO substrate
Authors: Bai Zhenyu , Li Ping , Fu Hao , Chen Peicai , Feng Xiaoyang , Hu Xueping , Song Xingliang , Chen Lingxin
Published: August 2022

A fluorescent and electrochemical dual-signal sensor has been fabricated for the visual and sensitive detection of Fe3+ in water.