bluuebunny/crossref_metadata_2025 huggingface dataset:
Delayed subsidence of the Dead Sea shore due to hydro-meteorological changes
Authors: Vey Sibylle , Al-Halbouni D. , Haghighi M. Haghshenas , Alshawaf F. , Vüllers J. , Güntner A. , Dick G. , Ramatschi M. , Teatini P. , Wickert J. , Weber M.
Published: June 2021

Many studies show the sensitivity of our environment to manmade changes, especially the anthropogenic impact on atmospheric and hydrological processes. The effect on Solid Earth processes such as subsidence is less straightforward. Subsidence is usually slow and relates to the interplay of complex hydro-mechanical processes, thus making relations to atmospheric changes difficult to observe. In the Dead Sea (DS) region, however, climatic forcing is strong and over-use of fresh water is massive. An observation period of 3 years was thus sufficient to link the high evaporation (97 cm/year) and the subsequent drop of the Dead Sea lake level (− 110 cm/year), with high subsidence rates of the Earth’s surface (− 15 cm/year). Applying innovative Global Navigation Satellite System (GNSS) techniques, we are able to resolve this subsidence of the “Solid Earth” even on a monthly basis and show that it behaves synchronous to atmospheric and hydrological changes with a time lag of two months. We show that the amplitude and fluctuation period of ground deformation is related to poro-elastic hydro-mechanical soil response to lake level changes. This provides, to our knowledge, a first direct link between shore subsidence, lake-level drop and evaporation.
Risk of esophageal and gastric adenocarcinoma in men receiving androgen deprivation therapy for prostate cancer
Authors: Shore Richard , Yu Jingru , Ye Weimin , Lagergren Jesper , Rutegård Martin , Akre Olof , Stattin Pär , Lindblad Mats
Published: June 2021

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006–2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24–0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60–2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40–2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31–3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.
Reporter cell assay for human CD33 validated by specific antibodies and human iPSC-derived microglia
Authors: Wißfeld Jannis , Mathews Mona , Mossad Omar , Picardi Paola , Cinti Alessandro , Redaelli Loredana , Pradier Laurent , Brüstle Oliver , Neumann Harald
Published: June 2021

CD33/Sialic acid-binding Ig-like lectin 3 (SIGLEC3) is an innate immune receptor expressed on myeloid cells and mediates inhibitory signaling via tyrosine phosphatases. Variants of CD33 are associated with Alzheimer’s disease (AD) suggesting that modulation of CD33 signaling might be beneficial in AD. Hence, there is an urgent need for reliable cellular CD33 reporter systems. Therefore, we generated a CD33 reporter cell line expressing a fusion protein consisting of the extracellular domain of either human full-length CD33 (CD33M) or the AD-protective variant CD33ΔE2 (D2-CD33/CD33m) linked to TYRO protein tyrosine kinase binding protein (TYROBP/DAP12) to investigate possible ligands and antibodies for modulation of CD33 signaling. Application of the CD33-specific antibodies P67.6 and 1c7/1 to the CD33M-DAP12 reporter cells resulted in increased phosphorylation of the kinase SYK, which is downstream of DAP12. CD33M-DAP12 but not CD33ΔE2-DAP12 expressing reporter cells showed increased intracellular calcium levels upon treatment with CD33 antibody P67.6 and partially for 1c7/1. Furthermore, stimulation of human induced pluripotent stem cell-derived microglia with the CD33 antibodies P67.6 or 1c7/1 directly counteracted the triggering receptor expressed on myeloid cells 2 (TREM2)-induced phosphorylation of SYK and decreased the phagocytic uptake of bacterial particles. Thus, the developed reporter system confirmed CD33 pathway activation by CD33 antibody clones P67.6 and 1c7/1. In addition, data showed that phosphorylation of SYK by TREM2 activation and phagocytosis of bacterial particles can be directly antagonized by CD33 signaling.
Cell wall integrity is compromised under temperature stress in Schizosaccharomyces pombe expressing a valproic acid-sensitive vas4 mutant
Authors: Qiao Sen , Luo Xiaofang , Wang Hui , Fang Yue , Zhang Lili
Published: June 2021

Valproic acid (VPA) is widely used as a eutherapeutic and safe anticonvulsant drug, but the mechanism is not well elucidated. Histone deacetylases (HDACs) were first identified as direct targets of VPA. Many loss-of function mutants in S. pombe have been shown to be VPA sensitive but not sensitive to other HDAC inhibitors, such as sodium butyrate or trichostatin A (TSA). This difference suggests that there are multiple VPA target genes. In the current study, we isolated a VPA-sensitive (vas) mutant, vas4-1, and cloned the VPA target gene vas4+/vrg4+ by performing complementation experiments. The vas4+/vrg4+ gene encodes a putative Golgi GDP-mannose transporter, Vrg4, which is highly homologous with ScVrg4p. Physiological experiments indicated that SpVrg4p is involved in maintaining cell wall integrity (CWI) under high- or low-temperature stress. The results of a coimmunoprecipitation assay suggested that SpVrg4p may be transferred from the ER to the Golgi through SpGot1p loaded COPII vesicles, and both single and double mutations (S263C and A271V) in SpVrg4p compromised this transfer. Our results suggested that CWI in S. pombe is compromised under temperature stress by the VPA-sensitive vas4 mutant.
Prediction of fear of falling at 6 months after stroke based on 279 individuals from the Fall Study of Gothenburg
Authors: Hussain Netha , Hansson Per-Olof , Persson Carina U.
Published: June 2021

The early identification of individuals at risk of fear of falling after stroke is crucial in order to individualise preventive actions and interventions. The aim of this study was to identify the incidence of, and baseline factors in acute stroke that are associated with fear of falling at 6 months after stroke. Fear of falling was assessed by one question, which was answered by 279 of 452 eligible individuals. Univariable and multivariable logistic regression analyses were performed to determine the factors that were associated with fear of falling. The dependent variable was fear of falling at 6 months after stroke. The independent variables were related to function, activity and participation, including personal and environmental factors. Fear of falling was reported by 117 (41.9%) individuals. Poor postural control in acute stroke, measured using the modified version of the Postural Assessment Scale for Stroke Patients (odds ratio [OR]: 2.60, 95% confidence interval [CI]: 1.26–5.36), and being physically inactive prior to the stroke, measured using the Saltin-Grimby Physical Activity Scale (OR: 2.04, 95% CI: 1.01–4.12), were found to be associated with fear of falling at 6 months after stroke. The findings in this study are useful in clinical practice to optimise rehabilitation after stroke.
Comparison of the effectiveness of Martin’s equation, Friedewald’s equation, and a Novel equation in low-density lipoprotein cholesterol estimation
Authors: Song Youhyun , Lee Hye Sun , Baik Su Jung , Jeon Soyoung , Han Donghee , Choi Su-Yeon , Chun Eun Ju , Han Hae-Won , Park Sung Hak , Sung Jidong , Jung Hae Ok , Lee Ji Won , Chang Hyuk-Jae
Published: June 2021

Low-density-lipoprotein cholesterol (LDL-C) is the main target in atherosclerotic cardiovascular disease (ASCVD). We aimed to validate and compare a new LDL-C estimation equation with other well-known equations. 177,111 samples were analysed from two contemporary population-based cohorts comprising asymptomatic Korean adults who underwent medical examinations. Performances of the Friedewald (FLDL), Martin (MLDL), and Sampson (SLDL) equations in estimating direct LDL-C by homogenous assay were assessed by measures of concordance (R2, RMSE, and mean absolute difference). Analyses were performed according to various triglyceride (TG) and/or LDL-C strata. Secondary analyses were conducted within dyslipidaemia populations of each database. MLDL was superior or at least similar to other equations regardless of TG/LDL-C, in both the general and dyslipidaemia populations (RMSE = 11.45/9.20 mg/dL; R2 = 0.88/0.91; vs FLDL: RMSE = 13.66/10.42 mg/dL; R2 = 0.82/0.89; vs SLDL: RMSE = 12.36/9.39 mg/dL; R2 = 0.85/0.91, per Gangnam Severance Hospital Check-up/Korea Initiatives on Coronary Artery Calcification data). MLDL had a slight advantage over SLDL with the lowest MADs across the full spectrum of TG levels, whether divided into severe hyper/non-hyper to moderate hypertriglyceridaemia samples or stratified by 100-mg/dL TG intervals, even up to TG values of 500–600 mg/dL. MLDL may be a readily adoptable and cost-effective alternative to direct LDL-C measurement, irrespective of dyslipidaemia status. In populations with relatively high prevalence of mild-to-moderate hypertriglyceridaemia, Martin’s equation may be optimal for LDL-C and ASCVD risk estimation.
Concept for using magnetic particle imaging for intraoperative margin analysis in breast-conserving surgery
Authors: Mason Erica E. , Mattingly Eli , Herb Konstantin , Śliwiak Monika , Franconi Sofia , Cooley Clarissa Zimmerman , Slanetz Priscilla J. , Wald Lawrence L.
Published: June 2021

Breast-conserving surgery (BCS) is a commonly utilized treatment for early stage breast cancers but has relatively high reexcision rates due to post-surgical identification of positive margins. A fast, specific, sensitive, easy-to-use tool for assessing margins intraoperatively could reduce the need for additional surgeries, and while many techniques have been explored, the clinical need is still unmet. We assess the potential of Magnetic Particle Imaging (MPI) for intraoperative margin assessment in BCS, using a passively or actively tumor-targeted iron oxide agent and two hardware devices: a hand-held Magnetic Particle detector for identifying residual tumor in the breast, and a small-bore MPI scanner for quickly imaging the tumor distribution in the excised specimen. Here, we present both hardware systems and demonstrate proof-of-concept detection and imaging of clinically relevant phantoms.
Annual climatic fluctuations and short-term genetic variation in the eastern spadefoot toad
Authors: Cohen Orly , Ram Yoav , Hadany Lilach , Gafny Sarig , Geffen Eli
Published: June 2021

In addition to variations on the spatial scale, short- and long-term temporal variations, too, can impose intense selection on the overall genetic diversity and composition of a population. We hypothesized that the allelic composition in populations of the eastern spadefoot toad (Pelobates syriacus) would change among successive years in accordance with the short-term changes in environmental conditions. Surprisingly, the effect of short-term climate fluctuations on genetic composition have rarely been addressed in the literature, and to our knowledge the effect of annual climatic fluctuations have not been considered meaningful. Our findings show that climatic variation among successive years, primarily the amount of rainfall and rainy days, can significantly alter both microsatellite allelic composition and diversity. We suggest that environmental (i.e. fluctuating) selection is differential across the globe, and that its intensity is expected to be greatest in regions where short-term climatic conditions are least stable.
Nonalcoholic fatty liver disease is associated with the development of obstructive sleep apnea
Authors: Chung Goh Eun , Cho Eun Ju , Yoo Jeong-Ju , Chang Young , Cho Yuri , Park Sang-Hyun , Shin Dong Wook , Han Kyungdo , Yu Su Jong
Published: June 2021

Increasing evidence suggests that obstructive sleep apnea (OSA) is a metabolic syndrome-related disease; however, the association between nonalcoholic fatty liver disease (NAFLD) and OSA is not firmly established. In this study, we investigated the relationship between NAFLD and OSA in a general population drawn from a nationwide population-based cohort. Data from the Korean National Health Insurance System between January 2009 and December 2009 were analyzed using Cox proportional hazards model. NAFLD was defined as a fatty liver index (FLI) ≥ 60 in patients without excessive alcohol consumption (who were excluded from the study). Newly diagnosed OSA during follow-up was identified using claims data. Among the 8,116,524 participants, 22.6% had an FLI score of 30–60 and 11.5% had an FLI ≥ 60. During median follow-up of 6.3 years, 45,143 cases of incident OSA occurred. In multivariable analysis, the risk of OSA was significantly higher in the higher FLI groups (adjusted hazard ratio [aHR] 1.15, 95% confidence interval [CI] 1.12–1.18 for FLI 30–60 and aHR 1.21, 95% CI 1.17–1.26 for FLI ≥ 60). These findings were consistent regardless of body mass index and presence of abdominal obesity. In conclusion, a high FLI score may help identify individuals with a high risk of OSA. Understanding the association between NAFLD and OSA may have clinical implications for risk-stratification of individuals with NAFLD.
Treatment patterns and appropriateness of antipsychotic prescriptions in patients with schizophrenia
Authors: Gamón Verónica , Hurtado Isabel , Salazar-Fraile José , Sanfélix-Gimeno Gabriel
Published: June 2021

Schizophrenia is a chronic mental condition presenting a wide range of symptoms. Although it has a low prevalence compared to other mental conditions, it has a negative impact on social and occupational functions. This study aimed to assess the appropriateness of antipsychotic medications administered to schizophrenic patients and describe current treatment patterns for schizophrenia. A retrospective cohort study was conducted in all patients over the age of 15 with an active diagnosis of schizophrenia and treated with antipsychotics between 2008 and 2013 in the Valencia region. A total of 19,718 patients were eligible for inclusion. The main outcome assessed was inappropriateness of the pharmacotherapeutic management, including polypharmacy use. Altogether, 30.4% of patients received antipsychotic polypharmacy, and 6.8% were prescribed three or more antipsychotics. Overdosage affected 318 individuals (1.6%), and 21.5% used concomitant psychotropics without an associated psychiatric diagnosis. Women and people with a comorbid condition like anxiety or depression were less likely to receive antipsychotic polypharmacy. In contrast, increased polypharmacy was associated with concomitant treatment with other psychoactive drugs, and only in user on maintenance therapy, with more visits to the mental health hospital. Overall, we observed a high level of inappropriateness in antipsychotic prescriptions. Greater adherence to guidelines could maximize the benefits of antipsychotic medications while minimizing risk of adverse effects.
Expansion of inflammatory monocytes in periphery and infiltrated into thyroid tissue in Graves’ disease
Authors: Chen Xinxin , Wang Yanqiu , Qi Yicheng , Yan Jiqi , Huang Fengjiao , Zhou Mengxi , Wang Weiqing , Ning Guang , Zhou Yulin , Wang Shu
Published: June 2021

Monocytes are important mediators of immune system and are reported to be altered in autoimmune disorders. Little is known about the pathological role of monocytes in Graves’ disease (GD). Thus, we investigated monocytes in periphery and thyroid tissue in GD. Untreated GD patients were enrolled and followed up until remission. Monocytes were significantly increased and positively correlated with anti-thyrotropin receptor antibody (TRAb) in untreated GD (rcounts = 0.269, P < 0.001; rpercentage = 0.338, P < 0.001). Flow cytometry showed CD14++ CD16+ monocytes were increased and CD14++ CD16- monocytes were decreased in untreated GD (both P < 0.001). Skewed monocyte subsets were recovered in GD with remission. Serum B cell-activating factor (BAFF) was positively correlated with TRAb (r = 0.384 and P = 0.001). CD14++ CD16+ monocytes expressed higher level of BAFF in untreated GD (P < 0.05). The frequency of CD14+ monocytes and CD14+ CD16+ monocytes were significantly higher in GD thyroid tissue than in normal thyroid tissue (both P < 0.001). Our study suggested CD14++ CD16+ monocytes were significantly expanded and involved in the production of TRAb via secreting a higher level of BAFF in periphery. Besides, monocytes infiltrated into thyroid tissue and thus could serve as an important participant in GD pathogenesis.
The effect of protein mutations on drug binding suggests ensuing personalised drug selection
Authors: Wan Shunzhou , Kumar Deepak , Ilyin Valentin , Al Homsi Ussama , Sher Gulab , Knuth Alexander , Coveney Peter V.
Published: June 2021

The advent of personalised medicine promises a deeper understanding of mechanisms and therefore therapies. However, the connection between genomic sequences and clinical treatments is often unclear. We studied 50 breast cancer patients belonging to a population-cohort in the state of Qatar. From Sanger sequencing, we identified several new deleterious mutations in the estrogen receptor 1 gene (ESR1). The effect of these mutations on drug treatment in the protein target encoded by ESR1, namely the estrogen receptor, was achieved via rapid and accurate protein–ligand binding affinity interaction studies which were performed for the selected drugs and the natural ligand estrogen. Four nonsynonymous mutations in the ligand-binding domain were subjected to molecular dynamics simulation using absolute and relative binding free energy methods, leading to the ranking of the efficacy of six selected drugs for patients with the mutations. Our study shows that a personalised clinical decision system can be created by integrating an individual patient’s genomic data at the molecular level within a computational pipeline which ranks the efficacy of binding of particular drugs to variant proteins.
Serum anti-AP3D1 antibodies are risk factors for acute ischemic stroke related with atherosclerosis
Authors: Li Shu-Yang , Yoshida Yoichi , Kobayashi Eiichi , Kubota Masaaki , Matsutani Tomoo , Mine Seiichiro , Machida Toshio , Maezawa Yoshiro , Takemoto Minoru , Yokote Koutaro , Kobayashi Yoshio , Takizawa Hirotaka , Sata Mizuki , Yamagishi Kazumasa , Iso Hiroyasu , Sawada Norie , Tsugane Shoichiro , Kobayashi Sohei , Matsushita Kazuyuki , Nomura Fumio , Matsubara Hisahiro , Sumazaki Makoto , Ito Masaaki , Yajima Satoshi , Shimada Hideaki , Iwase Katsuro , Ashino Hiromi , Wang Hao , Goto Kenichiro , Tomiyoshi Go , Shinmen Natsuko , Nakamura Rika , Kuroda Hideyuki , Iwadate Yasuo , Hiwasa Takaki
Published: June 2021

Atherosclerosis has been considered as the main cause of morbidity, mortality, and disability worldwide. The first screening for antigen markers was conducted using the serological identification of antigens by recombinant cDNA expression cloning, which has identified adaptor-related protein complex 3 subunit delta 1 (AP3D1) as an antigen recognized by serum IgG antibodies of patients with atherosclerosis. Serum antibody levels were examined using the amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) using a recombinant protein as an antigen. It was determined that the serum antibody levels against AP3D1 were higher in patients with acute ischemic stroke (AIS), transient ischemic attack, diabetes mellitus (DM), cardiovascular disease, chronic kidney disease (CKD), esophageal squamous cell carcinoma (ESCC), and colorectal carcinoma than those in the healthy donors. The area under the curve values of DM, nephrosclerosis type of CKD, and ESCC calculated using receiver operating characteristic curve analysis were higher than those of other diseases. Correlation analysis showed that the anti-AP3D1 antibody levels were highly associated with maximum intima-media thickness, which indicates that this marker reflected the development of atherosclerosis. The results of the Japan Public Health Center-based Prospective Study indicated that this antibody marker is deemed useful as risk factors for AIS.
Long-term cancer survival prediction using multimodal deep learning
Authors: Vale-Silva Luís A. , Rohr Karl
Published: June 2021

The age of precision medicine demands powerful computational techniques to handle high-dimensional patient data. We present MultiSurv, a multimodal deep learning method for long-term pan-cancer survival prediction. MultiSurv uses dedicated submodels to establish feature representations of clinical, imaging, and different high-dimensional omics data modalities. A data fusion layer aggregates the multimodal representations, and a prediction submodel generates conditional survival probabilities for follow-up time intervals spanning several decades. MultiSurv is the first non-linear and non-proportional survival prediction method that leverages multimodal data. In addition, MultiSurv can handle missing data, including single values and complete data modalities. MultiSurv was applied to data from 33 different cancer types and yields accurate pan-cancer patient survival curves. A quantitative comparison with previous methods showed that Multisurv achieves the best results according to different time-dependent metrics. We also generated visualizations of the learned multimodal representation of MultiSurv, which revealed insights on cancer characteristics and heterogeneity.
Constrained G4 structures unveil topology specificity of known and new G4 binding proteins
Authors: Pipier A. , Devaux A. , Lavergne T. , Adrait A. , Couté Y. , Britton S. , Calsou P. , Riou J. F. , Defrancq E. , Gomez D.
Published: June 2021

G-quadruplexes (G4) are non-canonical secondary structures consisting in stacked tetrads of hydrogen-bonded guanines bases. An essential feature of G4 is their intrinsic polymorphic nature, which is characterized by the equilibrium between several conformations (also called topologies) and the presence of different types of loops with variable lengths. In cells, G4 functions rely on protein or enzymatic factors that recognize and promote or resolve these structures. In order to characterize new G4-dependent mechanisms, extensive researches aimed at identifying new G4 binding proteins. Using G-rich single-stranded oligonucleotides that adopt non-controlled G4 conformations, a large number of G4-binding proteins have been identified in vitro, but their specificity towards G4 topology remained unknown. Constrained G4 structures are biomolecular objects based on the use of a rigid cyclic peptide scaffold as a template for directing the intramolecular assembly of the anchored oligonucleotides into a single and stabilized G4 topology. Here, using various constrained RNA or DNA G4 as baits in human cell extracts, we establish the topology preference of several well-known G4-interacting factors. Moreover, we identify new G4-interacting proteins such as the NELF complex involved in the RNA-Pol II pausing mechanism, and we show that it impacts the clastogenic effect of the G4-ligand pyridostatin.
Noncytotoxic silver nanoparticles as a new antimicrobial strategy
Authors: Skóra Bartosz , Krajewska Urszula , Nowak Anna , Dziedzic Andrzej , Barylyak Adriana , Kus-Liśkiewicz Małgorzata
Published: June 2021

Drug-resistance of bacteria is an ongoing problem in hospital treatment. The main mechanism of bacterial virulency in human infections is based on their adhesion ability and biofilm formation. Many approaches have been invented to overcome this problem, i.e. treatment with antibacterial biomolecules, which have some limitations e.g. enzymatic degradation and short shelf stability. Silver nanoparticles (AgNPs) may be alternative to these strategies due to their unique and high antibacterial properties. Herein, we report on yeast Saccharomyces cerevisiae extracellular-based synthesis of AgNPs. Transmission electron microscopy (TEM) revealed the morphology and structure of the metallic nanoparticles, which showed a uniform distribution and good colloid stability, measured by hydrodynamic light scattering (DLS). The energy dispersive X-ray spectroscopy (EDS) of NPs confirms the presence of silver and showed that sulfur-rich compounds act as a capping agent being adsorbed on the surface of AgNPs. Antimicrobial tests showed that AgNPs inhibit the bacteria growth, while have no impact on fungi growth. Moreover, tested NPs was characterized by high inhibitory potential of bacteria biofilm formation but also eradication of established biofilms. The cytotoxic effect of the NPs on four mammalian normal and cancer cell lines was tested through the metabolic activity, cell viability and wound-healing assays. Last, but not least, ability to deep penetration of the silver colloid to the root canal was imaged by scanning electron microscopy (SEM) to show its potential as the material for root-end filling.
Tumor perfusion evaluation using dynamic contrast-enhanced ultrasound after electrochemotherapy and IL-12 plasmid electrotransfer in murine melanoma
Authors: Brloznik Maja , Boc Nina , Cemazar Maja , Sersa Gregor , Bosnjak Masa , Brezar Simona Kranjc , Pavlin Darja
Published: June 2021

Electrochemotherapy with bleomycin (ECT BLM) is an effective antitumor treatment already used in clinical oncology. However, ECT alone is still considered a local antitumor therapy because it cannot induce systemic immunity. When combined with adjuvant gene electrotransfer of plasmid DNA encoding IL-12 (GET pIL-12), the combined therapy leads to a systemic effect on untreated tumors and distant metastases. Although the antitumor efficacy of both therapies alone or in combination has been demonstrated at both preclinical and clinical levels, data on the predictors of efficacy of the treatments are still lacking. Herein, we evaluated the results of dynamic contrast-enhanced ultrasound (DCE-US) as a predictive factor for ECT BLM and GET pIL-12 in murine melanoma. Melanoma B16F10 tumors grown in female C57Bl/6NCrl mice were treated with GET pIL-12 and ECT BLM. Immediately after therapy, 6 h and 1, 3, 7 and 10 days later, tumors were examined by DCE-US. Statistical analysis was performed to inspect the correlation between tumor doubling time (DT) and DCE-US measurements using semilinear regression models and Bland–Altman plots. Therapeutic groups in which DCE-US showed reduced tumor perfusion had longer tumor DTs. It was confirmed that the DCE-US parameter peak enhancement (PE), reflecting relative blood volume, had predictive value for the outcome of therapy: larger PE correlated with shorter DT. In addition, perfusion heterogeneity was also associated with outcome: tumors that had more heterogeneous perfusion had faster growth, i.e., shorter DTs. This study demonstrates that DCE-US can be used as a method to predict the efficacy of electroporation-based treatment.
Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer
Authors: Woock Alicia E. , Grible Jacqueline M. , Olex Amy L. , Harrell J. Chuck , Zot Patricija , Idowu Michael , Clevenger Charles V.
Published: June 2021

In breast cancer, prolactin-induced activation of the transcription factor STAT5a results from the phosphorylation of STAT5a tyrosine residue 694. However, its role in mammary oncogenesis remains an unsettled debate as STAT5a exhibits functional dichotomy with both pro-differentiative and pro-proliferative target genes. Phosphorylation of STAT5a serine residues, S726 and S780, may regulate STAT5a in such a way to underlie this duality. Given hematopoiesis studies showing phospho-serine STAT5a as necessary for transformation, we hypothesized that serine phosphorylation regulates STAT5a activity to contribute to its role in mammary oncogenesis, specifically in luminal breast cancer. Here, phosphorylation of S726-, S780-, and Y694-STAT5a in response to prolactin in MCF7 luminal breast cancer cells was investigated with STAT5a knockdown and rescue with Y694F-, S726A-, or S780A-STAT5a, where the phospho-sites were mutated. RNA-sequencing and subsequent Ingenuity Pathway Analysis predicted that loss of each phospho-site differentially affected both prolactin-induced gene expression as well as functional pathways of breast cancer (e.g. cell survival, proliferation, and colony formation). In vitro studies of anchorage-independent growth and proliferation confirmed distinct phenotypes: whereas S780A-STAT5a decreased clonogenicity, S726A-STAT5a decreased proliferation in response to prolactin compared to wild type STAT5a. Collectively, these studies provide novel insights into STAT5a activation in breast cancer pathogenesis.
Dynamic anti-plane behavior of rare earth giant magnetostrictive medium with a circular cavity defect in semi-space
Authors: Liu Zhiwei , Qi Hui
Published: June 2021

An analytical solution to the anti-plane dynamics problem of semi-space rare earth giant magnetostrictive media with circular cavity defects near the horizontal boundary under the action of SH wave is studied. Based on the Helmholtz theorem and the theory of complex function, the elastic-magnetic dynamic equation of magnetostrictive medium is established, and the semi-space incident wave field is written. In addition, based on the theory of complex function and the method of wave function expansion, the expression of the wave function of the scattered displacement field and the corresponding magnetic potential of the scattered wave under the condition of no stress and magnetic insulation of the horizontal boundary are obtained. Then, based on the conditions of free boundary stress, continuous magnetic induction intensity and continuous magnetic potential around the circular cavity, the infinite linear algebraic equations are established. Finally, the analytical expressions of dynamic stress concentration factor and magnetic field intensity concentration factor around circular cavity in semi-space rare earth giant magnetostrictive medium are obtained. Numerical examples show that the analysis results depend on the following parameters: permeability, dimensional-piezomagnetic coefficient, frequency of the incident wave, incident angle, distance between the circular cavity and horizontal boundary. These results have certain reference value for the study of non-destructive testing and failure analysis of rare earth giant magnetostrictive materials.
Zebrafish behavior feature recognition using three-dimensional tracking and machine learning
Authors: Yang Peng , Takahashi Hiro , Murase Masataka , Itoh Motoyuki
Published: June 2021

In this work, we aim to construct a new behavior analysis method by using machine learning. We used two cameras to capture three-dimensional (3D) tracking data of zebrafish, which were analyzed using fuzzy adaptive resonance theory (FuzzyART), a type of machine learning algorithm, to identify specific behavioral features. The method was tested based on an experiment in which electric shocks were delivered to zebrafish and zebrafish swimming was tracked in 3D simultaneously to find electric shock-associated behaviors. By processing the obtained data with FuzzyART, we discovered that distinguishing behaviors were statistically linked to the electric shock based on the machine learning algorithm. Moreover, our system could accept user-supplied data for detection and quantitative analysis of the behavior features, such as the behavior features defined by the 3D tracking analysis above. This system could be applied to discover new distinct behavior features in mutant zebrafish and used for drug administration screening and cognitive ability tests of zebrafish in the future.
Serum neurofilament light chain as a severity marker for spinocerebellar ataxia
Authors: Shin Hye-Rim , Moon Jangsup , Lee Woo-Jin , Lee Han Sang , Kim Eun Young , Shin Seoyi , Lee Soon-Tae , Jung Keun-Hwa , Park Kyung-Il , Jung Ki-Young , Lee Sang Kun , Chu Kon
Published: June 2021

Since the serum neurofilament light (NfL) chain is known as a promising biomarker in neurodegenerative diseases, we aimed to evaluate serum NfL as a biomarker indicating neuronal damage in autosomal-dominant (AD) spinocerebellar ataxia (SCA). We reviewed patients diagnosed with AD SCA in the outpatient clinic of Seoul National University Hospital’s (SNUH) Department of Neurology between May and August of 2019. We reviewed the demographic data, clinical characteristics, Scale for the Assessment and Rating of Ataxia (SARA) score, and brain magnetic resonance imaging (MRI) scans. The serum NfL was measured by electrochemiluminescence (ECL) immunoassay. Forty-nine patients with AD SCA were reviewed and their serum NfL level was determined. The median serum NfL level (109.5 pg/mL) was higher than control (41.1 pg/mL) (p-value < 0.001). Among the AD SCA patients, there was a positive correlation between the serum NfL level and the trinucleotide repeat number (r = 0.47, p-value = 0.001), disease duration (r = 0.35, p-value = 0.019), disease duration/age × trinucleotide repeat number (r = 0.330, p-value = 0.021), and SARA score (n = 33; r = 0.37, p-value = 0.033). This study shows that serum NfL is elevated in AD SCA patients and correlates with clinical severity.
The maintenance of microbial community in human fecal samples by a cost effective preservation buffer
Authors: Wu Chongming , Chen Tianda , Xu Wenyi , Zhang Tingting , Pei Yuwei , Yang Yanan , Zhang Fang , Guo Hao , Wang Qingshi , Wang Li , Zhao Bowen
Published: June 2021

In the burgeoning microbiome field, powerful sequencing approaches and accompanied bioanalytical methods have made tremendous contributions to the discoveries of breakthroughs, which favor to unravel the intimate interplay between gut microbiota and human health. The proper preservation of samples before being processed is essential to guarantee the authenticity and reliability of microbiome studies. Hence, the development of preservation methods is extremely important to hold samples eligible for the consequent analysis, especially population cohort-based investigations or those spanning species or geography, which frequently facing difficulties in suppling freezing conditions. Although there are several commercial products available, the exploration of cost-efficient and ready-to-use preservation methods are still in a large demand. Here, we performed shotgun metagenomic sequencing and demonstrated that microbial consortia in human fecal samples were substantially preserved within a temporary storage of 4 h, independent of the storage temperature. We also verified a previous reported self-made preservation buffer (PB buffer) could not only preserve fecal microbiota at room temperature up to 4 weeks but also enable samples to endure a high temperature condition which mimics temperature variations in summer logistics. Moreover, PB buffer exhibited suitability for human saliva as well. Collectively, PB buffer may be a valuable choice to stabilize samples if neither freezing facilities nor liquid nitrogen is available.
Experimental study on the ratio model of similar materials in the simulation test of coal and gas outburst
Authors: Sun Peng , Sun Haitao , Lin Fujin , Yang Xuelin , Jiang Wangang , Wu Winbin , Jia Quanmin
Published: June 2021

To obtain the similar materials with specific physical and mechanical parameters and adsorption and desorption indexes used in coal and gas outburst simulation tests, pulverized coal was selected as aggregate, and sodium humate was selected as cementing agent and river sand was selected as auxiliary materials. Based on this, orthogonal tests with 6 factors and 5 levels were designed, and the tests of weighing, uniaxial compression, firmness, adsorption and desorption were carried out. The parameters such as density, uniaxial compressive strength, elastic modulus, firmness coefficient and adsorption–desorption index of similar materials with different ratios were obtained, and the sensitivity of each factor was analyzed by range analysis. The influence of various factors on the similar materials was studied, and the ratio model of similar materials was obtained. The reliability of the model was verified, and a complete method for determining the ratio model of similar materials of outburst coal was put forward. The results show that the density of the similar materials increases with the river sand content, and the uniaxial compressive strength and elastic modulus increase significantly with the pulverized coal ratio and sodium humate content, and the firmness coefficient increases linearly with the pulverized coal ratio. The adsorption constant increases linearly with the sodium humate content, while the adsorption constant b decreases linearly with the sodium humate content. The initial elution rate Δp of similar materials increases at first and then decreases with the increase of sodium humate content.
Refined premature chromosome condensation (G0-PCC) with cryo-preserved mitotic cells for rapid radiation biodosimetry
Authors: Yadav Usha , Bhat Nagesh N. , Shirsaath Kapil B. , Mungse Utkarsha S. , Sapra Balvinder K.
Published: June 2021

Mitotic cell fusion induced Premature Chromosome Condensation (G0-PCC) assay in human lymphocytes allows rapid detection of cytogenetic damage in interphase stage, within few hours after blood collection. Hence, it is the most suitable method for rapid and high dose biodosimetry. Mitotic cells, used for G0-PCC could be either freshly isolated or previously cryo-preserved. However, under emergency scenarios, only cryo-preserved cells can be relied upon, fresh isolation will only delay the process by 18–24 h. Impact of cryopreservation on mitotic cells and their efficacy to induce PCC are not reported. In the present study, we investigated effect of cryopreservation on mitotic cells and refined the parameters for G0-PCC. More than 95% of the cells were recoverable after 4 months of cryopreservation, within 20 min recovery at 37 °C, without significant change in the mitotic index or viability. Recovered mitotic cells have shown mitotic index of 89 ± 4% and viability of 90 ± 4%, similar to that of freshly isolated cells. Decrease in metaphases was observed within 40 min after recovery as the mitotic cells progressed through cell cycle and reduced to 21% at 1 h. Nevertheless, in presence of Colcemid, the cells progressed slowly and considerably high metaphase index (60%) persisted up to ~ 2 h. The recovered cells efficiently fused with lymphocytes and induced PCC. Average PCC index varied from 10 to 20%, which did not change with cryopreservation duration. Post fusion incubation duration of 2 h was found to be optimum for proper chromosome condensation. In conclusion, use of cryo-preserved mitotic cells is the most practical approach for rapid biodosimetry. The cells can be recovered quickly and efficiently without alteration in viability or mitotic index. Recovered cells are fully competent to induce G0-PCC.
Mendelian randomization analysis of arsenic metabolism and pulmonary function within the Hispanic Community Health Study/Study of Latinos
Authors: Scannell Bryan Molly , Sofer Tamar , Afshar Majid , Mossavar-Rahmani Yasmin , Hosgood H. Dean , Punjabi Naresh M. , Zeng Donglin , Daviglus Martha L. , Argos Maria
Published: June 2021

Arsenic exposure has been linked to poor pulmonary function, and inefficient arsenic metabolizers may be at increased risk. Dietary rice has recently been identified as a possible substantial route of exposure to arsenic, and it remains unknown whether it can provide a sufficient level of exposure to affect pulmonary function in inefficient metabolizers. Within 12,609 participants of HCHS/SOL, asthma diagnoses and spirometry-based measures of pulmonary function were assessed, and rice consumption was inferred from grain intake via a food frequency questionnaire. After stratifying by smoking history, the relationship between arsenic metabolism efficiency [percentages of inorganic arsenic (%iAs), monomethylarsenate (%MMA), and dimethylarsinate (%DMA) species in urine] and the measures of pulmonary function were estimated in a two-sample Mendelian randomization approach (genotype information from an Illumina HumanOmni2.5-8v1-1 array), focusing on participants with high inferred rice consumption. Among never-smoking high inferred consumers of rice (n = 1395), inefficient metabolism was associated with past asthma diagnosis and forced vital capacity below the lower limit of normal (LLN) (OR 1.40, p = 0.0212 and OR 1.42, p = 0.0072, respectively, for each percentage-point increase in %iAs; OR 1.26, p = 0.0240 and OR 1.24, p = 0.0193 for %MMA; OR 0.87, p = 0.0209 and OR 0.87, p = 0.0123 for the marker of efficient metabolism, %DMA). Among ever-smoking high inferred consumers of rice (n = 1127), inefficient metabolism was associated with peak expiratory flow below LLN (OR 1.54, p = 0.0108/percentage-point increase in %iAs, OR 1.37, p = 0.0097 for %MMA, and OR 0.83, p = 0.0093 for %DMA). Less efficient arsenic metabolism was associated with indicators of pulmonary dysfunction among those with high inferred rice consumption, suggesting that reductions in dietary arsenic could improve respiratory health.
Mining chemical information in Swedish wastewaters for simultaneous assessment of population consumption, treatment efficiency and environmental discharge of illicit drugs
Authors: Haalck Inga , Löffler Paul , Baduel Christine , Wiberg Karin , Ahrens Lutz , Lai Foon Yin
Published: June 2021

Consumption of illicit drugs poses health risks to the public and environment. Knowledge on their usage helps better implementations of intervention strategies to reduce drug-related harms in the society and also policies to limit their releases as emerging contaminants to recipient environments. This study aimed to investigate from the daily consumption to treatment efficiency and subsequent discharge of illicit drugs by the Swedish urban populations based on simultaneous collection and analysis of influent and effluent wastewater. Two different weekly monitoring campaigns showed similar drug prevalence in Stockholm and Uppsala, with amphetamine as the most popular drug. Almost all target drug residues were still measurable in effluent wastewater. High removal efficiencies (> 94%) were observed for amphetamine, cocaine and benzoylecgonine, whereas ketamine, 3,4-methylenedioxymethamphetamine (MDMA), mephedrone and methamphetamine were the least removed substances (< 64%), with the highest discharge observed for MDMA in both catchments (~ 3.0 g/day in Uppsala; ~ 18 g/day in Stockholm). Our study provides new insights into short-term changes in the use and related discharge of illicit drugs by urban populations. Such wastewater monitoring can provide useful information to public health, forensic and environmental authorities in planning future intervention and regulation policies.
Analysis of strength property and pore characteristics of Taihang limestone using X-ray computed tomography at high temperatures
Authors: Liu Shi , Huang Zhe
Published: June 2021

Rising temperature will cause the changes of pore characteristics and strength property in rock. This research takes the limestone produced in Taihang Mountains as the research object, and performs high-temperature treatment within 25–1000 °C. The high-resolution X-ray computed tomography (CT) scanning test method is used to visually reconstruct the three-dimensional image of the sample, and obtain the spatial distribution status of the mesoscopic parameters of the bones, pores/cracks, etc. The results show that when the temperature exceeded 700 °C, the samples appeared milky white in appearance and as the temperature increased, the color gradually turned white, macroscopic cracks began to appear on the surface, while the meso-pores connected rapidly, reflecting a typical progressive destruction process from inside to outside. The change law of volume porosity with temperature has a consistent trend with that of the apparent morphology of the sample. Similarly, the mechanical test results suggest that 700 °C is also the turning temperature for strength deterioration and brittle-plastic transformation of sample. Based on the results of high-temperature test, CT test and mechanical test, there are enough evidences to show that, for the limestone sample, 700 °C is probably to be the mutation temperature of physical–mechanical behavior.
Patterns of combustible and electronic cigarette use during pregnancy and associated pregnancy outcomes
Authors: Regan Annette K. , Pereira Gavin
Published: June 2021

Although pregnant smokers may perceive electronic cigarettes (e-cigarettes) as safe alternatives to smoking combustible cigarettes, few studies have evaluated perinatal e-cigarette use and its associated health effects. We analyzed data from the Pregnancy Risk Assessment Monitoring System (PRAMS, 2016–2018) for 16,022 women who recently gave birth and reported smoking combustible cigarettes prior to pregnancy. Using average marginal predictive values from multivariable logistic regression to produce adjusted prevalence ratios (aPRs), we estimated the prevalence of combustible cigarette smoking during pregnancy and adverse birth outcomes associated with e-cigarette use. In total, 14.8% of smoking women reported using e-cigarettes prior to pregnancy. There was no association between e-cigarette use prior to pregnancy and combustible cigarette smoking during pregnancy (aPR 0.95; 95% CI 0.88, 1.02); however, e-cigarette use during pregnancy was associated with higher prevalence of combustible cigarette smoking during pregnancy (aPR 1.65; 95% CI 1.52, 1.80). In this sample, we did not observe evidence to support reduced risk of preterm birth, small-for-gestational age and low birthweight compared to combustible cigarette smoking during pregnancy. The prevalence of LBW was higher for those who used e-cigarettes, even exclusively, compared to women who quit smoking cigarettes entirely. These results suggest that e-cigarettes should not be considered a safe alternative to combustible cigarette smoking during pregnancy.
Overlapping regions of Caf20 mediate its interactions with the mRNA-5′cap-binding protein eIF4E and with ribosomes
Authors: Nwokoye Ebelechukwu C. , AlNaseem Eiman , Crawford Robert A. , Castelli Lydia M. , Jennings Martin D. , Kershaw Christopher J. , Pavitt Graham D.
Published: June 2021

By interacting with the mRNA 5′ cap, the translation initiation factor eIF4E plays a critical role in selecting mRNAs for protein synthesis in eukaryotic cells. Caf20 is a member of the family of proteins found across eukaryotes termed 4E-BPs, which compete with eIF4G for interaction with eIF4E. Caf20 independently interacts with ribosomes. Thus, Caf20 modulates the mRNA selection process via poorly understood mechanisms. Here we performed unbiased mutagenesis across Caf20 to characterise which regions of Caf20 are important for interaction with eIF4E and with ribosomes. Caf20 binding to eIF4E is entirely dependent on a canonical motif shared with other 4E-BPs. However, binding to ribosomes is weakened by mutations throughout the protein, suggesting an extended binding interface that partially overlaps with the eIF4E-interaction region. By using chemical crosslinking, we identify a potential ribosome interaction region on the ribosome surface that spans both small and large subunits and is close to a known interaction site of eIF3. The function of ribosome binding by Caf20 remains unclear.