bluuebunny/crossref_metadata_2025 huggingface dataset:
Hexaferrocenium tri[hexa(isothiocyanato)iron(III)] trihydroxonium complex as a new DNA intercalator for electrochemical DNA biosensor
Authors: Ariffin Eda Yuhana , Zakariah Emma Izzati , Ruslin Farah , Kassim Muhammad , Yamin Bohari M. , Heng Lee Yook , Hasbullah Siti Aishah
Published: April 2021

Ferrocene or ferrocenium has been widely studied in the field of organometallic complexes because of its stable thermodynamic, kinetic and redox properties. Novel hexaferrocenium tri[hexa(isothiocyanato)iron(III)]trihydroxonium (HexaFc) complex was the product from the reaction of ferrocene, maleic acid and ammonium thiocyanate and was confirmed by elemental analysis CHNS, FTIR and single crystal X-ray crystallography. In this study, HexaFc was used for the first time as an electroactive indicator for porcine DNA biosensor. The UV–Vis DNA titrations with this compound showed hypochromism and redshift at 250 nm with increasing DNA concentrations. The binding constant (Kb) for HexaFc complex towards CT-DNA (calf-thymus DNA) was 3.1 × 104 M−1, indicated intercalator behaviour of the complex. To test the usefulness of this complex for DNA biosensor application, a porcine DNA biosensor was constructed. The recognition probes were covalently immobilised onto silica nanospheres (SiNSs) via glutaraldehyde linker on a screen-printed electrode (SPE). After intercalation with the HexaFc complex, the response of the biosensor to the complementary porcine DNA was measured using differential pulse voltammetry. The DNA biosensor demonstrated a linear response range to the complementary porcine DNA from 1 × 10−6to 1 × 10−3 µM (R2 = 0.9642) with a limit detection of 4.83 × 10−8 µM and the response was stable up to 23 days of storage at 4 °C with 86% of its initial response. The results indicated that HexaFc complex is a feasible indicator for the DNA hybridisation without the use of a chemical label for the detection of porcine DNA.
Key biomarkers within the colorectal cancer related inflammatory microenvironment
Authors: Calu Valentin , Ionescu Adriana , Stanca Loredana , Geicu Ovidiu Ionut , Iordache Florin , Pisoschi Aurelia Magdalena , Serban Andreea Iren , Bilteanu Liviu
Published: April 2021

Therapeutic approaches focused on the inflammatory microenvironment are currently gaining more support, as biomolecules involved in the inflammatory colorectal cancer (CRC) tumor microenvironment are being explored. We analyzed tumor and paired normal tissue samples from CRC patients (n = 22) whom underwent tumor resection surgery. We assessed 39 inflammation-involved biomolecules (multiplex magnetic bead-based immunoassay), CEA and CA19-9 (ELISA assay) and the tissue expression levels of occludin and also pErk, STAT1 and STAT3 transcriptional factors (western blot). Tumor staging has been established by histopathological evaluation of HE stained tumor tissue sections. We report 32 biomarkers displaying statistically significant differences in tumor vs. control. Additionally, positive statistical biomarker correlations were found between MMP2–IL8 and BAFF–IL8 (Pearson correlation coefficients > 0.751), while APRIL–MMP2, APRIL–BAFF and APRIL–IL8 were negatively correlated (correlation coefficients < − 0.650). While APRIL, BAFF, IL8 and MMP2 did not modulate with tumor stage, they were inversely related to the immune infiltrate level and CD163 tissue expression. We conclude that the significantly decreased APRIL and increased BAFF, IL8 and MMP2 expression were tumor-specific and deserve consideration in the development of new treatments. Also, the positive correlation between Chitinase 3-like 1 and IL8 (0.57) or MMP2 (0.50) suggest a role in tumor growth and metastasis pathways.
Raman and photoluminescence spectroscopy analysis of gamma irradiated human hair
Authors: Lam Siok Ee , Mat Nawi Siti Nurasiah , Abdul Sani Siti Fairus , Khandaker Mayeen Uddin , Bradley David Andrew
Published: April 2021

Preliminary study has been made of black human hair, carbon concentration of some 53%, a model in examining the potential of hair of the human head in retrospective and emergency biodosimetry applications, also offering effective atomic number near to that of water. The hair samples were exposed to $$^{60}$$

60

Co gamma rays, delivering doses from 0 to 200 Gy. Structural alterations were observed, use being made of Raman and photoluminescence (PL) spectroscopy. Most prominent among the features observed in the first-order Raman spectra are the D and G peaks, appearing at 1370 $${{\pm }} 18\,{\hbox {cm}}^{-1}$$

±
18

cm

-
1

and 1589 $${{\pm }} 11\,{\hbox {cm}}^{-1}$$

±
11

cm

-
1

respectively, the intensity ratio $${{{I}}}_{{{D}}}{{/}}{{{I}}}_{{{G}}}$$

I
D

/

I
G

indicating dose-dependent defects generation and annealing of structural alterations. The wavelengths of the PL absorption and emission peaks are found to be centred at $$592.3 \pm 12.5$$

592.3
±
12.5

nm and $$1077.4 \pm 7.3$$

1077.4
±
7.3

nm, respectively. The hair samples mean band gap energy ($${{{E}}}_{{{g}}}$$

E
g

) post-irradiation was found to be $$2.10 \pm 0.04$$

2.10
±
0.04

eV, of the order of a semiconductor and approximately two times the $${{{E}}}_{{{g}}}$$

E
g

of other carbon-rich materials reported via the same methodology.
Adaptive optimal allocation of water resources response to future water availability and water demand in the Han River basin, China
Authors: Tian Jing , Guo Shenglian , Deng Lele , Yin Jiabo , Pan Zhengke , He Shaokun , Li Qianxun
Published: April 2021

Global warming and anthropogenic changes can result in the heterogeneity of water availability in the spatiotemporal scale, which will further affect the allocation of water resources. A lot of researches have been devoted to examining the responses of water availability to global warming while neglected future anthropogenic changes. What’s more, only a few studies have investigated the response of optimal allocation of water resources to the projected climate and anthropogenic changes. In this study, a cascade model chain is developed to evaluate the impacts of projected climate change and human activities on optimal allocation of water resources. Firstly, a large set of global climate models (GCMs) associated with the Daily Bias Correction (DBC) method are employed to project future climate scenarios, while the Cellular Automaton–Markov (CA–Markov) model is used to project future Land Use/Cover Change (LUCC) scenarios. Then the runoff simulation is based on the Soil and Water Assessment Tool (SWAT) hydrological model with necessary inputs under the future conditions. Finally, the optimal water resources allocation model is established based on the evaluation of water supply and water demand. The Han River basin in China was selected as a case study. The results show that: (1) the annual runoff indicates an increasing trend in the future in contrast with the base period, while the ascending rate of the basin under RCP 4.5 is 4.47%; (2) a nonlinear relationship has been identified between the optimal allocation of water resources and water availability, while a linear association exists between the former and water demand; (3) increased water supply are needed in the water donor area, the middle and lower reaches should be supplemented with 4.495 billion m3 water in 2030. This study provides an example of a management template for guiding the allocation of water resources, and improves understandings of the assessments of water availability and demand at a regional or national scale.
Structural basis for an exceptionally strong preference for asparagine residue at the S2 subsite of Stenotrophomonas maltophilia dipeptidyl peptidase 7
Authors: Nakamura Akihiro , Suzuki Yoshiyuki , Sakamoto Yasumitsu , Roppongi Saori , Kushibiki Chisato , Yonezawa Natsuri , Takahashi Masato , Shida Yosuke , Gouda Hiroaki , Nonaka Takamasa , Tanaka Nobutada , Ogasawara Wataru
Published: April 2021

The emergence of drug-resistant bacteria has become a major problem worldwide. Bacterial dipeptidyl peptidases 7 and 11 (DPP7s and DPP11s), belonging to the family-S46 peptidases, are important enzymes for bacterial growth and are not present in mammals. Therefore, specific inhibitors for these peptidases are promising as potential antibiotics. While the molecular mechanisms underlining strict specificity at the S1 subsite of S46 peptidases have been well studied, those of relatively broad preference at the S2 subsite of these peptidases are unknown. In this study, we performed structural and biochemical analyses on DPP7 from Stenotrophomonas maltophilia (SmDPP7). SmDPP7 showed preference for the accommodation of hydrophobic amino acids at the S2 subsite in general, but as an exception, also for asparagine, a hydrophilic amino acid. Structural analyses of SmDPP7 revealed that this exceptional preference to asparagine is caused by a hydrogen bonding network at the bottom of the S2 subsite. The residues in the S2 subsite are well conserved among S46 peptidases as compared with those in the S1 subsite. We expect that our findings will contribute toward the development of a universal inhibitor of S46 peptidases.
Abundance and size of hyaluronan in naked mole-rat tissues and plasma
Authors: del Marmol Delphine , Holtze Susanne , Kichler Nadia , Sahm Arne , Bihin Benoit , Bourguignon Virginie , Dogné Sophie , Szafranski Karol , Hildebrandt Thomas Bernd , Flamion Bruno
Published: April 2021

Large amounts of ultra-high molecular weight hyaluronan (HA) have been described as the main cause of cancer resistance in naked mole-rats (Heterocephalus glaber, NMR). Our work examined HA metabolism in these rodents more closely. HA was localized and quantified using HA binding proteins. Its molecular weight was determined using size exclusion chromatography and gel electrophoresis, HA family gene expression using RNAseq analysis, and hyaluronidase activity using zymography. Guinea pigs (Cavia porcellus) and mice (Mus musculus) were used as controls for some experiments. We found that HA localization was similar in NMR, guinea pig, and mouse tissues but NMR had larger amounts and higher molecular weight (maximum, around 2.5 MDa) of HA in serum and almost all tissues tested. We could not find ultra-high molecular weight HA (≥ 4 MDa) in NMR samples, in contrast to previous descriptions. Hyaluronidase-1 had lower expression and activity in NMR than mouse lymph nodes. RNAseq results showed that, among HA family genes, Tnfaip6 and hyaluronidase-3 (Hyal3) were systematically overexpressed in NMR tissues. In conclusion, NMR samples, contrary to expectations, do not harbor ultra-high molecular weight HA, although its amount and average molecular weight are higher in NMR than in guinea pig tissues and serum. Although hyaluronidase expression and activity are lower in NMR than mouse lymph nodes, this not sufficient to explain the presence of high molecular weight HA. A different activity of the NMR HA synthases remains possible. These characteristics, together with extremely high Hyal3 and Tnfaip6 expression, may provide the NMR with a bespoke, and perhaps protective, HA metabolism.
Geographically varying relationships of COVID-19 mortality with different factors in India
Authors: Middya Asif Iqbal , Roy Sarbani
Published: April 2021

COVID-19 is a global crisis where India is going to be one of the most heavily affected countries. The variability in the distribution of COVID-19-related health outcomes might be related to many underlying variables, including demographic, socioeconomic, or environmental pollution related factors. The global and local models can be utilized to explore such relations. In this study, ordinary least square (global) and geographically weighted regression (local) methods are employed to explore the geographical relationships between COVID-19 deaths and different driving factors. It is also investigated whether geographical heterogeneity exists in the relationships. More specifically, in this paper, the geographical pattern of COVID-19 deaths and its relationships with different potential driving factors in India are investigated and analysed. Here, better knowledge and insights into geographical targeting of intervention against the COVID-19 pandemic can be generated by investigating the heterogeneity of spatial relationships. The results show that the local method (geographically weighted regression) generates better performance ($$R^{2}=0.97$$

R
2

=
0.97

) with smaller Akaike Information Criterion (AICc $$=-66.42$$

=
-
66.42

) as compared to the global method (ordinary least square). The GWR method also comes up with lower spatial autocorrelation (Moran’s $$I=-0.0395$$

I
=
-
0.0395

and $$p < 0.01$$

p
<
0.01

) in the residuals. It is found that more than 86% of local $$R^{2}$$

R
2

values are larger than 0.60 and almost 68% of $$R^{2}$$

R
2

values are within the range 0.80–0.97. Moreover, some interesting local variations in the relationships are also found.
Tens of images can suffice to train neural networks for malignant leukocyte detection
Authors: Schouten Jens P. E. , Matek Christian , Jacobs Luuk F. P. , Buck Michèle C. , Bošnački Dragan , Marr Carsten
Published: April 2021

Convolutional neural networks (CNNs) excel as powerful tools for biomedical image classification. It is commonly assumed that training CNNs requires large amounts of annotated data. This is a bottleneck in many medical applications where annotation relies on expert knowledge. Here, we analyze the binary classification performance of a CNN on two independent cytomorphology datasets as a function of training set size. Specifically, we train a sequential model to discriminate non-malignant leukocytes from blast cells, whose appearance in the peripheral blood is a hallmark of leukemia. We systematically vary training set size, finding that tens of training images suffice for a binary classification with an ROC-AUC over 90%. Saliency maps and layer-wise relevance propagation visualizations suggest that the network learns to increasingly focus on nuclear structures of leukocytes as the number of training images is increased. A low dimensional tSNE representation reveals that while the two classes are separated already for a few training images, the distinction between the classes becomes clearer when more training images are used. To evaluate the performance in a multi-class problem, we annotated single-cell images from a acute lymphoblastic leukemia dataset into six different hematopoietic classes. Multi-class prediction suggests that also here few single-cell images suffice if differences between morphological classes are large enough. The incorporation of deep learning algorithms into clinical practice has the potential to reduce variability and cost, democratize usage of expertise, and allow for early detection of disease onset and relapse. Our approach evaluates the performance of a deep learning based cytology classifier with respect to size and complexity of the training data and the classification task.
The kebab technique uses a bipolar pencil to retrieve a dropped nucleus of the lens via a small incision
Authors: Aso Hiroshi , Yokota Harumasa , Hanazaki Hirotsugu , Yamagami Satoru , Nagaoka Taiji
Published: April 2021

We developed a new method to retrieve a dropped nucleus of the lens via a small incision using bipolar pencils, the kebab technique, to solve the lack of small-gauge fragmatomes, and the expense and toxicity of perfluorocarbon liquids (PFCL). A total of 8 eyes in 6 patients underwent this technique and were reviewed. After vitrectomy, the dropped nucleus of the lens was lifted from the retina by adhesion with a bipolar pencil, and phacoemulsification was performed while rotating the lens. The outcome measures were best-corrected visual acuity (BCVA), intraocular pressure (IOP), and corneal endothelial cell density before and after surgery. Surgical indications included zonular weakness, trauma, acute angle closure attack, and phacolytic glaucoma. At 1 month, BCVA improved from a mean (standard deviation, SD) 1.67 logMAR (0.90) to 1.14 logMAR (1.01). The mean preoperative IOP was 24.5 (16.8) mmHg and postoperative IOP was 11.0 (2.8) mmHg. The mean preoperative corneal endothelial cell count was 2600 (322) cells/mm2 (one eye was unmeasurable) and postoperative corneal endothelial cell count was 2387 (431) cells/mm2. There were no postoperative complications. The retrieval of a dropped nucleus of the lens using a bipolar pencil enables small incisions without using PFCL.
Sustained high expression of multiple APOBEC3 cytidine deaminases in systemic lupus erythematosus
Authors: Perez-Bercoff Danielle , Laude Hélène , Lemaire Morgane , Hunewald Oliver , Thiers Valérie , Vignuzzi Marco , Blanc Hervé , Poli Aurélie , Amoura Zahir , Caval Vincent , Suspène Rodolphe , Hafezi François , Mathian Alexis , Vartanian Jean-Pierre , Wain-Hobson Simon
Published: April 2021

APOBEC3 (A3) enzymes are best known for their role as antiviral restriction factors and as mutagens in cancer. Although four of them, A3A, A3B, A3F and A3G, are induced by type-1-interferon (IFN-I), their role in inflammatory conditions is unknown. We thus investigated the expression of A3, and particularly A3A and A3B because of their ability to edit cellular DNA, in Systemic Lupus Erythematosus (SLE), a chronic inflammatory disease characterized by high IFN-α serum levels. In a cohort of 57 SLE patients, A3A and A3B, but also A3C and A3G, were upregulated ~ 10 to 15-fold (> 1000-fold for A3B) compared to healthy controls, particularly in patients with flares and elevated serum IFN-α levels. Hydroxychloroquine, corticosteroids and immunosuppressive treatment did not reverse A3 levels. The A3AΔ3B polymorphism, which potentiates A3A, was detected in 14.9% of patients and in 10% of controls, and was associated with higher A3A mRNA expression. A3A and A3B mRNA levels, but not A3C or A3G, were correlated positively with dsDNA breaks and negatively with lymphopenia. Exposure of SLE PBMCs to IFN-α in culture induced massive and sustained A3A levels by 4 h and led to massive cell death. Furthermore, the rs2853669 A > G polymorphism in the telomerase reverse transcriptase (TERT) promoter, which disrupts an Ets-TCF-binding site and influences certain cancers, was highly prevalent in SLE patients, possibly contributing to lymphopenia. Taken together, these findings suggest that high baseline A3A and A3B levels may contribute to cell frailty, lymphopenia and to the generation of neoantigens in SLE patients. Targeting A3 expression could be a strategy to reverse cell death and the generation of neoantigens.
Machine learning reveals that structural features distinguishing promiscuous and non-promiscuous compounds depend on target combinations
Authors: Feldmann Christian , Bajorath Jürgen
Published: April 2021

Compounds with defined multi-target activity (promiscuity) play an increasingly important role in drug discovery. However, the molecular basis of multi-target activity is currently only little understood. In particular, it remains unclear whether structural features exist that generally characterize promiscuous compounds and set them apart from compounds with single-target activity. We have devised a test system using machine learning to systematically examine structural features that might characterize compounds with multi-target activity. Using this system, more than 860,000 diagnostic predictions were carried out. The analysis provided compelling evidence for the presence of structural characteristics of promiscuous compounds that were dependent on given target combinations, but not generalizable. Feature weighting and mapping identified characteristic substructures in test compounds. Taken together, these findings are relevant for the design of compounds with desired multi-target activity.
Decreased choroidal and scleral thicknesses in highly myopic eyes with posterior staphyloma
Authors: Park Un Chul , Lee Eun Kyoung , Kim Bo Hee , Oh Baek-Lok
Published: April 2021

In this cross-sectional study, we investigated choroidal thickness (CT) and scleral thickness (ST) in highly myopic eyes and their associations with ocular factors. Patients underwent widefield swept-source optical coherence tomography (OCT) to measure the CT and ST at the subfovea and 3000 μm superior, inferior, temporal, and nasal to the fovea and macular curvature. A total of 237 eyes (154 patients) were included. At all five measurement points, thinner CTs and STs were associated with longer axial lengths (r = − 0.548 to − 0.357, all P < 0.001) and greater macular curvatures (r = − 0.542 to − 0.305, all P < 0.001). The CT and ST were significantly thinner in eyes with posterior staphyloma than in those without at all measurement points (all P ≤ 0.006) but did not differ between eyes with the wide macular and narrow macular type of staphyloma. Eyes with myopic maculopathy of category ≥ 3 according to the International Meta-Analysis for Pathologic Myopia classification had significantly thinner CTs and STs than those with category ≤ 2 (all P ≤ 0.005). In highly myopic eyes, a decrease in the CT and ST was more pronounced in eyes with more structural changes, such as longer axial length, steeper macular curvature, and the presence of posterior staphyloma.
An efficient vector-based CRISPR/Cas9 system in an Oreochromis mossambicus cell line using endogenous promoters
Authors: Hamar Jens , Kültz Dietmar
Published: April 2021

CRISPR/Cas9 gene editing is effective in manipulating genetic loci in mammalian cell cultures and whole fish but efficient platforms applicable to fish cell lines are currently limited. Our initial attempts to employ this technology in fish cell lines using heterologous promoters or a ribonucleoprotein approach failed to indicate genomic alteration at targeted sites in a tilapia brain cell line (OmB). For potential use in a DNA vector approach, endogenous tilapia beta Actin (OmBAct), EF1 alpha (OmEF1a), and U6 (TU6) promoters were isolated. The strongest candidate promoter determined by EGFP reporter assay, OmEF1a, was used to drive constitutive Cas9 expression in a modified OmB cell line (Cas9-OmB1). Cas9-OmB1 cell transfection with vectors expressing gRNAs driven by the TU6 promoter achieved mutational efficiencies as high as 81% following hygromycin selection. Mutations were not detected using human and zebrafish U6 promoters demonstrating the phylogenetic proximity of U6 promoters as critical when used for gRNA expression. Sequence alteration to TU6 improved mutation rate and cloning efficiency. In conclusion, we report new tools for ectopic expression and a highly efficient, economical system for manipulation of genomic loci and evaluation of their causal relationship with adaptive cellular phenotypes by CRISPR/Cas9 gene editing in fish cells.
Prevalence of lipase producer Aspergillus niger in nuts and anti-biofilm efficacy of its crude lipase against some human pathogenic bacteria
Authors: Yassein Asmaa S. , Hassan Mohamed M. , Elamary Rokaia B.
Published: April 2021

Nuts are the natural source of healthy lipids, proteins, and omega-3. They are susceptible to fungal and mycotoxins contamination because of their high nutritional value. Twenty-five species comprising 12 genera were isolated from 80 samples of dried fruits and nuts using the dilution plate method. Peanut recorded the highest level of contamination followed by coconut; almond and raisin were the lowest. Aspergillus was the most prevalent genus and A.niger, was the most dominant species. The morphological identification of the selected A.niger isolates as they were detected in high frequency of occurrence was confirmed by using 18SrRNA sequence. Ochratoxin biosynthesis gene Aopks was detected in the tested isolates. Lipase production by the selected A.niger isolates was determined with enzyme activity index (EAI) ranging from 2.02 to 3.28. A.niger-26 was the highest lipase producer with enzyme activity of 0.6 ± 0.1 U/ml by the trimetric method. Lip2 gene was also detected in the tested isolates. Finally, the antibacterial and antibiofilm efficiency of crude lipase against some human pathogens was monitored. Results exhibited great antibacterial efficacy with minimum bactericidal concentration (MBC) of 20 to 40 µl/100 µl against Escherichiacoli, Pseudomonasaeruginosa, Proteusmirabilis, and Methicillin-resistant Staphylococcusaureus (MRSA). Interestingly, significant anti-biofilm efficacy with inhibition percentages of 95.3, 74.9, 77.1 and 93.6% was observed against the tested pathogens, respectively.
Social and ethnic disparities in stillbirth and infant death in Denmark, 2005–2016
Authors: Damsted Rasmussen Trine , Villadsen Sarah Fredsted , Kragh Andersen Per , Smith Jervelund Signe , Nybo Andersen Anne-Marie
Published: April 2021

Ethnic disparity in stillbirth and infant death has been demonstrated in Europe. As the relation between migration and health change over time, this population based register study investigated the recent figures and explored if potential differences could be explained by the well-known educational and income inequalities in stillbirth and infant death using a novel approach. Stillbirth and infant mortality varied considerably according to country of origin, with only immigrants from China, Norway, and Poland having an overall lower risk than Danish women. Women of Pakistani, Turkish, and Somali origin had a particularly high risk of both outcomes. Women from recent high conflict areas displayed a pattern with increased stillbirth risk. An observed excess risks across generations was found, which is disturbing and rule out factors related to language barriers or newness. Differences in educational level and household income explained only part of the observed inequalities. Strengthening of the maternity care system to better understand and meet the needs of immigrant women seems needed to mitigate the disparities.
Author Correction: Estradiol and high fat diet associate with changes in gut microbiota in female ob/ob mice
Authors: Acharya Kalpana D. , Gao Xing , Bless Elizabeth P. , Chen Jun , Tetel Marc J.
Published: April 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Comprehensive surgical treatment strategy for spinal metastases
Authors: Wagner Arthur , Haag Elena , Joerger Ann-Kathrin , Jost Philipp , Combs Stephanie E. , Wostrack Maria , Gempt Jens , Meyer Bernhard
Published: April 2021

The management of patients with spinal metastases (SM) requires a multidisciplinary team of specialists involved in oncological care. Surgical management has evolved significantly over the recent years, which warrants reevaluation of its role in the oncological treatment concept. Any patient with a SM was screened for study inclusion. We report baseline characteristics, surgical procedures, complication rates, functional status and outcome of a large consecutive cohort undergoing surgical treatment according to an algorithm. 667 patients underwent 989 surgeries with a mean age of 65 years (min/max 20–94) between 2007 and 2018. The primary cancers mostly originated from the prostate (21.7%), breast (15.9%) and lung (10.0%). Surgical treatment consisted of dorsoventral stabilization in 69.5%, decompression without instrumentation in 12.5% and kyphoplasty in 18.0%. Overall survival reached 18.4 months (95% CI 9.8–26.9) and the median KPS increased by 10 within hospital stay. Surgical management of SMs should generally represent the first step of a conclusive treatment algorithm. The need to preserve long-term symptom control and biomechanical stability requires a surgical strategy currently not supported by level I evidence.
The quantitative comparison between high wall shear stress and high strain in the formation of paraclinoid aneurysms
Authors: Kim Jung-Jae , Yang Hyeondong , Kim Yong Bae , Oh Je Hoon , Cho Kwang-Chun
Published: April 2021

In the hemodynamic study, computational fluid dynamics (CFD) analysis has shown that high wall shear stress (WSS) is an important parameter in cerebral aneurysm formation. However, CFD analysis is not more realistic than fluid–structure interaction (FSI) analysis given its lack of considering the involvement of vascular structures. To investigate the relationship between the hemodynamic parameters and the aneurysm formation, the locations of high WSS and high strain were extracted from the CFD and FSI analyses, respectively. Then the distances between the aneurysm formation site and the locations of high WSS or high strain were calculated. A total of 37 intracranial paraclinoid aneurysms were enrolled for quantitative comparison. Additionally, the dura mater was modeled to facilitate realistic results in FSI analysis. The average distance from the location of the aneurysm formation site to the high strain (1.74 mm $$\pm $$
±
1.04 mm) was smaller than the average distance to the high WSS (3.33 mm $$\pm $$
±
1.18 mm). The presence of dura mater also influenced the findings in the aneurysm formation site. High strain extracted by FSI analysis is an important hemodynamic factor related to the formation of cerebral aneurysms. Strain parameter could help to predict the formation of aneurysms and elucidate the appropriate treatment.
A combined RAD-Seq and WGS approach reveals the genomic basis of yellow color variation in bumble bee Bombus terrestris
Authors: Rahman Sarthok Rasique , Cnaani Jonathan , Kinch Lisa N. , Grishin Nick V. , Hines Heather M.
Published: April 2021

Bumble bees exhibit exceptional diversity in their segmental body coloration largely as a result of mimicry. In this study we sought to discover genes involved in this variation through studying a lab-generated mutant in bumble bee Bombus terrestris, in which the typical black coloration of the pleuron, scutellum, and first metasomal tergite is replaced by yellow, a color variant also found in sister lineages to B. terrestris. Utilizing a combination of RAD-Seq and whole-genome re-sequencing, we localized the color-generating variant to a single SNP in the protein-coding sequence of transcription factor cut. This mutation generates an amino acid change that modifies the conformation of a coiled-coil structure outside DNA-binding domains. We found that all sequenced Hymenoptera, including sister lineages, possess the non-mutant allele, indicating different mechanisms are involved in the same color transition in nature. Cut is important for multiple facets of development, yet this mutation generated no noticeable external phenotypic effects outside of setal characteristics. Reproductive capacity was reduced, however, as queens were less likely to mate and produce female offspring, exhibiting behavior similar to that of workers. Our research implicates a novel developmental player in pigmentation, and potentially caste, thus contributing to a better understanding of the evolution of diversity in both of these processes.
Blood pressure dipping during REM and non-REM sleep in patients with moderate to severe obstructive sleep apnea
Authors: BaHammam Ahmed S. , Alshahrani Mana , Aleissi Salih A. , Olaish Awad H. , Alhassoon Mohammed H. , Shukr Afnan
Published: April 2021

A limited number of papers have addressed the association between non-dipping-blood pressure (BP) obstructive sleep apnea (OSA), and no study has assessed BP-dipping during rapid eye movement (REM) and non-REM sleep in OSA patients. This study sought to noninvasively assess BP-dipping during REM and non-REM (NREM)-sleep using a beat-by-beat measurement method (pulse-transit-time (PTT)). Thirty consecutive OSA patients (men = 50%) who had not been treated for OSA before and who had > 20-min of REM-sleep were included. During sleep, BP was indirectly determined via PTT. Patients were divided into dippers and non-dippers based on the average systolic-BP during REM and NREM-sleep. The studied group had a a median age of 50 (42–58.5) years and a body mass index of 33.8 (27.6–37.5) kg/m2. The median AHI of the study group was 32.6 (20.1–58.1) events/h (range: 7–124), and 89% of them had moderate-to-severe OSA. The prevalence of non-dippers during REM-sleep was 93.3%, and during NREM-sleep was 80%. During NREM sleep, non-dippers had a higher waist circumference and waist-hip-ratio, higher severity of OSA, longer-time spent with oxygen saturation < 90%, and a higher mean duration of apnea during REM and NREM-sleep. Severe OSA (AHI ≥ 30) was defined as an independent predictor of non-dipping BP during NREM sleep (OR = 19.5, CI: [1.299–292.75], p-value = 0.03). This short report demonstrated that BP-dipping occurs during REM and NREM-sleep in patients with moderate-to-severe OSA. There was a trend of more severe OSA among the non-dippers during NREM-sleep, and severe OSA was independently correlated with BP non-dipping during NREM sleep.
Detecting early onset of anthracyclines-induced cardiotoxicity using a novel panel of biomarkers in West-Virginian population with breast cancer
Authors: Lakhani Hari Vishal , Pillai Sneha S. , Zehra Mishghan , Dao Benjamin , Tirona Maria Tria , Thompson Ellen , Sodhi Komal
Published: April 2021

Cardiotoxic manifestation associated with breast cancer treatment by anthracycline regimen increases patients’ susceptibility to myocardial injury, reduction in left ventricular ejection fraction and complications associated with heart failure. There is currently no standardized, minimally invasive, cost effective and clinically verified procedure to monitor cardiotoxicity post-anthracycline therapy initiation, and to detect early onset of irreversible cardiovascular complications. This study aims to create a panel of novel biomarkers and circulating miRNAs associated with cardiotoxicity, further assessing their correlation with cardiac injury specific markers, troponin I and T, and demonstrate the development of cardiac dysfunction in breast cancer patients. Blood obtained from West Virginian females clinically diagnosed with breast cancer and receiving anthracyclines showed upregulated level of biomarkers and circulating miRNAs after 3 and 6 months of chemotherapy initiation with increased levels of cardiac troponin I and T. These biomarkers and miRNAs significantly correlated with elevated troponins. Following 6 months of anthracycline-regimens, 23% of the patient population showed cardiotoxicity with reduced left ventricular ejection fraction. Our results support the clinical application of plasma biomarkers and circulating miRNAs to develop a panel for early diagnosis of chemotherapy related cardiac dysfunction which will enable early detection of disease progression and management of irreversible cardiac damage.
Girls exhibit greater empathy than boys following a minor accident
Authors: Benenson Joyce F. , Gauthier Evelyne , Markovits Henry
Published: April 2021

Hundreds of studies find that girls and women report feeling greater empathy than boys and men in response to adverse events befalling others. Despite this, few non-self-report measures demonstrate similar sex differences. This produces the oft-cited conclusion that to conform to societal expectations of appropriate sex-typed behavior females report higher levels of empathy. Several studies of sex differences in areas of brain activation and on infants’ and young children’s behavior however provide suggestive findings that self-reports reflect actual underlying sex differences in experiencing concern about others. We demonstrate using behavioral indices that females experience more empathy than males after witnessing an adverse event befall a same-sex classmate. In our study, one member of a pair experienced a minor accident on the way to constructing a tower while a bystander observed. We measured whether bystanders ceased their ongoing activity, looked at the victim, waited for the victim to recover from the accident, and actively intervened to help the victim. Female more than male bystanders engaged in these activities. These behavioral results suggest that an adverse event produces different subjective experiences in females than males that motivate objectively different behaviors, consistent with findings from self-report measures of empathy.
Hand preference for the visual and auditory modalities in humans
Authors: Yang Yuqian , Weiss Peter H. , Fink Gereon R. , Chen Qi
Published: April 2021

The sensory dominance effect refers to the phenomenon that one sensory modality more frequently receives preferential processing (and eventually dominates consciousness and behavior) over and above other modalities. On the other hand, hand dominance is an innate aspect of the human motor system. To investigate how the sensory dominance effect interacts with hand dominance, we applied the adapted Colavita paradigm and recruited a large cohort of healthy right-handed participants (n = 119). While the visual dominance effect in bimodal trials was observed for the whole group (n = 119), about half of the right-handers (48%) showed a visual preference, i.e., their dominant hand effect manifested in responding to the visual stimuli. By contrast, 39% of the right-handers exhibited an auditory preference, i.e., the dominant hand effect occurred for the auditory responses. The remaining participants (13%) did not show any dominant hand preference for either visual or auditory responses. For the first time, the current behavioral data revealed that human beings possess a characteristic and persistent preferential link between different sensory modalities and the dominant vs. non-dominant hand. Whenever this preferential link between the sensory and the motor system was adopted, one dominance effect peaks upon the other dominance effect’s best performance.
The effects of lipid-lowering therapy on coronary plaque regression: a systematic review and meta-analysis
Authors: Li Yingrui , Deng Songbai , Liu Bin , Yan Yulin , Du Jianlin , Li Yu , Jing Xiaodong , Liu Yajie , Wang Jing , Du Jun , She Qiang
Published: April 2021

To assess the influence of lipid-lowering therapy on coronary plaque volume, and to identify the LDL and HDL targets for plaque regression to provide a comprehensive overview. The databases searched (from inception to 15 July 2020) to identify prospective studies investigating the impact of lipid-lowering therapy on coronary plaque volume and including quantitative measurement of plaque volume by intravascular ultrasound after treatment. Thirty-one studies that included 4997 patients were selected in the final analysis. Patients had significantly lower TAV (SMD: 0.123 mm3; 95% CI 0.059, 0.187; P = 0.000) and PAV (SMD: 0.123%; 95% CI 0.035, 0.212; P = 0.006) at follow-up. According to the subgroup analyses, TAV was significantly reduced in the LDL < 80 mg/dL and HDL > 45 mg/dL group (SMD: 0.163 mm3; 95% CI 0.092, 0.234; P = 0.000), and PAV was significantly reduced in the LDL < 90 mg/dL and HDL > 45 mg/dL group (SMD: 0.186%; 95% CI 0.081, 0.291; P = 0.001).Thirty-one studies that included 4997 patients were selected in the final analysis. Patients had significantly lower TAV (SMD: 0.123 mm3; 95% CI 0.059, 0.187; P = 0.000) and PAV (SMD: 0.123%; 95% CI 0.035, 0.212; P = 0.006) at follow-up. According to the subgroup analyses, TAV was significantly reduced in the LDL < 80 mg/dL and HDL > 45 mg/dL group (SMD: 0.163 mm3; 95% CI 0.092, 0.234; P = 0.000), and PAV was significantly reduced in the LDL < 90 mg/dL and HDL > 45 mg/dL group (SMD: 0.186%; 95% CI 0.081, 0.291; P = 0.001). Our meta-analysis suggests that not only should LDL be reduced to a target level of < 80 mg/dL, but HDL should be increased to a target level of > 45 mg/dL to regress coronary plaques.

Trial Registration PROSPERO identifier: CRD42019146170.
Clinical application of a lung cancer organoid (tumoroid) culture system
Authors: Yokota Etsuko , Iwai Miki , Yukawa Takuro , Yoshida Masakazu , Naomoto Yoshio , Haisa Minoru , Monobe Yasumasa , Takigawa Nagio , Guo Minzhe , Maeda Yutaka , Fukazawa Takuya , Yamatsuji Tomoki
Published: April 2021

Despite high expectations for lung tumoroids, they have not been applied in the clinic due to the difficulty of their long-term culture. Here, however, using AO (airway organoid) media developed by the Clevers laboratory, we succeeded in generating 3 lung tumoroid lines for long-term culture (>13 months) from 41 lung cancer cases (primary or metastatic). Use of nutlin-3a was key to selecting lung tumoroids that harbor mutant p53 in order to eliminate normal lung epithelial organoids. Next-generation sequencing (NGS) analysis indicated that each lung tumoroid carried BRAFG469A, TPM3-ROS1 or EGFRL858R/RB1E737*, respectively. Targeted therapies using small molecule drugs (trametinib/erlotinib for BRAFG469A, crizotinib/entrectinib for TPM3-ROS1 and ABT-263/YM-155 for EGFRL858R/RB1E737*) significantly suppressed the growth of each lung tumoroid line. AO media was superior to 3 different media developed by other laboratories. Our experience indicates that long-term lung tumoroid culture is feasible, allowing us to identify NGS-based therapeutic targets and determine the responsiveness to corresponding small molecule drugs.
COVID-19 information retrieval with deep-learning based semantic search, question answering, and abstractive summarization
Authors: Esteva Andre , Kale Anuprit , Paulus Romain , Hashimoto Kazuma , Yin Wenpeng , Radev Dragomir , Socher Richard
Published: April 2021

The COVID-19 global pandemic has resulted in international efforts to understand, track, and mitigate the disease, yielding a significant corpus of COVID-19 and SARS-CoV-2-related publications across scientific disciplines. Throughout 2020, over 400,000 coronavirus-related publications have been collected through the COVID-19 Open Research Dataset. Here, we present CO-Search, a semantic, multi-stage, search engine designed to handle complex queries over the COVID-19 literature, potentially aiding overburdened health workers in finding scientific answers and avoiding misinformation during a time of crisis. CO-Search is built from two sequential parts: a hybrid semantic-keyword retriever, which takes an input query and returns a sorted list of the 1000 most relevant documents, and a re-ranker, which further orders them by relevance. The retriever is composed of a deep learning model (Siamese-BERT) that encodes query-level meaning, along with two keyword-based models (BM25, TF-IDF) that emphasize the most important words of a query. The re-ranker assigns a relevance score to each document, computed from the outputs of (1) a question–answering module which gauges how much each document answers the query, and (2) an abstractive summarization module which determines how well a query matches a generated summary of the document. To account for the relatively limited dataset, we develop a text augmentation technique which splits the documents into pairs of paragraphs and the citations contained in them, creating millions of (citation title, paragraph) tuples for training the retriever. We evaluate our system (http://einstein.ai/covid) on the data of the TREC-COVID information retrieval challenge, obtaining strong performance across multiple key information retrieval metrics.
An engineered ligand trap inhibits leukemia inhibitory factor as pancreatic cancer treatment strategy
Authors: Hunter Sean A. , McIntosh Brianna J. , Shi Yu , Sperberg R. Andres Parra , Funatogawa Chie , Labanieh Louai , Soon Erin , Wastyk Hannah C. , Mehta Nishant , Carter Catherine , Hunter Tony , Cochran Jennifer R.
Published: April 2021

Leukemia inhibitory factor (LIF), a cytokine secreted by stromal myofibroblasts and tumor cells, has recently been highlighted to promote tumor progression in pancreatic and other cancers through KRAS-driven cell signaling. We engineered a high affinity soluble human LIF receptor (LIFR) decoy that sequesters human LIF and inhibits its signaling as a therapeutic strategy. This engineered ‘ligand trap’, fused to an antibody Fc-domain, has ~50-fold increased affinity (~20 pM) and improved LIF inhibition compared to wild-type LIFR-Fc, potently blocks LIF-mediated effects in pancreatic cancer cells, and slows the growth of pancreatic cancer xenograft tumors. These results, and the lack of apparent toxicity observed in animal models, further highlights ligand traps as a promising therapeutic strategy for cancer treatment.
Bisphenols exert detrimental effects on neuronal signaling in mature vertebrate brains
Authors: Schirmer Elisabeth , Schuster Stefan , Machnik Peter
Published: April 2021

Bisphenols are important plasticizers currently in use and are released at rates of hundreds of tons each year into the biosphere1–3. However, for any bisphenol it is completely unknown if and how it affects the intact adult brain4–6, whose powerful homeostatic mechanisms could potentially compensate any effects bisphenols might have on isolated neurons. Here we analyzed the effects of one month of exposition to BPA or BPS on an identified neuron in the vertebrate brain, using intracellular in vivo recordings in the uniquely suited Mauthner neuron in goldfish. Our findings demonstrate an alarming and uncompensated in vivo impact of both BPA and BPS—at environmentally relevant concentrations—on essential communication functions of neurons in mature vertebrate brains and call for the rapid development of alternative plasticizers. The speed and resolution of the assay we present here could thereby be instrumental to accelerate the early testing phase of next-generation plasticizers.
Global climate and nutrient controls of photosynthetic capacity
Authors: Peng Yunke , Bloomfield Keith J. , Cernusak Lucas A. , Domingues Tomas F. , Colin Prentice I.
Published: April 2021

There is huge uncertainty about how global exchanges of carbon between the atmosphere and land will respond to continuing environmental change. A better representation of photosynthetic capacity is required for Earth System models to simulate carbon assimilation reliably. Here we use a global leaf-trait dataset to test whether photosynthetic capacity is quantitatively predictable from climate, based on optimality principles; and to explore how this prediction is modified by soil properties, including indices of nitrogen and phosphorus availability, measured in situ. The maximum rate of carboxylation standardized to 25 °C (Vcmax25) was found to be proportional to growing-season irradiance, and to increase—as predicted—towards both colder and drier climates. Individual species’ departures from predicted Vcmax25 covaried with area-based leaf nitrogen (Narea) but community-mean Vcmax25 was unrelated to Narea, which in turn was unrelated to the soil C:N ratio. In contrast, leaves with low area-based phosphorus (Parea) had low Vcmax25 (both between and within communities), and Parea increased with total soil P. These findings do not support the assumption, adopted in some ecosystem and Earth System models, that leaf-level photosynthetic capacity depends on soil N supply. They do, however, support a previously-noted relationship between photosynthesis and soil P supply.
Staphylococcus aureus vWF-binding protein triggers a strong interaction between clumping factor A and host vWF
Authors: Viljoen Albertus , Viela Felipe , Mathelié-Guinlet Marion , Missiakas Dominique , Pietrocola Giampiero , Speziale Pietro , Dufrêne Yves F.
Published: April 2021

The Staphylococcus aureus cell wall-anchored adhesin ClfA binds to the very large blood circulating protein, von Willebrand factor (vWF) via vWF-binding protein (vWbp), a secreted protein that does not bind the cell wall covalently. Here we perform force spectroscopy studies on living bacteria to unravel the molecular mechanism of this interaction. We discover that the presence of all three binding partners leads to very high binding forces (2000 pN), largely outperforming other known ternary complexes involving adhesins. Strikingly, our experiments indicate that a direct interaction involving features of the dock, lock and latch mechanism must occur between ClfA and vWF to sustain the extreme tensile strength of the ternary complex. Our results support a previously undescribed mechanism whereby vWbp activates a direct, ultra-strong interaction between ClfA and vWF. This intriguing interaction represents a potential target for therapeutic interventions, including synthetic peptides inhibiting the ultra-strong interactions between ClfA and its ligands.