bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxethazaine inhibits esophageal squamous cell carcinoma proliferation and metastasis by targeting aurora kinase A
Authors: Bao Zhuo , Li Ang , Lu Xuebo , Wang Zitong , Yu Yin , Wu Wenjie , Zhao Lili , Li Bo , Wu Xiangyu , Laster Kyle Vaughn , Zhang Chengjuan , Jiang Yanan , Dong Zigang , Liu Kangdong
Published: February 2022

Esophageal squamous cell carcinoma (ESCC), a malignant neoplasm with high incidence, is a severe global public health threat. The current modalities used for treating ESCC include surgery, chemotherapy, and radiotherapy. Although ESCC management and treatment strategies have improved over the last decade, the overall 5-year survival rate remains <20%. Therefore, the identification of novel therapeutic strategies that can increase ESCC patient survival rates is urgently needed. Oxethazaine, an amino-amide anesthetic agent, is mainly prescribed in combination with antacids to relieve esophagitis, dyspepsia, and other gastric disorders. In the present study, we found that oxethazaine inhibited the proliferation and migration of esophageal cancer cells. According to the results of in vitro screening and binding assays, oxethazaine binds directly to AURKA, suppresses AURKA activity, and inhibits the downstream effectors of AURKA. Notably, we found that oxethazaine suppressed tumor growth in three patient-derived esophageal xenograft mouse models and tumor metastasis in vivo. Our findings suggest that oxethazaine can inhibit ESCC proliferation and metastasis in vitro and in vivo by targeting AURKA.
m6A methyltransferase KIAA1429 acts as an oncogenic factor in colorectal cancer by regulating SIRT1 in an m6A-dependent manner
Authors: Zhou Yuan , Pei Zhengda , Maimaiti Aizezi , Zheng Linyi , Zhu Zhongcheng , Tian Mengxiang , Zhou Zhongyi , Tan Fengbo , Pei Qian , Li Yuqiang , Liu Wenxue
Published: February 2022

N6-methyladenosine (m6A) modifications of RNAs are involved in various aspects of colorectal carcinogenesis via regulation of mRNA stability, splicing, and translation. KIAA1429, an m6A methyltransferase, was found deregulated in multiple cancer types. However, its role in colorectal cancer remains elusive. By analyzing TCGA and GEPIA database, we found that KIAA1429 in colorectal cancer was highly expressed. In addition, we used immunohistochemistry, western blotting, and QRT-PCR to detect the expression of KIAA1429 in colorectal cancer samples and cell lines, and we found that KIAA1429 was overexpressed in colorectal cancer sample and cell line. Functionally, silencing of KIAA1429 by shRNA in colorectal cancer cell lines resulted in decreased cell proliferation, colony formation, and migration. On the contrary, overexpression of KIAA1429 increased cell proliferation, colony formation, and migration. Further mechanism analysis demonstrated that KIAA1429 increased the expression of SIRT1 via regulating its mRNA stability in an m6A-dependent manner. More importantly, in vivo experiment showed that depletion of KIAA1429 significantly inhibited colorectal tumor growth. In conclusion, our results suggested that the m6A methyltransferase KIAA1429 promotes the growth and motility of colorectal cancer and could be a potent therapeutic target.
Growth of two-dimensional Janus MoSSe by a single in situ process without initial or follow-up treatments
Authors: Jang Chan Wook , Lee Won Jun , Kim Jae Kuk , Park Sang Minh , Kim Sung , Choi Suk-Ho
Published: February 2022

Two-dimensional (2D) Janus transition metal dichalcogenides (TMDCs) are highly attractive as an emerging class of 2D materials, but only a few methods are available for fabricating them. These methods rely on the initial growth of 2D TMDCs in one process, followed by an additional plasma or high-temperature (T) process. To overcome these drawbacks, we employ the new approach of NaCl-assisted single-process chemical vapor deposition, which consists of three steps that proceed only by altering the temperature in situ. In the first step, MoS2 is deposited onto a SiO2/Si substrate with the Mo and S atoms activated in different temperature zones. In the second step, S vacancies are formed in the upper layer of the grown MoS2 by annealing. In the third step, the vacancies are filled with activated Se atoms. Throughout the steps, NaCl lowers the melting point of the constituent atoms, while the T in each zone is properly controlled. The growth mechanism is clarified by a separate annealing experiment that does not involve a supply of activated atoms. These results highlight a simple and cost-effective approach for growing Janus MoSSe, which is more useful for fundamental studies and device applications.
Ferroelastic oligocrystalline microwire with unprecedented high-temperature superelastic and shape memory effects
Authors: Chen Zhen , Cong Daoyong , Ren Yang , Zhang Yin , Yan Haile , You Li , Song Chao , Li Shaohui , Cao Yuxian , Li Shengwei , Zuo Changchang , Wang Li , Gao Zhiyong , Cai Wei , Wang Yandong
Published: February 2022

A compelling demand exists for high-performance high-temperature shape memory alloys (HTSMAs) that can be applied as intelligent components in the rapidly developing aerospace, robotics, manufacturing, and energy exploration industries. However, existing HTSMAs are handicapped by their high cost and unsatisfactory functional properties, which impede their practical application. Here, by using the strategy of creating an oligocrystalline structure, we have developed a high-performance, cost-effective high-temperature shape memory microwire exhibiting an exceptional combination of superb superelasticity with a large recoverable strain of up to 15%, an outstanding one-way shape memory effect with a maximum recoverable strain as high as 13% and a remarkable two-way shape memory effect with a large recoverable strain of 6.3%. These unparalleled comprehensive properties provide this microwire with a high potential for use in high-temperature actuation, sensing, and energy conversion applications, especially in miniature intelligent devices, such as high-temperature microelectromechanical systems. The present strategy may be universally applicable to other brittle phase-transforming alloys for achieving outstanding functional properties at high temperatures.
Hemoglobinopathy prevention in primary care: a reflection of underdetection and difficulties with accessibility of medical care, a quantitative study
Authors: van Vliet Margo E. , Kerkhoffs Jean-Louis H. , Harteveld Cornelis L. , Houwink Elisa J. F.
Published: February 2022

As in most Northern European countries, the prevalence of hemoglobinopathies in The Netherlands is increasing due to migration. Although hemoglobinopathies are severe chronic diseases with few treatment options, timely detection of carriers allows at-risk couples to make informed reproductive choices such as pre-implantation diagnosis, prenatal diagnosis or termination of affected pregnancies. Using a quantitative design, we evaluated the prevalence of hemoglobinopathies in The Hague region, The Netherlands. Patient and carrier registries from hospital, laboratory and general practitioners allowed this quantitative analysis. The highest prevalence of hemoglobinopathies was seen in immigrant neighborhoods, and a large gap was noted between estimated carrier prevalence and the actual registration of carriers in electronic patient records. Carrier prevalence was estimated to be 13,704; however, the ELAN database contains only 1542 cases with ICPC codes for sickle cell disease or thalassemia. Although more research is needed to define the requirements of the healthcare system to address this challenge, this study clearly shows the gap between estimated carrier prevalence and registration and thereby the pressing need for action.
Quantifying arousal and awareness in altered states of consciousness using interpretable deep learning
Authors: Lee Minji , Sanz Leandro R. D. , Barra Alice , Wolff Audrey , Nieminen Jaakko O. , Boly Melanie , Rosanova Mario , Casarotto Silvia , Bodart Olivier , Annen Jitka , Thibaut Aurore , Panda Rajanikant , Bonhomme Vincent , Massimini Marcello , Tononi Giulio , Laureys Steven , Gosseries Olivia , Lee Seong-Whan
Published: February 2022

Consciousness can be defined by two components: arousal (wakefulness) and awareness (subjective experience). However, neurophysiological consciousness metrics able to disentangle between these components have not been reported. Here, we propose an explainable consciousness indicator (ECI) using deep learning to disentangle the components of consciousness. We employ electroencephalographic (EEG) responses to transcranial magnetic stimulation under various conditions, including sleep (n = 6), general anesthesia (n = 16), and severe brain injury (n = 34). We also test our framework using resting-state EEG under general anesthesia (n = 15) and severe brain injury (n = 34). ECI simultaneously quantifies arousal and awareness under physiological, pharmacological, and pathological conditions. Particularly, ketamine-induced anesthesia and rapid eye movement sleep with low arousal and high awareness are clearly distinguished from other states. In addition, parietal regions appear most relevant for quantifying arousal and awareness. This indicator provides insights into the neural correlates of altered states of consciousness.
A putative cap binding protein and the methyl phosphate capping enzyme Bin3/MePCE function in telomerase biogenesis
Authors: Páez-Moscoso Diego J. , Ho David V. , Pan Lili , Hildebrand Katie , Jensen Kristi L. , Levy Michaella J. , Florens Laurence , Baumann Peter
Published: February 2022

Telomerase reverse transcriptase (TERT) and the noncoding telomerase RNA (TR) subunit constitute the core of telomerase. Additional subunits are required for ribonucleoprotein complex assembly and in some cases remain stably associated with the active holoenzyme. Pof8, a member of the LARP7 protein family is such a constitutive component of telomerase in fission yeast. Using affinity purification of Pof8, we have identified two previously uncharacterized proteins that form a complex with Pof8 and participate in telomerase biogenesis. Both proteins participate in ribonucleoprotein complex assembly and are required for wildtype telomerase activity and telomere length maintenance. One factor we named Thc1 (Telomerase Holoenzyme Component 1) shares structural similarity with the nuclear cap binding complex and the poly-adenosine ribonuclease (PARN), the other is the ortholog of the methyl phosphate capping enzyme (Bin3/MePCE) in metazoans and was named Bmc1 (Bin3/MePCE 1) to reflect its evolutionary roots. Thc1 and Bmc1 function together with Pof8 in recognizing correctly folded telomerase RNA and promoting the recruitment of the Lsm2-8 complex and the catalytic subunit to assemble functional telomerase.
Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2
Authors: Zhuang Youwen , Wang Lei , Guo Jia , Sun Dapeng , Wang Yue , Liu Weiyi , Xu H. Eric , Zhang Cheng
Published: February 2022

The formylpeptide receptors (FPRs) mediate pattern recognition of formylated peptides derived from invading pathogens or mitochondria from dead host cells. They can also sense other structurally distinct native peptides and even lipid mediators to either promote or resolve inflammation. Pharmacological targeting of FPRs represents a novel therapeutic approach in treating inflammatory diseases. However, the molecular mechanisms underlying FPR ligand recognition are elusive. We report cryo-EM structures of Gi-coupled FPR1 and FPR2 bound to a formylpeptide and Gi-coupled FPR2 bound to two synthetic peptide and small-molecule agonists. Together with mutagenesis data, our structures reveal the molecular mechanism of formylpeptide recognition by FPRs and structural variations of FPR1 and FPR2 leading to their different ligand preferences. Structural analysis also suggests that diverse FPR agonists sample a conserved activation chamber at the bottom of ligand-binding pockets to activate FPRs. Our results provide a basis for rational drug design on FPRs.
The E3 ubiquitin-protein ligase Trim31 alleviates non-alcoholic fatty liver disease by targeting Rhbdf2 in mouse hepatocytes
Authors: Xu Minxuan , Tan Jun , Dong Wei , Zou Benkui , Teng Xuepeng , Zhu Liancai , Ge Chenxu , Dai Xianling , Kuang Qin , Zhong Shaoyu , Lai Lili , Yi Chao , Tang Tingting , Zhao Junjie , Wang Longyan , Liu Jin , Wei Hao , Sun Yan , Yang Qiufeng , Li Qiang , Lou Deshuai , Hu Linfeng , Liu Xi , Kuang Gang , Luo Jing , Xiong Mingxin , Feng Jing , Zhang Chufeng , Wang Bochu
Published: February 2022

Systemic metabolic syndrome significantly increases the risk of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). However, no effective therapeutic strategies are available, practically because our understanding of its complicated pathogenesis is poor. Here we identify the tripartite motif-containing protein 31 (Trim31) as an endogenous inhibitor of rhomboid 5 homolog 2 (Rhbdf2), and we further determine that Trim31 directly binds to Rhbdf2 and facilitates its proteasomal degradation. Hepatocyte-specific Trim31 ablation facilitates NAFLD-associated phenotypes in mice. Inversely, transgenic or ex vivo gene therapy-mediated Trim31 gain-of-function in mice with NAFLD phenotypes virtually alleviates severe deterioration and progression of steatohepatitis. The current findings suggest that Trim31 is an endogenous inhibitor of Rhbdf2 and downstream cascades in the pathogenic process of steatohepatitis and that it may serve as a feasible therapeutical target for the treatment of NAFLD/NASH and associated metabolic disorders.
Cryo-EM structure of translesion DNA synthesis polymerase ζ with a base pair mismatch
Authors: Malik Radhika , Johnson Robert E. , Prakash Louise , Prakash Satya , Ubarretxena-Belandia Iban , Aggarwal Aneel K.
Published: February 2022

The B-family multi-subunit DNA polymerase ζ (Polζ) is important for translesion DNA synthesis (TLS) during replication, due to its ability to extend synthesis past nucleotides opposite DNA lesions and mismatched base pairs. We present a cryo-EM structure of Saccharomyces cerevisiae Polζ with an A:C mismatch at the primer terminus. The structure shows how the Polζ active site responds to the mismatched duplex DNA distortion, including the loosening of key protein-DNA interactions and a fingers domain in an “open” conformation, while the incoming dCTP is still able to bind for the extension reaction. The structure of the mismatched DNA-Polζ ternary complex reveals insights into mechanisms that either stall or favor continued DNA synthesis in eukaryotes.
Dark matter from axion strings with adaptive mesh refinement
Authors: Buschmann Malte , Foster Joshua W. , Hook Anson , Peterson Adam , Willcox Don E. , Zhang Weiqun , Safdi Benjamin R.
Published: February 2022

Axions are hypothetical particles that may explain the observed dark matter density and the non-observation of a neutron electric dipole moment. An increasing number of axion laboratory searches are underway worldwide, but these efforts are made difficult by the fact that the axion mass is largely unconstrained. If the axion is generated after inflation there is a unique mass that gives rise to the observed dark matter abundance; due to nonlinearities and topological defects known as strings, computing this mass accurately has been a challenge for four decades. Recent works, making use of large static lattice simulations, have led to largely disparate predictions for the axion mass, spanning the range from 25 microelectronvolts to over 500 microelectronvolts. In this work we show that adaptive mesh refinement simulations are better suited for axion cosmology than the previously-used static lattice simulations because only the string cores require high spatial resolution. Using dedicated adaptive mesh refinement simulations we obtain an over three order of magnitude leap in dynamic range and provide evidence that axion strings radiate their energy with a scale-invariant spectrum, to within ~5% precision, leading to a mass prediction in the range (40,180) microelectronvolts.
A mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6
Authors: Schmidt Jan Marten , Yang Ran , Kumar Ashish , Hunker Olivia , Seebacher Jan , Bleichert Franziska
Published: February 2022

The coordinated action of multiple replicative helicase loading factors is needed for the licensing of replication origins prior to DNA replication. Binding of the Origin Recognition Complex (ORC) to DNA initiates the ATP-dependent recruitment of Cdc6, Cdt1 and Mcm2-7 loading, but the structural details for timely ATPase site regulation and for how loading can be impeded by inhibitory signals, such as cyclin-dependent kinase phosphorylation, are unknown. Using cryo-electron microscopy, we have determined several structures of S. cerevisiae ORC·DNA·Cdc6 intermediates at 2.5–2.7 Å resolution. These structures reveal distinct ring conformations of the initiator·co-loader assembly and inactive ATPase site configurations for ORC and Cdc6. The Orc6 N-terminal domain laterally engages the ORC·Cdc6 ring in a manner that is incompatible with productive Mcm2-7 docking, while deletion of this Orc6 region alleviates the CDK-mediated inhibition of Mcm7 recruitment. Our findings support a model in which Orc6 promotes the assembly of an autoinhibited ORC·DNA·Cdc6 intermediate to block origin licensing in response to CDK phosphorylation and to avert DNA re-replication.
Understanding self-assembly at molecular level enables controlled design of DNA G-wires of different properties
Authors: Pavc Daša , Sebastian Nerea , Spindler Lea , Drevenšek-Olenik Irena , Podboršek Gorazd Koderman , Plavec Janez , Šket Primož
Published: February 2022

A possible engineering of materials with diverse bio- and nano-applications relies on robust self-assembly of oligonucleotides. Bottom-up approach utilizing guanine-rich DNA oligonucleotides can lead to formation of G-wires, nanostructures consisting of continuous stacks of G-quartets. However, G-wire structure and self-assembly process remain poorly understood, although they are crucial for optimizing properties needed for specific applications. Herein, we use nuclear magnetic resonance to get insights at molecular level on how chosen short, guanine-rich oligonucleotides self-assemble into G-wires, whereas complementary methods are used for their characterization. Additionally, unravelling mechanistic details enable us to guide G-wire self-assembly in a controlled manner. MD simulations provide insight why loop residues with considerably different properties, i.e., hydrogen-bond affinity, stacking interactions, electronic effects and hydrophobicity extensively increase or decrease G-wire length. Our results provide fundamental understanding of G-wire self-assembly process useful for future design of nanomaterials with specific properties.
Winter wheat yield prediction using convolutional neural networks from environmental and phenological data
Authors: Srivastava Amit Kumar , Safaei Nima , Khaki Saeed , Lopez Gina , Zeng Wenzhi , Ewert Frank , Gaiser Thomas , Rahimi Jaber
Published: February 2022

Crop yield forecasting depends on many interactive factors, including crop genotype, weather, soil, and management practices. This study analyzes the performance of machine learning and deep learning methods for winter wheat yield prediction using an extensive dataset of weather, soil, and crop phenology variables in 271 counties across Germany from 1999 to 2019. We proposed a Convolutional Neural Network (CNN) model, which uses a 1-dimensional convolution operation to capture the time dependencies of environmental variables. We used eight supervised machine learning models as baselines and evaluated their predictive performance using RMSE, MAE, and correlation coefficient metrics to benchmark the yield prediction results. Our findings suggested that nonlinear models such as the proposed CNN, Deep Neural Network (DNN), and XGBoost were more effective in understanding the relationship between the crop yield and input data compared to the linear models. Our proposed CNN model outperformed all other baseline models used for winter wheat yield prediction (7 to 14% lower RMSE, 3 to 15% lower MAE, and 4 to 50% higher correlation coefficient than the best performing baseline across test data). We aggregated soil moisture and meteorological features at the weekly resolution to address the seasonality of the data. We also moved beyond prediction and interpreted the outputs of our proposed CNN model using SHAP and force plots which provided key insights in explaining the yield prediction results (importance of variables by time). We found DUL, wind speed at week ten, and radiation amount at week seven as the most critical features in winter wheat yield prediction.
Understanding calcium functionality by examining growth characteristics and structural aspects in calcium-deficient grapevine
Authors: Duan Shuyan , Zhang Chengjun , Song Shiren , Ma Chao , Zhang Caixi , Xu Wenping , Bondada Bhaskar , Wang Lei , Wang Shiping
Published: February 2022

This study characterized growth characteristics and cellular details employing microscopy techniques in hydroponically-grown Ca2+-sufficient and Ca2+-deficient grapevines (Vitis vinifera) in a glasshouse. The Ca2+-deficient vines exhibited significant reductions in shoot length, shoot and trunk fresh weights, leaf area, chlorophyll, which eventually led to drooping, yellowing, and chlorosis of leaves. Roots were less dense and primarily dark and necrotic. Furthermore, their xylem vessels were small, polygonal, and appeared to be collapsed yet increased in number and developed lateral roots. Despite such alterations, the anatomical organization of leaves was not affected, yet they developed with more xylem vessels with thick walls and lignin in their mesophyll and vascular tissues. The chloroplasts in internodes’ chlorenchyma, phloem, and cambium underwent significant ultrastructural modifications. The concentrations of macro and micronutrients varied significantly among the roots, trunk, canes, and leaves, including the growth characteristics. These structural and growth modifications of calcium deficiency enable us to understand better the link between the symptoms and functions and for a holistic understanding of Ca2+ functionalities.
Extracellular circulating miRNAs as stress-related signature to search and rescue dogs
Authors: Guelfi Gabriella , Iaboni Martina , Sansone Anna , Capaccia Camilla , Santoro Michele Matteo , Diverio Silvana
Published: February 2022

Our research explores serum extracellular circulating miRNAs (ecmiRNAs) involved in dog stress response immediately after the search and rescue (SAR) of missing people. The experimental plan considers four arduous SAR simulations. The SAR dogs are trained by the Alpine School of the Military Force of Guardia di Finanza (Passo Rolle, Italy). The First SAR Trial analyzed dog serum samples at rest time (T0), and immediately after SAR performance (T1) using the miRNome-wide screening next-generation sequencing (NGS). T1 versus T0 NGS results revealed a different expression level of let-7a and let-7f. Subsequently, in a large sample size including: 1st (n = 6), 2nd (n = 6), 3rd (n = 6), and 4th (n = 4) trials, let-7a and let-7f were validated by qPCR. Bioinformatics analysis with TarBase (v.8) and the Diana-mirPath (v.3) revealed a functional role of let-7a and let-7f in the p53 pathway to restore cellular homeostasis. Let-7a and let-7f, highly expressed at T1, could stop MDMs-p53 inhibition inducing the p53 increase in level. In addition, let-7a and let-7f, via p53 post-transcriptional regulation, buffers p53 transcription spikes. During SAR stress, the possibility of p53 preconditioning could explain the phenomenon of “stress hardening” where the tolerance of particular stress increases after preconditioning.
Assessment of life loss due to dam breach using improved variable fuzzy method
Authors: Jiao Hongbo , Li Wei , Ma Ding
Published: February 2022

In recent years, several factors, such as frequent extreme weather, disrepair of dams, and improper management, have caused frequent dam failures, posing a significant threat to people's lives downstream. At present, the life loss is evaluated using the empirical formula method, in which the recommended approximate and threshold results are obtained through linear regression or statistical analysis. However, this method is sometimes insufficient because of the lack of a historical dataset and low availability, and it tends to simplify or ignore the influence of some factors in regression. During the research, most objects are considered as individual cases, and thus, the universality and scientificity of the application of evaluation models or parameters need further discussion. The variable fuzzy set theory features rigorous mathematical clarity and fuzziness of things and is widely used in the optimal decision evaluation model. Although, the traditional variable fuzzy evaluation method is widely used to deal with the linear variation in the index, some indexes, such as dam storage capacity and downstream population at risk, can cause non-linear problems, directly affecting the accuracy of membership evaluation results. Therefore, an improved model was proposed, where the relative difference formula was improved through logarithmic transformation and boundary constraint. The improved method was applied to the sequencing of life loss risk consequences for four reservoirs. The evaluation result was consistent with the actual situation of the disaster and the actual mortality rate. The scientificity and practicability of the improved model were verified, providing a new perspective for reservoir risk ranking and enriching the risk management theory.
Multivariate prediction of pain perception based on pre-stimulus activity
Authors: Taesler Philipp , Rose Michael
Published: February 2022

The perception of pain is modulated by different processes such as, for example, expectations and attention regarding the upcoming stimulus. Such processes are initiated prior to the actual stimulus and are reflected in ongoing brain activity. Different processes that are by definition also complex in itself are reflected in pre-stimulus activity and therefore the detection of this activity pattern should benefit from a multivariate approach. To identify specific pre-stimulus EEG activity patterns related to subsequent pain perception in humans, we contrasted painful with non-painful sensations delivered at the individual threshold level during EEG measurements. The results of the multivariate EEG analysis revealed a high level of accuracy (group mean 68%) in predicting the pain categorization solely based on pre-stimulus activity. In particular, fronto-central regions and activity in the higher gamma band (60:120 Hz) were of maximal importance for classification. Additional analyses supported the specific role of the pattern of high gamma band activity prior to the stimulus for predicting the behavioral outcome and demonstrated that the informational value embedded in the pre-stimulus activity is nearly as informative as the post-stimulus processing and reflects a specific preparatory state. Further, a close relation between pre- and post-stimulus processing in the high gamma band was observed. These findings support the important role of a multivariate cognitive state prior to stimulus appearance for the emergence of the subjective perception of pain and the functional role of widespread high gamma band activity.
Pulmonary toxicity of craniospinal irradiation using helical tomotherapy
Authors: Lee Joongyo , Kim Euidam , Kim Nalee , Suh Chang-Ok , Chung Yoonsun , Yoon Hong In
Published: February 2022

Craniospinal irradiation using helical tomotherapy (HT-CSI) has advantages in aspects of homogeneous dose distribution. Physicians, however, still have concerns of pulmonary toxicity due to HT-CSI’s relatively large, low-dose irradiated volume from continuous and 360° rotation delivery. In this study, we investigated the pulmonary toxicity of HT-CSI. We retrospectively reviewed 105 patients who received HT-CSI between January 2014 and December 2019. Grade 2 + pulmonary toxicities were evaluated. Intensive systemic treatment was defined as systemic treatment administration before, during, and after HT-CSI. VX Gy was defined as % volume receiving ≥ X Gy. Thirteen patients (12.4%) presented with grade 2 + pulmonary toxicities after HT-CSI. Of these patients, only one experienced grade 2 radiation pneumonitis combined with pembrolizumab-induced pneumonitis. Conversely, pneumonia was observed in 12 patients. Intensive systemic treatment (p = 0.004), immunosuppressive drugs (p = 0.031), and bilateral lung V5 Gy ≥ 65% (p = 0.031) were identified as independent risk factors for pneumonia. The risk factor for pneumonia in pediatric patients were immunosuppressive drugs (p = 0.035) and bilateral lung V5 Gy ≥ 65% (p = 0.047). HT-CSI can be a safe treatment modality with tolerable pulmonary toxicities. Intensive systemic treatment, immunosuppressive drugs, and bilateral lung V5 Gy ≥ 65% were significantly associated with pneumonia. In these patients, close follow-up should be considered for proper management of pneumonia.
Salivary biomarkers in children with juvenile idiopathic arthritis and healthy age-matched controls: a prospective observational study
Authors: Collin Malin , Ernberg Malin , Christidis Nikolaos , Hedenberg-Magnusson Britt
Published: February 2022

Monitoring the immune system’s regulation and signaling using saliva could be of interest for clinicians and researchers. Saliva, a biofluid with close exchange with serum, is influenced by circadian variance and oral factors such as masticatory function. This study investigated the detectability and concentration of cytokines and chemokines in saliva in children with juvenile idiopathic arthritis (JIA) as well as saliva flow and the influence of orofacial pain on saliva flow. Of the 60 participants (7–14 years old) enrolled, 30 had a diagnosis of JIA and active disease, and 30 were sex- and age-matched healthy controls. Demographic data and three validated questions regarding presence of orofacial pain and dysfunction were recorded. Stimulated whole saliva was collected and analyzed using a customized R&D bead-based immunoassay with 21 targeted biomarkers. Fourteen of these were detectable and showed similar levels in both children with JIA and controls: TNF-alpha, TNFRSF1B, MMP-2, MMP-3, IL-1alpha, IL-1beta, IL-6R alpha, IL-8, S100A8, CCL2, CCL3, IL-10, CCL11, and CXCL9. In addition, there was no difference in salivary flow rate between groups, but there was an association between orofacial pain and reduced saliva flow rate for both groups.

Trial registration: ClinicalTrials.gov Protocol id: 2010/2089-31/2.
The metabolism of cells regulates their sensitivity to NK cells depending on p53 status
Authors: Belkahla Sana , Brualla Joaquin Marco , Fayd’herbe de Maudave Alexis , Falvo Paolo , Allende-Vega Nerea , Constantinides Michael , Khan Abrar Ul Haq , Coenon Lois , Alexia Catherine , Mitola Giulia , Massa Paul , Orecchioni Stefania , Bertolini Francesco , Mnif Wissem , Hernandez Javier , Anel Alberto , Villalba Martin
Published: February 2022

Leukemic cells proliferate faster than non-transformed counterparts. This requires them to change their metabolism to adapt to their high growth. This change can stress cells and facilitate recognition by immune cells such as cytotoxic lymphocytes, which express the activating receptor Natural Killer G2-D (NKG2D). The tumor suppressor gene p53 regulates cell metabolism, but its role in the expression of metabolism-induced ligands, and subsequent recognition by cytotoxic lymphocytes, is unknown. We show here that dichloroacetate (DCA), which induces oxidative phosphorylation (OXPHOS) in tumor cells, induces the expression of such ligands, e.g. MICA/B, ULBP1 and ICAM-I, by a wtp53-dependent mechanism. Mutant or null p53 have the opposite effect. Conversely, DCA sensitizes only wtp53-expressing cells to cytotoxic lymphocytes, i.e. cytotoxic T lymphocytes and NK cells. In xenograft in vivo models, DCA slows down the growth of tumors with low proliferation. Treatment with DCA, monoclonal antibodies and NK cells also decreased tumors with high proliferation. Treatment of patients with DCA, or a biosimilar drug, could be a clinical option to increase the effectiveness of CAR T cell or allogeneic NK cell therapies.
Impact of the structure on the thermal burnout effect induced by microwave pulses of PIN limiter diodes
Authors: Zhao Jingtao , Chen Quanyou , Chen Zhidong , Chen Chaoyang , Zhao Zhenguo , Liu Zhong , Zhao Gang
Published: February 2022

Positive-intrinsic-negative (PIN) limiters are widely used to protect sensitive components from leakage power itself and adjacent high-power injection. Being the core of a PIN limiter, the PIN diode is possible to be burnt out by the external microwave pulses. Here, using a parallel computing program for semiconductor multi-physics effects designed by ourselves, we studied the influence of the thickness of the I layer and the anode diameter of the PIN diode on the maximum temperature change curve of the PIN diode limiter. The damage threshold criterion in the numerical simulation was first studied by comparing experimental results with simulation results. Then, we determined the impact of the structure on the thermal burnout effect induced by microwave pulses of PIN limiter diodes.
Endometriosis pain and epithelial neutrophil activating peptide-78 levels
Authors: Gardella Barbara , Dominoni Mattia , Gritti Andrea , Arrigo Anna , Antonucci Silvia , Carletti Giulia Vittoria , Musacchi Valentina , Pietrocola Giampiero
Published: February 2022

Endometriosis is a chronic gynecological disorder involved in the pathogenesis of chronic pelvic pain, based on a probable up regulation of the inflammatory system. The objective of the study is to investigate the peritoneal and serum levels of ENA-78 with the severity of endometriosis symptoms (dysmenorrhea, chronic pelvic pain and dyspareunia) using the visual analogue scale (VAS). This is a prospective case–control study that included 53 symptomatic women with evidence of endometriosis and 53 age-matched controls who underwent elective laparoscopic surgery for benign diseases. The concentration of ENA-78 was assessed in blood and peritoneal fluid samples in the follicular phase. In peritoneal fluid and plasma, the concentration of ENA-78 was significantly higher in cases than in controls (p < 0.001). A significant correlation was observed between peritoneal fluid ENA-78 levels and the severity of dysmenorrhea (Spearman Rho = 0.237; p = 0.014), and chronic pelvic pain (Spearman Rho = 0.220; p = 0.022) in endometriosis patients. Plasma levels ENA-78 showed a significant correlation with the severity (VAS score) of chronic pelvic pain (Spearman Rho = 0.270, p = 0.005 for cases), though a weak correlation was evident between plasma levels of ENA-78 and severity of dysmenorrhea (Spearman Rho = 0.083, p = 0.399 for cases). In conclusion, chronic pelvic pain in endometriosis is caused by changes of local and systemic activated chemokine patterns. These modifications involve the relationship between pro-inflammatory, angiogenic and angiostatic chemokines that modulate the severity of endometriosis associated symptoms.
Single-cell spatial architectures associated with clinical outcome in head and neck squamous cell carcinoma
Authors: Blise Katie E. , Sivagnanam Shamilene , Banik Grace L. , Coussens Lisa M. , Goecks Jeremy
Published: February 2022

There is increasing evidence that the spatial organization of cells within the tumor-immune microenvironment (TiME) of solid tumors influences survival and response to therapy in numerous cancer types. Here, we report results and demonstrate the applicability of quantitative single-cell spatial proteomics analyses in the TiME of primary and recurrent human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) tumors. Single-cell compositions of a nine patient, primary and recurrent (n = 18), HNSCC cohort is presented, followed by deeper investigation into the spatial architecture of the TiME and its relationship with clinical variables and progression free survival (PFS). Multiple spatial algorithms were used to quantify the spatial landscapes of immune cells within TiMEs and demonstrate that neoplastic tumor-immune cell spatial compartmentalization, rather than mixing, is associated with longer PFS. Mesenchymal (αSMA+) cellular neighborhoods describe distinct immune landscapes associated with neoplastic tumor-immune compartmentalization and improved patient outcomes. Results from this investigation are concordant with studies in other tumor types, suggesting that trends in TiME cellular heterogeneity and spatial organization may be shared across cancers and may provide prognostic value in multiple cancer types.
Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay
Authors: Narayanan Anoop , Narwal Manju , Majowicz Sydney A. , Varricchio Carmine , Toner Shay A. , Ballatore Carlo , Brancale Andrea , Murakami Katsuhiko S. , Jose Joyce
Published: February 2022

SARS-CoV-2 proteases Mpro and PLpro are promising targets for antiviral drug development. In this study, we present an antiviral screening strategy involving a novel in-cell protease assay, antiviral and biochemical activity assessments, as well as structural determinations for rapid identification of protease inhibitors with low cytotoxicity. We identified eight compounds with anti-SARS-CoV-2 activity from a library of 64 repurposed drugs and modeled at protease active sites by in silico docking. We demonstrate that Sitagliptin and Daclatasvir inhibit PLpro, and MG-101, Lycorine HCl, and Nelfinavir mesylate inhibit Mpro of SARS-CoV-2. The X-ray crystal structure of Mpro in complex with MG-101 shows a covalent bond formation between the inhibitor and the active site Cys145 residue indicating its mechanism of inhibition is by blocking the substrate binding at the active site. Thus, we provide methods for rapid and effective screening and development of inhibitors for blocking virus polyprotein processing as SARS-CoV-2 antivirals. Additionally, we show that the combined inhibition of Mpro and PLpro is more effective in inhibiting SARS-CoV-2 and the delta variant.
Bifidobacterium castoris strains isolated from wild mice show evidence of frequent host switching and diverse carbohydrate metabolism potential
Authors: Kujawska Magdalena , Raulo Aura , Millar Molly , Warren Fred , Baltrūnaitė Laima , Knowles Sarah C L , Hall Lindsay J
Published: February 2022

Members of the gut microbiota genus Bifidobacterium are widely distributed human and animal symbionts believed to exert beneficial effects on their hosts. However, in-depth genomic analyses of animal-associated species and strains are somewhat lacking, particularly in wild animal populations. Here, to examine patterns of host specificity and carbohydrate metabolism capacity, we sequenced whole genomes of Bifidobacterium isolated from wild-caught small mammals from two European countries (UK and Lithuania). Members of Bifidobacterium castoris, Bifidobacterium animalis and Bifodobacterium pseudolongum were detected in wild mice (Apodemus sylvaticus, Apodemus agrarius and Apodemus flavicollis), but not voles or shrews. B. castoris constituted the most commonly recovered Bifidobacterium (78% of all isolates), with the majority of strains only detected in a single population, although populations frequently harboured multiple co-circulating strains. Phylogenetic analysis revealed that the mouse-associated B. castoris clades were not specific to a particular location or host species, and their distribution across the host phylogeny was consistent with regular host shifts rather than host-microbe codiversification. Functional analysis, including in vitro growth assays, suggested that mouse-derived B. castoris strains encoded an extensive arsenal of carbohydrate-active enzymes, including putative novel glycosyl hydrolases such as chitosanases, along with genes encoding putative exopolysaccharides, some of which may have been acquired via horizontal gene transfer. Overall, these results provide a rare genome-level analysis of host specificity and genomic capacity among important gut symbionts of wild animals, and reveal that Bifidobacterium has a labile relationship with its host over evolutionary time scales.
A highly flexible Ni–Co MOF nanosheet coated Au/PDMS film based wearable electrochemical sensor for continuous human sweat glucose monitoring
Authors: Shu Yun , Shang Zhenjiao , Su Tong , Zhang Shenghao , Lu Qin , Xu Qin , Hu Xiaoya
Published: February 2022

The development of flexible substrate materials and nanomaterials with high electrochemical performance is of great significance for constructing efficient wearable electrochemical sensors for real-time health monitoring.
Osteogenic peptides in periodontal ligament stem cell-containing three-dimensional bioscaffolds promote bone healing
Authors: Cai Mingxiang , Liu Yaoyao , Tian Yinping , Liang Yan , Xu Zinan , Liu Fangchen , Lai Renfa , Zhou Zhiying , Liu Minyi , Dai Jian , Liu Xiangning
Published: February 2022

The oligopeptide SDSSD promotes the osteogenic differentiation of human periodontal ligament stem cells. The 3D bioscaffolds with SDSSD enhance bone formation and the repair effect of bone defects in mice by regulating the AKT signaling pathway.
Elliptic dichroism in strong-field ionization of atoms subjected to tailored laser fields
Authors: Becker Wilhelm , Milošević Dejan B.
Published: February 2022

Elliptic dichroism parameter (from −1 (blue) to +1 (yellow)) in strong-field ionization of argon by an ω–2ω BEOTC (ε = 0.4 and 0.6) field.
Dissociative electron attachment to 5-bromo-uracil: non-adiabatic dynamics on complex-valued potential energy surfaces
Authors: Cornetta Lucas M. , Martinez Todd J. , Varella Marcio T. do N.
Published: February 2022

A novel theoretical approach for calculating dissociative electron attachment cross section.
Plasmonic photothermal properties of silver nanoparticle grating films
Authors: Anuthum Siriporn , Hasegawa Fugo , Lertvachirapaiboon Chutiparn , Shinbo Kazunari , Kato Keizo , Ounnunkad Kontad , Baba Akira
Published: February 2022

A grating structure fabricated by AgNPs strongly enhances electric field intensity in the large area of the film, which results in higher heat generation.
A tetra Co(ii/iii) complex with an open cubane Co4O4 core and square-pyramidal Co(ii) and octahedral Co(iii) centres: bifunctional electrocatalytic activity towards water splitting at neutral pH
Authors: Srivastava Ankit Kumar , Mondal Arpan , Konar Sanjit , Pal Samudranil
Published: February 2022

A paramagnetic and redox active open cubane Co4O4 core containing complex [CoIICoIII(μ-OAc)(μ3-OH)(μ-L)]2 (L3− = ONONO-donor compartmental ligand) and its heterogeneous electrocatalytic activity for water splitting at neutral pH are reported.
Elucidation of the sorbent role in sorption thermodynamics of uranium(vi) on goethite
Authors: Kumar Sumit , Dumpala Rama Mohana Rao , Chandane Annapurna , Bahadur Jitendra
Published: February 2022

Calorimetric determination of U(vi) sorption enthalpy on goethite and the role of the sorbent in sorption thermodynamics.
Selenium concentration in herring from the Baltic Sea tracks decadal and spatial trends in external sources
Authors: Soerensen Anne L. , Feinberg Aryeh , Schartup Amina T.
Published: February 2022

We link selenium concentrations in herring muscle and liver spanning four decades and twenty stations along the Swedish coastline to spatio-temporal variability in deposition and riverine source loads.
Climate change influence on the levels and trends of persistent organic pollutants (POPs) and chemicals of emerging Arctic concern (CEACs) in the Arctic physical environment – a review
Authors: Hung Hayley , Halsall Crispin , Ball Hollie , Bidleman Terry , Dachs Jordi , De Silva Amila , Hermanson Mark , Kallenborn Roland , Muir Derek , Sühring Roxana , Wang Xiaoping , Wilson Simon
Published: February 2022

Direct and indirect effects of climate change influence contaminant sources, transport, re-distribution and circulation in the physical environment of the Arctic. Linkages of such observations to Arctic ecosystem exposure and effects are needed.
Occurrence and fate of chiral and achiral drugs in estuarine water – a case study of the Clyde Estuary, Scotland
Authors: Petrie Bruce , Moffat Colin F.
Published: February 2022

This is the most comprehensive enantiospecific study of chiral drugs in the estuarine environment. Notable differences were found in the enantiomeric composition of drugs between water samples and fish tissues.
Simultaneous prediction of trihalomethanes, haloacetic acids, haloacetonitriles and haloacetamides using simulated distribution system tests
Authors: Sfynia Chrysoula , Bond Tom , Kanda Rakesh , Templeton Michael R.
Published: February 2022

This study analysed the spatial and temporal occurrence of 29 disinfection by-products (DBPs) formed by chlorination and chloramination.
In vitrodigestion of protein and starch in sponge cakes formulated with pea (Pisum sativumL.) ingredients
Authors: Krause Svenja , Debon Stéphane , Pälchen Katharina , Jakobi Ralf , Rega Barbara , Bonazzi Catherine , Grauwet Tara
Published: February 2022

This study investigated thein vitrodigestion of purified pea fractions (protein isolate and starch) in sponge cakes when compared to unrefined pea flour and to the whole wheat flour and purified maize starch commonly used in the food industry.
Blue LED induced solvent-free multicomponent reactions among aryl diazoacetates, pyridine derivatives and maleimides: direct eco-friendly synthesis of densely functionalized itaconimides
Authors: Maiti Debajit , Das Ranajit , Prabakar Tejas , Sen Subhabrata
Published: February 2022

We report a multicomponent reaction involving pyridine and its derivatives, aryl diazoesters and N-alkylmaleimides, using a blue LED under neat (solvent-free) conditions and in the absence of any metal catalysts or bases at r. t. to generate densely substituted itaconimides.
Structures, solvatochromism, protonation and photoswitching of tetra-(ortho)substituted azobenzenes bearing 3,5-dimethoxy groups
Authors: Ramírez-Rave Sandra , Flores-Alamo Marcos , Yatsimirsky Anatoly K.
Published: February 2022

Di-ortho-methoxy azobenzenes demonstrate high basicity, the ability to bind metal ions in water and an inverted solvent effect on the rate of thermal cis-to-trans isomerization, which decreases on increase in the solvent polarity.
Expanding the interlamellar spacing of biomass-derived hybrids with intercalated nanotubes for enhanced oxygen reduction reaction
Authors: Sun Junting , Jin Jiaxiang , Yang Yukan , Wang Jing , Guo Junjie
Published: February 2022

An efficient method has been designed for creating mesopores in electrocatalysts using in situ grown CNTs.
Molecular locker probe enrichment of gene fusion variants from matched patient liquid biopsy specimens for magneto-bioelectrocatalytic nanosensing
Authors: Koo Kevin M. , Trau Matt
Published: February 2022

This work introduces a novel nanosensing technique using modified nucleic acid-based biotarget enrichment and magneto-bioelectrocatalytic cycling readout for analysis of three fusion mutant variants in matched plasma and urine specimens (n = 80).
Synthesis of colorless and high-refractive-index sulfoxide-containing polymers by the oxidation of poly(phenylene sulfide) derivatives
Authors: Watanabe Seigo , Takayama Teru , Nishio Hiromichi , Matsushima Kanta , Tanaka Yoko , Saito Seiya , Sun Yushun , Oyaizu Kenichi
Published: February 2022

A series of poly(phenylene sulfide) (PPS) derivatives can be bleached while maintaining high refractive indices, by partially incorporating sulfoxide bonds through their mCPBA oxidation, owing to the loss of lone pairs around the sulfide atoms.
High-efficiency solution-processed green thermally activated delayed fluorescence OLEDs using a polymer-small molecule mixed host
Authors: Cho Seunguk , Kwon Na Yeon , Kim Chai Won , Lee Hyoseong , Ha Jung Min , Kim Hyung Jong , Woo Han Young , Park Sungnam , Cho Min Ju , Choi Dong Hoon
Published: February 2022

A polymer and a small molecule were developed as a mixed host with an exciplex for high performance of green TADF OLEDs.