bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced dispersibility of flushable wet wipes after wet storage
Authors: Harter Thomas , Bernt Ingo , Winkler Stefanie , Hirn Ulrich
Published: April 2021

Scientific publications and newsfeeds recently focused on flushable wet wipes and their role in sewage system blockages. It is stated that although products are marked as flushable, they do not disintegrate after being disposed of via the toilet. In this work it is shown that wetlaid hydroentangled wet wipes lose their initially good dispersive properties during their storage in wet condition. As a consequence, we are suggesting to add tests after defined times of wet storage when assessing the flushability of wet wipes. Loss of dispersibility is found for both, wet wipes from industrial pilot production and wipes produced on laboratory pilot facilities. We found it quite surprising that the wet wipes’ dispersibility is deteriorating after storage in exactly the same liquid they are dispersed in, i.e. water. This is probably why the effect of wet storage has not been investigated earlier. It is demonstrated that the deteriorating dispersibility of these wipes is linked to the used type of short cellulosic fibres — only wipes containing unbleached softwood pulp as short fibre component were preserving good dispersibility during wet storage. Possible mechanisms that might be responsible are discussed, e.g. long term fiber swelling causing a tightening of the fiber network, or surface interdiffusion.
Incidental detection of prostate cancer with computed tomography scans
Authors: Korevaar Steven , Tennakoon Ruwan , Page Mark , Brotchie Peter , Thangarajah John , Florescu Cosmin , Sutherland Tom , Kam Ning Mao , Bab-Hadiashar Alireza
Published: April 2021

Prostate cancer (PCa) is the second most frequent type of cancer found in men worldwide, with around one in nine men being diagnosed with PCa within their lifetime. PCa often shows no symptoms in its early stages and its diagnosis techniques are either invasive, resource intensive, or has low efficacy, making widespread early detection onerous. Inspired by the recent success of deep convolutional neural networks (CNN) in computer aided detection (CADe), we propose a new CNN based framework for incidental detection of clinically significant prostate cancer (csPCa) in patients who had a CT scan of the abdomen/pelvis for other reasons. While CT is generally considered insufficient to diagnose PCa due to its inferior soft tissue characterisation, our evaluations on a relatively large dataset consisting of 139 clinically significant PCa patients and 432 controls show that the proposed deep neural network pipeline can detect csPCa patients at a level that is suitable for incidental detection. The proposed pipeline achieved an area under the receiver operating characteristic curve (ROC-AUC) of 0.88 (95% Confidence Interval: 0.86–0.90) at patient level csPCa detection on CT, significantly higher than the AUCs achieved by two radiologists (0.61 and 0.70) on the same task.
Stability and individual variability of social attachment in imprinting
Authors: Lemaire Bastien S. , Rucco Daniele , Josserand Mathilde , Vallortigara Giorgio , Versace Elisabetta
Published: April 2021

Filial imprinting has become a model for understanding memory, learning and social behaviour in neonate animals. This mechanism allows the youngs of precocial bird species to learn the characteristics of conspicuous visual stimuli and display affiliative response to them. Although longer exposures to an object produce stronger preferences for it afterwards, this relation is not linear. Sometimes, chicks even prefer to approach novel rather than familiar objects. To date, little is known about how filial preferences develop across time. This study aimed to investigate filial preferences for familiar and novel imprinting objects over time. After hatching, chicks were individually placed in an arena where stimuli were displayed on two opposite screens. Using an automated setup, the duration of exposure and the type of stimuli were manipulated while the time spent at the imprinting stimulus was monitored across 6 days. We showed that prolonged exposure (3 days vs 1 day) to a stimulus produced robust filial imprinting preferences. Interestingly, with a shorter exposure (1 day), animals re-evaluated their filial preferences in functions of their spontaneous preferences and past experiences. Our study suggests that predispositions influence learning when the imprinting memories are not fully consolidated, driving animal preferences toward more predisposed stimuli.
Hemostasis, coagulation and thrombin in venoarterial and venovenous extracorporeal membrane oxygenation: the HECTIC study
Authors: Cartwright Bruce , Bruce Hannah M. , Kershaw Geoffrey , Cai Nancy , Othman Jad , Gattas David , Robson Jacqueline L. , Hayes Sarah , Alicajic Hayden , Hines Anna , Whyte Alice , Chaikittisilpa Nophanan , Southwood Timothy James , Forrest Paul , Totaro Richard J. , Bannon Paul G. , Dunkley Scott , Chen Vivien M. , Dennis Mark
Published: April 2021

Extracorporeal membrane oxygenation (ECMO) support has a high incidence of both bleeding and thrombotic complications. Despite clear differences in patient characteristics and pathologies between veno-venous (VV) and veno-arterial (VA) ECMO support, anticoagulation practices are often the same across modalities. Moreover, there is very little data on their respective coagulation profiles and comparisons of thrombin generation in these patients. This study compares the coagulation profile and thrombin generation between patients supported with either VV and VA ECMO. A prospective cohort study of patients undergoing VA and VV ECMO at an Intensive care department of a university hospital and ECMO referral centre. In addition to routine coagulation testing and heparin monitoring per unit protocol, thromboelastography (TEG), multiplate aggregometry (MEA), calibrated automated thrombinography (CAT) and von-Willebrand’s activity (antigen and activity ratio) were sampled second-daily for 1 week, then weekly thereafter. VA patients had significantly lower platelets counts, fibrinogen, anti-thrombin and clot strength with higher d-dimer levels than VV patients, consistent with a more pronounced consumptive coagulopathy. Thrombin generation was higher in VA than VV patients, and the heparin dose required to suppress thrombin generation was lower in VA patients. There were no significant differences in total bleeding or thrombotic event rates between VV and VA patients when adjusted for days on extracorporeal support. VA patients received a lower median daily heparin dose 8500 IU [IQR 2500–24000] versus VV 28,800 IU [IQR 17,300–40,800.00]; < 0.001. Twenty-eight patients (72%) survived to hospital discharge; comprising 53% of VA patients and 77% of VV patients. Significant differences between the coagulation profiles of VA and VV patients exist, and anticoagulation strategies for patients of these modalities should be different. Further research into the development of tailored anticoagulation strategies that include the mode of ECMO support need to be completed.
A population-based study of self-reported adverse drug events among Lebanese outpatients
Authors: Ramia Elsy , Zeenny Rony M. , Hallit Souheil , Salameh Pascale
Published: April 2021

There is a limited number of studies assessing the epidemiology of Adverse Drug Events (ADEs) in the outpatient setting, especially those that do not result in healthcare use. The primary objective of this study was to assess the prevalence and determinants of self-reported ADEs among Lebanese outpatients. It was a cross-sectional observational study performed among Lebanese outpatients visiting community pharmacies across Lebanon. A questionnaire was designed to elicit patients’ relevant information. The association between categorical variables were evaluated using Pearson χ2 test or Fisher's exact test. Binary logistic regression was performed to identify factors that affect the experience of self-reported ADEs. The study comprised 3148 patients. Around 37% of patients reported experiencing an ADE in the previous year. When ADEs occur, 70.5% of the respondents reported informing their physicians. Increasing number of medications per patient, use of injectable medication, and inquiring about potential drug-drug interactions were associated with higher experience of ADEs (p = 0.049; p = 0.003; and p = 0.009 respectively). Patients who received hospital discharge counseling reported experiencing less ADEs (p = 0.002). Our study showed prevalence of ADEs among Lebanese outpatients especially patients with polypharmacy, and highlighted the need to educate patients about the importance of reporting ADEs to their physicians.
Physiological and pathological roles of the accommodation response in lower esophageal sphincter relaxation during wet swallows
Authors: Muta Kazumasa , Ihara Eikichi , Hamada Shohei , Ikeda Hiroko , Wada Masafumi , Hata Yoshitaka , Bai Xiaopeng , Nishihara Yuichiro , Tanaka Yoshimasa , Ogino Haruei , Ogawa Yoshihiro
Published: April 2021

The preparatory accommodation response of lower esophageal sphincter (LES) before swallowing is one of the mechanisms involved in LES relaxation during wet swallows, however, the physiological and/or pathological roles of LES accommodation remain to be determined in humans. To address this problem, we conducted a prospective observational study of 38 patients with normal high-resolution manometry (HRM) and 23 patients with idiopathic esophagogastric junction outflow obstruction (EGJOO) to assess dry and wet swallows. The LES accommodation measurement was proposed for practical use in evaluating the LES accommodation response. Although swallow-induced LES relaxation was observed in both dry and wet swallows, LES accommodation (6.4, 3.1–11.1 mmHg) was only observed in wet swallows. The extent of LES accommodation was impaired in idiopathic EGJOO (0.6, − 0.6–6 mmHg), and the LES accommodation measurement of patients with idiopathic EGJOO (36.8, 29.5–44.3 mmHg) was significantly higher in comparison to those with normal HRM (23.8, 18–28.6 mmHg). Successful LES relaxation in wet swallowing can be achieved by LES accommodation in combination with swallow-induced LES relaxation. Impaired LES accommodation is characteristic of idiopathic EGJOO. In addition to the IRP value, the LES accommodation measurement may be useful for evaluating the LES relaxation function in clinical practice.
Red blood cell distribution width as a novel prognostic marker after myocardial revascularization or cardiac valve surgery
Authors: Lazzeroni Davide , Moderato Luca , Marazzi P. L. , Pellegrino Carmen , Musiari Elisa , Castiglioni Paolo , Camaiora Umberto , Bini Matteo , Geroldi Simone , Brambilla Lorenzo , Brambilla Valerio , Coruzzi Paolo
Published: April 2021

The red blood cell distribution width (RDW) measures the variability in the size of circulating erythrocytes. Previous studies suggested a powerful correlation between RDW obtained from a standard complete blood count and cardiovascular diseases in both primary and secondary cardiovascular prevention. The current study aimed to evaluate the prognostic role of RDW in patients undergoing cardiac rehabilitation after myocardial revascularization and/or cardiac valve surgery. The study included 1.031 patients with available RDW levels, prospectively followed for a mean of 4.5 ± 3.5 years. The mean age was 68 ± 12 years, the mean RDW was 14.7 ± 1.8%; 492 patients (48%) underwent cardiac rehabilitation after myocardial revascularization, 371 (36%) after cardiac valve surgery, 102 (10%) after valve-plus-coronary artery by-pass graft surgery, 66 (6%) for other indications. Kaplan–Meier analysis and Cox hazard analysis were used to associate RDW with mortality. Kaplan–Meier analysis demonstrated worse survival curves free from overall (log-rank p < 0.0001) and cardiovascular (log-rank p < 0.0001) mortality in the highest RDW tertile. Cox analysis showed RDW levels correlated significantly with the probability of overall (HR 1.26; 95% CI 1.19–1.32; p < 0.001) and cardiovascular (HR 1.31; 95% CI 1.23–1.40; p < 0.001) mortality. After multiple adjustments for cardiovascular risk factors, hemoglobin, hematocrit, C-reactive protein, microalbuminuria, atrial fibrillation, glomerular filtration rate,left ventricular ejection fraction and number of exercise training sessions attended, the increased risk of overall (HR 1.10; 95% CI 1.01–1.27; p = 0.039) and cardiovascular (HR 1.13; 95% CI 1.01–1.34; p = 0.036)mortality with increasing RDW values remained significant. The RDW represents an independent predictor of overall and cardiovascular mortality in secondary cardiovascular prevention patients undergoing cardiac rehabilitation.
Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis
Authors: Miao Qiang , Yan Lin , Zhou Yanhong , Li Yi , Zou Yuangao , Wang Lanlan , Bai Yangjuan , Zhang Junlong
Published: April 2021

This study aimed to investigate the influence of TPMT*3C, ITPA, NUDT15, and 6-thioguanine nucleotides (6-TGN) on azathioprine (AZA)-induced myelosuppression in Southwest China patients with autoimmune hepatitis (AIH). A total of 113 Chinese patients with AIH receiving AZA maintenance treatment were evaluated. The relevant clinical data of the patients were collected from the hospital information system. Genotyping of TPMT*3C(rs1142345), ITPA (rs1127354) and NUDT15(rs116855232) was conducted using a TaqMan double fluorescent probe. The concentration of 6-TGN was determined using UPLC-MS/MS. Among AIH patients treated with AZA, 40 (35.4%) exhibited different degrees of myelosuppression. The NUDT15 variant was associated with leukopenia (P = 8.26 × 10–7; OR = 7.5; 95% CI 3.08–18.3) and neutropenia (P = 3.54 × 10–6; OR = 8.05; 95% CI 2.96–21.9); however, no significant association with myelosuppression was observed for TPMT*3C and ITPA variants (P > 0.05). There was no significant difference in 6-TGN concentration between AIH patients with or without myelosuppression (P = 0.556), nor was there a significant difference between patients with variant alleles of TPMT*3C, ITPA, or NUDT15 and wild-type patients (P > 0.05). Interestingly, it was found that patients with a lower BMI had higher adjusted 6-TGN levels and a higher incidence of myelosuppression (P = 0.026 and 0.003). This study confirmed that NUDT15 variants are a potential independent risk predictor for AZA-induced leukopenia and neutropenia. BMI may be a crucial non-genetic factor that affects the concentration of AZA metabolites and myelosuppression. In addition, the 6-TGN concentration in red blood cells does not reflect the toxicity of AZA treatment, and new biomarkers for AZA therapeutic drug monitoring need further research.
Characterization and significance of extracellular polymeric substances, reactive oxygen species, and extracellular electron transfer in methanogenic biocathode
Authors: Zakaria Basem S. , Dhar Bipro Ranjan
Published: April 2021

The microbial electrolysis cell assisted anaerobic digestion holds great promises over conventional anaerobic digestion. This article reports an experimental investigation of extracellular polymeric substances (EPS), reactive oxygen species (ROS), and the expression of genes associated with extracellular electron transfer (EET) in methanogenic biocathodes. The MEC-AD systems were examined using two cathode materials: carbon fibers and stainless-steel mesh. A higher abundance of hydrogenotrophic Methanobacterium sp. and homoacetogenic Acetobacterium sp. appeared to play a major role in superior methanogenesis from stainless steel biocathode than carbon fibers. Moreover, the higher secretion of EPS accompanied by the lower ROS level in stainless steel biocathode indicated that higher EPS perhaps protected cells from harsh metabolic conditions (possibly unfavorable local pH) induced by faster catalysis of hydrogen evolution reaction. In contrast, EET-associated gene expression patterns were comparable in both biocathodes. Thus, these results indicated hydrogenotrophic methanogenesis is the key mechanism, while cathodic EET has a trivial role in distinguishing performances between two cathode electrodes. These results provide new insights into the efficient methanogenic biocathode development.
The mechanical characteristics and performance evaluation of a newly developed silicone airway stent (GINA stent)
Authors: Jung Hwa Sik , Chae Ganghee , Kim Jin Hyoung , Park Chui Yong , Lim Soyeoun , Park Soon Eun , Kim Ho Chang , Lee Young Jae , Kang Sung Kwon , Kim Don Han , Lee Yongjik , Lee Taehoon
Published: April 2021

Central airway obstruction (CAO) can be attributed to several benign or malignant conditions. Although surgery is the preferred therapeutic option for the management of CAO, bronchoscopic treatment can be performed in scenarios where the surgical procedure is not possible. Recent years have witnessed several improvements in the field of bronchoscopic treatment, especially with regard to airway stents. Current research involves new attempts to overcome the existing shortcomings pertaining to the stents (migration, mucostasis, and granulation tissue formation). The authors have recently developed a new silicone airway stent (GINA stent) with an anti-migration design, dynamic structure that enables the reduction of stent cross-sectional area, and radio-opacity. The present study aimed to evaluate the mechanical characteristics and performance of the novel GINA stent using a porcine tracheal stenosis model. In the current study, all the tests involved the comparison of the GINA stent [outer diameter (OD, mm): 14; length (L, mm): 55] with the Dumon stent (OD: 14; L: 50). The mechanical tests were performed using a digital force gauge, in order to determine the anti-migration force, expansion force, and flexibility. The present study evaluated the short-term (3 weeks) performance of the two stents after implantation [GINA (n = 4) vs. Dumon (n = 3)] in the porcine tracheal stenosis model. The results pertaining to the comparison of the mechanical properties of the GINA and Dumon stents are stated as follows: anti-migration force (18.4 vs. 12.8 N, P = 0.008); expansion force (11.9 vs. 14.5 N, P = 0.008); and flexibility (3.1 vs. 4.5 N, P = 0.008). The results pertaining to the comparison of the short-term performance of the GINA and Dumon stents are stated as follows: mucus retention (0/4 vs. 0/3); granulation tissue formation (0/4 vs. 0/3); and migration (1/4 vs. 2/3). The GINA stent displayed better mechanical properties and comparable short-term performance, compared to the Dumon stent.
Cellulose intrafibrillar mineralization of biological silica in a rice plant
Authors: Nakamura Eri , Ozaki Noriaki , Oaki Yuya , Imai Hiroaki
Published: April 2021

The essence of morphological design has been a fascinating scientific problem with regard to understanding biological mineralization. Particularly shaped amorphous silicas (plant opals) play an important role in the vital activity in rice plants. Although various organic matters are associated with silica accumulation, their detailed functions in the shape-controlled mineralization process have not been sufficiently clarified. In the present study, cellulose nanofibers (CNFs) were found to be essential as a scaffold for silica accumulation in rice husks and leaf blades. Prior to silicification, CNFs ~ 10 nm wide are sparsely stacked in a space between the epidermal cell wall and the cuticle layer. Silica nanoparticles 20–50 nm in diameter are then deposited in the framework of the CNFs. The shape-controlled plant opals are formed through the intrafibrillar mineralization of silica nanoparticles on the CNF scaffold.
The expression of ATP-sensitive potassium channels in human umbilical arteries with severe pre-eclampsia
Authors: Yin Benlan , Zhang Yujiao , Wei Xiaohong , Pang Chunrong , Hou Ting , Yang Chao , Ning Yuzhi , Fu Xiaodong
Published: April 2021

The aim of this study is to establish the expression of ATP-sensitive potassium channels(KATP) in human umbilical arteries with severe pre-eclampsia. Real-time quantitative PCR and western blotting were used to detect the mRNA and protein expression levels of KATP channel subunits Kir6.1 and SUR2B in human umbilical arteries from normal pregnant and those with severe pre-eclampsia, early onset severe pre-eclampsia and late onset severe pre-eclampsia. The mRNA and protein levels of SUR2B in the severe pre-eclampsia group were lower than those in the normal group (P < 0.001), and the expression of Kir6.1 was not statistically significant between the two groups (P > 0.05). The mRNA and protein levels of SUR2B in early onset severe pre-eclampsia group were lower than those in late onset severe pre-eclampsia group (P < 0.001). There was no significant difference in expression of Kir6.1 between the two groups (P > 0.05). The mRNA and protein expression levels of SUR2B in pregnant women with severe pre-eclampsia were lower than those in normal pregnant women, suggesting that the expression of the SUR2B of the KATP channel may be related to the occurrence and development of severe pre-eclampsia. Compared with late onset severe pre-eclampsia, the mRNA and protein expression levels of SUR2B were lower in the umbilical arteries of women with early onset severe pre-eclampsia, suggesting that the occurrence time of severe pre-eclampsia may be related to the extent reduced expression of the SUR2B of the KATP channel.
Inflated prediction accuracy of neuropsychiatric biomarkers caused by data leakage in feature selection
Authors: Shim Miseon , Lee Seung-Hwan , Hwang Han-Jeong
Published: April 2021

In recent years, machine learning techniques have been frequently applied to uncovering neuropsychiatric biomarkers with the aim of accurately diagnosing neuropsychiatric diseases and predicting treatment prognosis. However, many studies did not perform cross validation (CV) when using machine learning techniques, or others performed CV in an incorrect manner, leading to significantly biased results due to overfitting problem. The aim of this study is to investigate the impact of CV on the prediction performance of neuropsychiatric biomarkers, in particular, for feature selection performed with high-dimensional features. To this end, we evaluated prediction performances using both simulation data and actual electroencephalography (EEG) data. The overall prediction accuracies of the feature selection method performed outside of CV were considerably higher than those of the feature selection method performed within CV for both the simulation and actual EEG data. The differences between the prediction accuracies of the two feature selection approaches can be thought of as the amount of overfitting due to selection bias. Our results indicate the importance of correctly using CV to avoid biased results of prediction performance of neuropsychiatric biomarkers.
A 3-month-delayed treatment with anatabine improves chronic outcomes in two different models of repetitive mild traumatic brain injury in hTau mice
Authors: Morin Alexander , Mouzon Benoit , Ferguson Scott , Paris Daniel , Saltiel Nicole , Browning Mackenzie , Mullan Mike , Crawford Fiona
Published: April 2021

To date, an overwhelming number of preclinical studies have addressed acute treatment in mild TBI (mTBI) and repetitive mTBI (r-mTBI), whereas, in humans, there often exists a significant time gap between the injury and the first medical intervention. Our study focused on a delayed treatment with anatabine, an anti-inflammatory compound, in hTau mice using two different models of r-mTBI. The rationale for using two models of the same impact but different frequencies (5 hit mTBI over 9 days and 24 hit mTBI over 90 days) was chosen to address the heterogeneity of r-mTBI in clinical population. Following the last injury in each model, three months elapsed before the initiation of treatment. Anatabine was administered in drinking water for 3 months thereafter. Our data demonstrated that a 3-month delayed treatment with anatabine mitigated astrogliosis in both TBI paradigms but improved cognitive functions only in more-frequently-injured mice (24 hit mTBI). We also found that anatabine decreased the phosphorylation of tau protein and NFκB, which were increased after r-mTBI in both models. The ability of anatabine to suppress these mechanisms suggests that delayed treatment can be effective for clinical population of r-mTBI. The discrepancy between the two models with regard to changes in cognitive performance suggests that r-mTBI heterogeneity may influence treatment efficiency and should be considered in therapeutic development.
Time-lag of urinary and salivary cortisol response after a psychological stressor in bonobos (Pan paniscus)
Authors: Verspeek Jonas , Behringer Verena , Laméris Daan W. , Murtagh Róisín , Salas Marina , Staes Nicky , Deschner Tobias , Stevens Jeroen M. G.
Published: April 2021

Cortisol is often measured as a marker for stress. Therefore, a profound validation of the time-lag between the stressor and the increase and peak in cortisol levels is needed. No study measured both the urinary and salivary cortisol time-lag after a psychological stressor. In this study, we used a frequent sampling study design to (1) describe the urinary and salivary cortisol pattern during a control day; and (2) characterize the induced excretion pattern of urinary and salivary cortisol after a psychological stressor in six zoo-housed bonobos. Liquid chromatography-tandem mass spectrometry was used to analyze 71 urine and 162 saliva samples collected on a control and a test day. We found that the time-lag between the stressor and the maximal cortisol concentration was similar in urine and saliva (160 min after the stressor). However, salivary cortisol after the stressor did show a faster and steeper increase than urinary cortisol. We also show inter-individual variation in the baseline and stress levels of cortisol, which should be considered in future cortisol studies. Our research highlights the importance of validation studies to confirm relevant sampling windows for cortisol sampling in order to obtain biologically meaningful results.
Eotaxin-1/CCL11 is involved in cell migration in rheumatoid arthritis
Authors: Wakabayashi Kuninobu , Isozaki Takeo , Tsubokura Yumi , Fukuse Sayaka , Kasama Tsuyoshi
Published: April 2021

Eotaxin-1 (CCL11) induces the migration of different leukocyte types by interacting with CCR3. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) are pathogenic effectors and a major CCR3-expressing cell. The aim of this study was to investigate the expression and function of CCL11 in RA FLS. The expression of CCL11 and CCR3 was evaluated by ELISA, immunofluorescence and quantitative PCR analysis. The CCL11 levels in serum and synovial fluids (SFs) from RA patients were significantly higher than those in serum from healthy controls and SFs from osteoarthritis patients. CCL11 and CCR3 were expressed in the RA synovial tissue lining layers. The secretion of CCL11 in RA FLS-conditioned medium and the mRNA expression of CCL11 and CCR3 were induced by TNF-α. Furthermore, CCL11 induced the mRNA expression of CCL11 and CCR3. Application of a CCR3 antagonist reduced TNF-α-induced CCL11 secretion from RA FLS. CCL11 induced the migration of RA FLS and monocytes. RA FLS migration was decreased by treatment with CCL11 siRNA. The migration of monocytes to medium conditioned with CCL11 siRNA-transfected and TNF-α-stimulated RA FLS was reduced. These data indicate that the self-amplification of CCL11 via CCR3 may play an important role in cell migration in RA.
Effects of interleukin-1 antagonism and corticosteroids on fibroblast growth factor-21 in patients with metabolic syndrome
Authors: Ebrahimi Fahim , Urwyler Sandrine Andrea , Betz Matthias Johannes , Christ Emanuel Remigius , Schuetz Philipp , Mueller Beat , Donath Marc Yves , Christ-Crain Mirjam
Published: April 2021

Fibroblast growth factor-21 (FGF21) is elevated in patients with the metabolic syndrome. Although the exact underlying mechanisms remain ill-defined, chronic low-grade inflammation with increased Interleukin-(IL)-1β expression may be responsible. The aim of this study was to investigate effects of two different anti-inflammatory treatments (IL-1 antagonism or high-dose corticosteroids) on FGF21 in patients with the metabolic syndrome. This is a secondary analysis of two interventional studies in patients with obesity and features of the metabolic syndrome. Trial A was an interventional trial (n = 73) investigating short-term effects of the IL-1 antagonist anakinra and of dexamethasone. Trial B was a randomized, placebo-controlled, double-blinded trial (n = 67) investigating longer-term effects of IL-1 antagonism. In total, 140 patients were included in both trials. Median age was 55 years (IQR 44–66), 26% were female and median BMI was 37 kg/m2 (IQR 34–39). Almost half of the patients were diabetic (45%) and had increased c-reactive protein levels of 3.4 mg/L. FGF21 levels correlated with fasting glucose levels, HOMA-index, C-peptide levels, HbA1c and BMI. Short-term treatment with anakinra led to a reduction of FGF21 levels by − 200 pg/mL (95%CI − 334 to − 66; p = 0.004). No effect was detectable after longer-term treatment (between-group difference: − 8.8 pg/mL (95%CI − 130.9 to 113.3; p = 0.89). Acute treatment with dexamethasone was associated with reductions of FGF21 by -175 pg/mL (95%CI − 236 to − 113; p < 0.001). Anti-inflammatory treatment with both, IL-1 antagonism and corticosteroids reduced FGF21 levels at short-term in individuals with the metabolic syndrome.

Trial registration: ClinicalTrials.gov Identifiers NCT02672592 and NCT00757276.
Septal chondrocyte hypertrophy contributes to midface deformity in a mouse model of Apert syndrome
Authors: Kim Bong-Soo , Shin Hye-Rim , Kim Hyun-Jung , Yoon Heein , Cho Young-Dan , Choi Kang-Young , Choi Je-Yong , Kim Woo-Jin , Ryoo Hyun-Mo
Published: April 2021

Midface hypoplasia is a major manifestation of Apert syndrome. However, the tissue component responsible for midface hypoplasia has not been elucidated. We studied mice with a chondrocyte-specific Fgfr2S252W mutation (Col2a1-cre; Fgfr2S252W/+) to investigate the effect of cartilaginous components in midface hypoplasia of Apert syndrome. In Col2a1-cre; Fgfr2S252W/+ mice, skull shape was normal at birth, but hypoplastic phenotypes became evident with age. General dimensional changes of mutant mice were comparable with those of mice with mutations in EIIa-cre; Fgfr2S252W/+, a classic model of Apert syndrome in mice. Col2a1-cre; Fgfr2S252W/+ mice showed some unique facial phenotypes, such as elevated nasion, abnormal fusion of the suture between the premaxilla and the vomer, and decreased perpendicular plate of the ethmoid bone volume, which are related to the development of the nasal septal cartilage. Morphological and histological examination revealed that the presence of increased septal chondrocyte hypertrophy and abnormal thickening of nasal septum is causally related to midface deformities in nasal septum-associated structures. Our results suggest that careful examination and surgical correction of the nasal septal cartilage may improve the prognosis in the surgical treatment of midface hypoplasia and respiratory problems in patients with Apert syndrome.
Statistical characterization of airplane delays
Authors: Mitsokapas Evangelos , Schäfer Benjamin , Harris Rosemary J. , Beck Christian
Published: April 2021

The aviation industry is of great importance for a globally connected economy. Customer satisfaction with airlines and airport performance is considerably influenced by how much flights are delayed. But how should the delay be quantified with thousands of flights for each airport and airline? Here, we present a statistical analysis of arrival delays at several UK airports between 2018 and 2020. We establish a procedure to compare both mean delay and extreme events among airlines and airports, identifying a power-law decay of large delays. Furthermore, we note drastic changes in plane delay statistics during the COVID-19 pandemic. Finally, we find that delays are described by a superposition of simple distributions, leading to a superstatistics.
Introducing the tablet-based Oxford Cognitive Screen-Plus (OCS-Plus) as an assessment tool for subtle cognitive impairments
Authors: Demeyere Nele , Haupt Marleen , Webb Sam S. , Strobel Lea , Milosevich Elise T. , Moore Margaret J. , Wright Hayley , Finke Kathrin , Duta Mihaela D.
Published: April 2021

Here, we present the Oxford Cognitive Screen-Plus, a computerised tablet-based screen designed to briefly assess domain-general cognition and provide more fine-grained measures of memory and executive function. The OCS-Plus was designed to sensitively screen for cognitive impairments and provide a differentiation between memory and executive deficits. The OCS-Plus contains 10 subtasks and requires on average 24 min to complete. In this study, 320 neurologically healthy ageing participants (age M = 62.66, SD = 13.75) from three sites completed the OCS-Plus. The convergent validity of this assessment was established in comparison to the ACE-R, CERAD and Rey–Osterrieth. Divergent validity was established through comparison with the BDI and tests measuring divergent cognitive domains. Internal consistency of each subtask was evaluated, and test–retest reliability was determined. We established the normative impairment cut-offs for each of the subtasks. Predicted convergent and divergent validity was found, high internal consistency for most measures was also found with the exception of restricted range tasks, as well as strong test–retest reliability, which provided evidence of test stability. Further research demonstrating the use and validity of the OCS-Plus in various clinical populations is required. The OCS-Plus is presented as a standardised cognitive assessment tool, normed and validated in a sample of neurologically healthy participants. The OCS-Plus will be available as an Android App and provides an automated report of domain-general cognitive impairments in executive attention and memory.
Publisher Correction: Upper critical field and superconductor-metal transition in ultrathin niobium films
Authors: Zaytseva Iryna , Abaloszew Aleksander , Camargo Bruno C. , Syryanyy Yevgen , Cieplak Marta Z.
Published: April 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Copper-graphene heterostructure for back-end-of-line compatible high-performance interconnects
Authors: Son Myungwoo , Jang Jaewon , Lee Yongsu , Nam Jungtae , Hwang Jun Yeon , Kim In S. , Lee Byoung Hun , Ham Moon-Ho , Chee Sang-Soo
Published: April 2021

Here, we demonstrate the fabrication of a Cu-graphene heterostructure interconnect by the direct synthesis of graphene on a Cu interconnect with an enhanced performance. Multilayer graphene films were synthesized on Cu interconnect patterns using a liquid benzene or pyridine source at 400 °C by atmospheric pressure chemical vapor deposition (APCVD). The graphene-capped Cu interconnects showed lower resistivity, higher breakdown current density, and improved reliability compared with those of pure Cu interconnects. In addition, an increase in the carrier density of graphene by doping drastically enhanced the reliability of the graphene-capped interconnect with a mean time to failure of >106 s at 100 °C under a continuous DC stress of 3 MA cm−2. Furthermore, the graphene-capped Cu heterostructure exhibited enhanced electrical properties and reliability even if it was a damascene-patterned structure, which indicates compatibility with practical applications such as next-generation interconnect materials in CMOS back-end-of-line (BEOL).
Dimensional crossover and band topology evolution in ultrathin semimetallic NiTe2 films
Authors: Hlevyack Joseph A. , Feng Liang-Ying , Lin Meng-Kai , Villaos Rovi Angelo B. , Liu Ro-Ya , Chen Peng , Li Yao , Mo Sung-Kwan , Chuang Feng-Chuan , Chiang T.-C.
Published: April 2021

Nickel ditelluride (NiTe2), a recently discovered Type-II Dirac semimetal with topological Dirac fermions near the Fermi energy, is expected to exhibit strong thickness-mediated electronic tunability and intrinsic two-gap superconductivity in the single-layer limit. Realizing such intriguing phenomena requires the fabrication of ultrathin NiTe2 films and an understanding of the underlying physics that is still under debate. By conducting experimental band mappings of ultrathin films prepared with molecular beam epitaxy, we reveal spectroscopic evidence for the dimensionality crossover of single-crystalline ultrathin NiTe2 films as a function of film thickness. As the film thickness increases from one to five layers, the gap in the conical topological surface states closes. Comparisons of experimental to first-principles results also highlight difficulties in fabricating atomically smooth single-layer NiTe2 films. Our results not only provide further impetus for studying emergent phenomena in NiTe2 but also underscore the limitations of fabricating NiTe2 films for device applications.
In-plane anisotropic optical and mechanical properties of two-dimensional MoO3
Authors: Puebla Sergio , D’Agosta Roberto , Sanchez-Santolino Gabriel , Frisenda Riccardo , Munuera Carmen , Castellanos-Gomez Andres
Published: April 2021

Molybdenum trioxide (MoO3) in-plane anisotropy has increasingly attracted the attention of the scientific community in the last few years. Many of the observed in-plane anisotropic properties stem from the anisotropic refractive index and elastic constants of the material but a comprehensive analysis of these fundamental properties is still lacking. Here we employ Raman and micro-reflectance measurements, using polarized light, to determine the angular dependence of the refractive index of thin MoO3 flakes and we study the directional dependence of the MoO3 Young’s modulus using the buckling metrology method. We found that MoO3 displays one of the largest in-plane anisotropic mechanical properties reported for 2D materials so far.
Surface-tailored graphene channels
Authors: Lee Chung Won , Suh Jun Min , Choi Seokhoon , Jun Sang Eon , Lee Tae Hyung , Yang Jin Wook , Lee Sol A , Lee Bo Reum , Yoo Donghyeon , Kim Soo Young , Kim Dong Sung , Jang Ho Won
Published: April 2021

The detection of ions and molecules in liquids has been receiving considerable attention for the realization of the electronic tongue. Solution-gated field-effect transistors (SFETs) with high sensitivity are useful for detecting ions and molecules by reading electrical transconductance. However, to date, ionic and molecular sensors that employ SFETs have limitations, such as the lack of a dynamic on–off function and low selectivity. In this study, we evaluate rationally designed graphene SFETs as pH and glucose-selective sensors. The integration of the microfluidic channel to the graphene SFET exhibits dynamic on–off functions by controlling injection and withdrawal of solutions. The graphene SFET device exhibits high pH and glucose selectivity when coated with Nafion as a molecular sieve and Au-decorated nanoparticles as receptors, respectively. The dynamic on–off functions and high selectivity of SFETs with tailored graphene channels have a high potential for advancing as a platform for electronic tongues by integrating the separate SFETs as an array for simultaneous sensing of multiple targets.
Deletion of LBR N-terminal domains recapitulates Pelger-Huet anomaly phenotypes in mouse without disrupting X chromosome inactivation
Authors: Young Alexander Neil , Perlas Emerald , Ruiz-Blanes Nerea , Hierholzer Andreas , Pomella Nicola , Martin-Martin Belen , Liverziani Alessandra , Jachowicz Joanna W. , Giannakouros Thomas , Cerase Andrea
Published: April 2021

Mutations in the gene encoding Lamin B receptor (LBR), a nuclear-membrane protein with sterol reductase activity, have been linked to rare human disorders. Phenotypes range from a benign blood disorder, such as Pelger-Huet anomaly (PHA), affecting the morphology and chromatin organization of white blood cells, to embryonic lethality as for Greenberg dysplasia (GRBGD). Existing PHA mouse models do not fully recapitulate the human phenotypes, hindering efforts to understand the molecular etiology of this disorder. Here we show, using CRISPR/Cas-9 gene editing technology, that a 236bp N-terminal deletion in the mouse Lbr gene, generating a protein missing the N-terminal domains of LBR, presents a superior model of human PHA. Further, we address recent reports of a link between Lbr and defects in X chromosome inactivation (XCI) and show that our mouse mutant displays minor X chromosome inactivation defects that do not lead to any overt phenotypes in vivo. We suggest that our N-terminal deletion model provides a valuable pre-clinical tool to the research community and will aid in further understanding the etiology of PHA and the diverse functions of LBR.
An engineered channelrhodopsin optimized for axon terminal activation and circuit mapping
Authors: Hamada Shun , Nagase Masashi , Yoshizawa Tomohiko , Hagiwara Akari , Isomura Yoshikazu , Watabe Ayako M. , Ohtsuka Toshihisa
Published: April 2021

Optogenetic tools such as channelrhodopsin-2 (ChR2) enable the manipulation and mapping of neural circuits. However, ChR2 variants selectively transported down a neuron’s long-range axonal projections for precise presynaptic activation remain lacking. As a result, ChR2 activation is often contaminated by the spurious activation of en passant fibers that compromise the accurate interpretation of functional effects. Here, we explored the engineering of a ChR2 variant specifically localized to presynaptic axon terminals. The metabotropic glutamate receptor 2 (mGluR2) C-terminal domain fused with a proteolytic motif and axon-targeting signal (mGluR2-PA tag) localized ChR2-YFP at axon terminals without disturbing normal transmission. mGluR2-PA-tagged ChR2 evoked transmitter release in distal projection areas enabling lower levels of photostimulation. Circuit connectivity mapping in vivo with the Spike Collision Test revealed that mGluR2-PA-tagged ChR2 is useful for identifying axonal projection with significant reduction in the polysynaptic excess noise. These results suggest that the mGluR2-PA tag helps actuate trafficking to the axon terminal, thereby providing abundant possibilities for optogenetic experiments.
A deimmunized and pharmacologically optimized Toll-like receptor 5 agonist for therapeutic applications
Authors: Mett Vadim , Kurnasov Oleg V. , Bespalov Ivan A. , Molodtsov Ivan , Brackett Craig M. , Burdelya Lyudmila G. , Purmal Andrei A. , Gleiberman Anatoli S. , Toshkov Ilia A. , Burkhart Catherine A. , Kogan Yakov N. , Andrianova Ekaterina L. , Gudkov Andrei V. , Osterman Andrei L.
Published: April 2021

The Toll-like receptor 5 (TLR5) agonist entolimod, a derivative of Salmonella flagellin, has therapeutic potential for several indications including radioprotection and cancer immunotherapy. However, in Phase 1 human studies, entolimod induced a rapid neutralizing immune response, presumably due to immune memory from prior exposure to flagellated enterobacteria. To enable multi-dose applications, we used structure-guided reengineering to develop a next-generation, substantially deimmunized entolimod variant, GP532. GP532 induces TLR5-dependent NF-κB activation like entolimod but is smaller and has mutations eliminating an inflammasome-activating domain and key B- and T-cell epitopes. GP532 is resistant to human entolimod-neutralizing antibodies and shows reduced de novo immunogenicity. GP532 also has improved bioavailability, a stronger effect on key cytokine biomarkers, and a longer-lasting effect on NF-κB. Like entolimod, GP532 demonstrated potent prophylactic and therapeutic efficacy in mouse models of radiation-induced death and tissue damage. These results establish GP532 as an optimized TLR5 agonist suitable for multi-dose therapies and for patients with high titers of preexisting flagellin-neutralizing antibodies.
Divalent metal transporter-related protein restricts animals to marine habitats
Authors: Sassa Mieko , Takagi Toshiyuki , Kinjo Azusa , Yoshioka Yuki , Zayasu Yuna , Shinzato Chuya , Kanda Shinji , Murakami-Sugihara Naoko , Shirai Kotaro , Inoue Koji
Published: April 2021

Utilization and regulation of metals from seawater by marine organisms are important physiological processes. To better understand metal regulation, we searched the crown-of-thorns starfish genome for the divalent metal transporter (DMT) gene, a membrane protein responsible for uptake of divalent cations. We found two DMT-like sequences. One is an ortholog of vertebrate DMT, but the other is an unknown protein, which we named DMT-related protein (DMTRP). Functional analysis using a yeast expression system demonstrated that DMT transports various metals, like known DMTs, but DMTRP does not. In contrast, DMTRP reduced the intracellular concentration of some metals, especially zinc, suggesting its involvement in negative regulation of metal uptake. Phylogenetic distribution of the DMTRP gene in various metazoans, including sponges, protostomes, and deuterostomes, indicates that it originated early in metazoan evolution. However, the DMTRP gene is only retained in marine species, and its loss seems to have occurred independently in ecdysozoan and vertebrate lineages from which major freshwater and land animals appeared. DMTRP may be an evolutionary and ecological limitation, restricting organisms that possess it to marine habitats, whereas its loss may have allowed other organisms to invade freshwater and terrestrial habitats.
Deconvolution of dissipative pathways for the interpretation of tapping-mode atomic force microscopy from phase-contrast
Authors: Phani Arindam , Jung Ho Sang , Kim Seonghwan
Published: April 2021

Phase-contrast in tapping-mode atomic force microscopy (TM-AFM) results from dynamic tip-surface interaction losses which allow soft and hard nanoscale features to be distinguished. So far, phase-contrast in TM-AFM has been interpreted using homogeneous Boltzmann-like loss distributions that ignore fluctuations. Here, we revisit the origin of phase-contrast in TM-AFM by considering the role of fluctuation-driven transitions and heterogeneous loss. At ultra-light tapping amplitudes <3 nm, a unique amplitude dependent two-stage distribution response is revealed, alluding to metastable viscous relaxations that originate from tapping-induced surface perturbations. The elastic and viscous coefficients are also quantitatively estimated from the resulting strain rate at the fixed tapping frequency. The transitional heterogeneous losses emerge as the dominant loss mechanism outweighing homogeneous losses at smaller amplitudes for a soft-material. Analogous fluctuation mediated phase-contrast is also apparent in contact resonance enhanced AFM-IR (infrared), showing promise in decoupling competing thermal loss mechanisms via radiative and non-radiative pathways. Understanding the loss pathways can provide insights on the bio-physical origins of heterogeneities in soft-bio-matter e.g., single cancer cell, tumors, and soft-tissues.
Construction of a G-quadruplex-specific DNA endonuclease
Authors: Dang Dung Thanh , Nguyen Le Tuan Anh , Truong Tuom Tinh Thi , Nguyen Hoang Duc , Phan Anh Tuân
Published: April 2021

A G-quadruplex-specific DNA endonuclease was constructed by fusing a RHAU G-quadruplex recognition domain with a Fok1 cleavage domain, providing a useful tool for detection of G-quadruplex structures.
Achieving high singlet-oxygen generation by applying the heavy-atom effect to thermally activated delayed fluorescent materials
Authors: Xiao Ya-Fang , Chen Jia-Xiong , Chen Wen-Cheng , Zheng Xiuli , Cao Chen , Tan Jihua , Cui Xiao , Yuan Zhanxiang , Ji Shaomin , Lu Guihong , Liu Weimin , Wang Pengfei , Li Shengliang , Lee Chun-Sing
Published: April 2021

Applying the heavy-atom effect to TADF photosensitizers achieves ultra-high 1O2 generation (ФΔ = 0.91) by the synergetic effect of small ΔEST and considerable SOC.