bluuebunny/crossref_metadata_2025 huggingface dataset:
Higher gametocyte production and mosquito infectivity in chronic compared to incident Plasmodium falciparum infections
Authors: Barry Aissata , Bradley John , Stone Will , Guelbeogo Moussa W. , Lanke Kjerstin , Ouedraogo Alphonse , Soulama Issiaka , Nébié Issa , Serme Samuel S. , Grignard Lynn , Patterson Catriona , Wu Lindsey , Briggs Jessica J. , Janson Owen , Awandu Shehu S. , Ouedraogo Mireille , Tarama Casimire W. , Kargougou Désiré , Zongo Soumanaba , Sirima Sodiomon B. , Marti Matthias , Drakeley Chris , Tiono Alfred B. , Bousema Teun
Published: April 2021

Plasmodium falciparum gametocyte kinetics and infectivity may differ between chronic and incident infections. In the current study, we assess parasite kinetics and infectivity to mosquitoes among children (aged 5–10 years) from Burkina Faso with (a) incident infections following parasite clearance (n = 48) and (b) chronic asymptomatic infections (n = 60). In the incident infection cohort, 92% (44/48) of children develop symptoms within 35 days, compared to 23% (14/60) in the chronic cohort. All individuals with chronic infection carried gametocytes or developed them during follow-up, whereas only 35% (17/48) in the incident cohort produce gametocytes before becoming symptomatic and receiving treatment. Parasite multiplication rate (PMR) and the relative abundance of ap2-g and gexp-5 transcripts are positively associated with gametocyte production. Antibody responses are higher and PMR lower in chronic infections. The presence of symptoms and sexual stage immune responses are associated with reductions in gametocyte infectivity to mosquitoes. We observe that most incident infections require treatment before the density of mature gametocytes is sufficient to infect mosquitoes. In contrast, chronic, asymptomatic infections represent a significant source of mosquito infections. Our observations support the notion that malaria transmission reduction may be expedited by enhanced case management, involving both symptom-screening and infection detection.
PAX8 and MECOM are interaction partners driving ovarian cancer
Authors: Bleu Melusine , Mermet-Meillon Fanny , Apfel Verena , Barys Louise , Holzer Laura , Bachmann Salvy Marianne , Lopes Rui , Amorim Monteiro Barbosa Inês , Delmas Cecile , Hinniger Alexandra , Chau Suzanne , Kaufmann Markus , Haenni Simon , Berneiser Karolin , Wahle Maria , Moravec Ivana , Vissières Alexandra , Poetsch Tania , Ahrné Erik , Carte Nathalie , Voshol Johannes , Bechter Elisabeth , Hamon Jacques , Meyerhofer Marco , Erdmann Dirk , Fischer Matteo , Stachyra Therese , Freuler Felix , Gutmann Sascha , Fernández César , Schmelzle Tobias , Naumann Ulrike , Roma Guglielmo , Lawrenson Kate , Nieto-Oberhuber Cristina , Cobos-Correa Amanda , Ferretti Stephane , Schübeler Dirk , Galli Giorgio Giacomo
Published: April 2021

The transcription factor PAX8 is critical for the development of the thyroid and urogenital system. Comprehensive genomic screens furthermore indicate an additional oncogenic role for PAX8 in renal and ovarian cancers. While a plethora of PAX8-regulated genes in different contexts have been proposed, we still lack a mechanistic understanding of how PAX8 engages molecular complexes to drive disease-relevant oncogenic transcriptional programs. Here we show that protein isoforms originating from the MECOM locus form a complex with PAX8. These include MDS1-EVI1 (also called PRDM3) for which we map its interaction with PAX8 in vitro and in vivo. We show that PAX8 binds a large number of genomic sites and forms transcriptional hubs. At a subset of these, PAX8 together with PRDM3 regulates a specific gene expression module involved in adhesion and extracellular matrix. This gene module correlates with PAX8 and MECOM expression in large scale profiling of cell lines, patient-derived xenografts (PDXs) and clinical cases and stratifies gynecological cancer cases with worse prognosis. PRDM3 is amplified in ovarian cancers and we show that the MECOM locus and PAX8 sustain in vivo tumor growth, further supporting that the identified function of the MECOM locus underlies PAX8-driven oncogenic functions in ovarian cancer.
Spontaneous nucleation on flat surface by depletion force in colloidal suspension
Authors: Nakamura Nobutomo , Sakamoto Yuto , Ogi Hirotsugu
Published: April 2021

Nucleation by sedimentation of colloidal particles on a flat surface is experimentally observed, and effect of attractive depletion force generated by polymers on nucleation is investigated. Sedimentation forms polycrystalline colloidal crystal on a flat surface, and above the threshold polymer concentration, ratio of the spontaneous nucleation increases, resulting in a decrease in the grain size, whereas dependence of the contact angle on the polymer concentration was not observed. We show that the interaction between particles and the flat surface mainly affects the spontaneous nucleation, not the interaction between the particles, and it is demonstrated that the nucleation process can be numerically reproduced using the rate equations.
Associations between green/blue spaces and mental health across 18 countries
Authors: White Mathew P. , Elliott Lewis R. , Grellier James , Economou Theo , Bell Simon , Bratman Gregory N. , Cirach Marta , Gascon Mireia , Lima Maria L. , Lõhmus Mare , Nieuwenhuijsen Mark , Ojala Ann , Roiko Anne , Schultz P. Wesley , van den Bosch Matilda , Fleming Lora E.
Published: April 2021

Living near, recreating in, and feeling psychologically connected to, the natural world are all associated with better mental health, but many exposure-related questions remain. Using data from an 18-country survey (n = 16,307) we explored associations between multiple measures of mental health (positive well-being, mental distress, depression/anxiety medication use) and: (a) exposures (residential/recreational visits) to different natural settings (green/inland-blue/coastal-blue spaces); and (b) nature connectedness, across season and country. People who lived in greener/coastal neighbourhoods reported higher positive well-being, but this association largely disappeared when recreational visits were controlled for. Frequency of recreational visits to green, inland-blue, and coastal-blue spaces in the last 4 weeks were all positively associated with positive well-being and negatively associated with mental distress. Associations with green space visits were relatively consistent across seasons and countries but associations with blue space visits showed greater heterogeneity. Nature connectedness was also positively associated with positive well-being and negatively associated with mental distress and was, along with green space visits, associated with a lower likelihood of using medication for depression. By contrast inland-blue space visits were associated with a greater likelihood of using anxiety medication. Results highlight the benefits of multi-exposure, multi-response, multi-country studies in exploring complexity in nature-health associations.
An examination of skeletal muscle and hepatic tissue transcriptomes from beef cattle divergent for residual feed intake
Authors: McKenna Clare , Keogh Kate , Porter Richard K. , Waters Sinead M. , Cormican Paul , Kenny David A.
Published: April 2021

The selection of cattle with enhanced feed efficiency is of importance with regard to reducing feed costs in the beef industry. Global transcriptome profiling was undertaken on liver and skeletal muscle biopsies from Simmental heifers and bulls divergent for residual feed intake (RFI), a widely acknowledged feed efficiency phenotype, in order to identify genes that may be associated with this trait. We identified 5 genes (adj. p < 0.1) to be differentially expressed in skeletal muscle between high and low RFI heifers with all transcripts involved in oxidative phosphorylation and mitochondrial homeostasis. A total of 11 genes (adj. p < 0. 1) were differentially expressed in liver tissue between high and low RFI bulls with differentially expressed genes related to amino and nucleotide metabolism as well as endoplasmic reticulum protein processing. No genes were identified as differentially expressed in either heifer liver or bull muscle analyses. Results from this study show that the molecular control of RFI in young cattle is modified according to gender, which may be attributable to differences in physiological maturity between heifers and bulls of the same age. Despite this we have highlighted a number of genes that may hold potential as molecular biomarkers for RFI cattle.
Functional modulation of phosphodiesterase-6 by calcium in mouse rod photoreceptors
Authors: Turunen Teemu , Koskelainen Ari
Published: April 2021

Phosphodiesterase-6 (PDE6) is a key protein in the G-protein cascade converting photon information to bioelectrical signals in vertebrate photoreceptor cells. Here, we demonstrate that PDE6 is regulated by calcium, contrary to the common view that PDE1 is the unique PDE class whose activity is modulated by intracellular Ca2+. To broaden the operating range of photoreceptors, mammalian rod photoresponse recovery is accelerated mainly by two calcium sensor proteins: recoverin, modulating the lifetime of activated rhodopsin, and guanylate cyclase-activating proteins (GCAPs), regulating the cGMP synthesis. We found that decreasing rod intracellular Ca2+ concentration accelerates the flash response recovery and increases the basal PDE6 activity (βdark) maximally by ~ 30% when recording local electroretinography across the rod outer segment layer from GCAPs−/− recoverin−/− mice. Our modeling shows that a similar elevation in βdark can fully explain the observed acceleration of flash response recovery in low Ca2+. Additionally, a reduction of the free Ca2+ in GCAPs−/− recoverin−/− rods shifted the inhibition constants of competitive PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) against the thermally activated and light-activated forms of PDE6 to opposite directions, indicating a complex interaction between IBMX, PDE6, and calcium. The discovered regulation of PDE6 is a previously unknown mechanism in the Ca2+-mediated modulation of rod light sensitivity.
The association between tobacco control policy implementation and country-level socioeconomic factors in 31 European countries
Authors: Feliu Ariadna , Filippidis Filippos T. , Joossens Luk , Amalia Beladenta , Tigova Olena , Martínez Cristina , Fernández Esteve
Published: April 2021

European countries have made significant progress in implementing tobacco control policies to reduce tobacco use; however, whether socioeconomic status (SES) of a country may influence the implementation of such policies is unknown. The aim of this study is to assess the association between country-level SES and the implementation level of tobacco control policies in 31 European countries. An ecological study using data from Eurostat, Human Development Reports on several SES indicators and the Tobacco Control Scale (TCS) of 2016 was conducted to measure country-level tobacco control policies. We analysed the relationship between SES indicators and the TCS by means of scatter-plots and Spearman’s rank correlation coefficients (rsp) and multivariable linear regression analysis. In Europe, no statistically significant association was found between SES factors and the level of implementation of tobacco control policies. Only public spending on tobacco control was associated with all SES factors, except for Gini Index (an income inequality index). The strongest associations of TCS scores for this policy domain were found with the Human Development Index (rsp = 0.586; p < 0.001) and the Gross Domestic Product per capita (in Euros) (rsp = 0.562; p = 0.001). The adjusted linear regression model showed an association of tobacco control policy implementation with countries’ geographical location (Western Europe, β = − 15.7; p = 0.009, compared to Northern Europe). In conclusion, no association was found between SES factors and the level of implementation of tobacco control policies in 31 European countries; policymakers should be aware that tobacco control policies could be successfully implemented despite socioeconomic constraints, especially when these policies are of low cost and cost-effective (i.e., smoke-free bans and taxation).
Clinical impact of left and right axis deviations with narrow QRS complex on 3-year outcomes in a hospital-based population in Japan
Authors: Seko Yuta , Kato Takao , Yamaji Yuhei , Haruna Yoshisumi , Nakane Eisaku , Haruna Tetsuya , Inoko Moriaki
Published: April 2021

While the prognostic impact of QRS axis deviation has been assessed, it has never been investigated in patients without conduction block. Thus, we evaluated the prognostic impact of QRS-axis deviation in patients without conduction block. We retrospectively analyzed 3353 patients who had undergone both scheduled transthoracic echocardiography and electrocardiography in 2013 in a hospital-based population, after excluding patients with a QRS duration of ≥ 110 ms, pacemaker placement, and an QRS-axis − 90° to − 180° (northwest axis). The study population was categorized into three groups depending on the mean frontal plane QRS axis as follows: patients with left axis deviation (N = 171), those with right axis deviation (N = 94), and those with normal axis (N = 3088). The primary outcome was a composite of all-cause death and major adverse cardiovascular events. The cumulative 3-year incidence of the primary outcome measure was significantly higher in the left axis deviation group (26.4% in the left axis deviation, 22.7% in the right axis deviation, and 18.4% in the normal axis groups, log-rank P = 0.004). After adjusting for confounders, the excess risk of primary outcome measure remained significant in the left axis deviation group (hazard ratio [HR] 1.44; 95% confidence interval [CI] 1.07–1.95; P = 0.02), while the excess risk of primary outcome measure was not significant in the right axis deviation group (HR 1.22; 95% CI 0.76–1.96; P = 0.41). Left axis deviation was associated with a higher risk of a composite of all-cause death and major adverse cardiovascular events in hospital-based patients without conduction block in Japan.
Quantitative evaluations of vortex vein ampullae by adjusted 3D reverse projection model of ultra-widefield fundus images
Authors: Funatsu Ryoh , Terasaki Hiroto , Shiihara Hideki , Kawano Sumihiro , Hirokawa Mariko , Tanabe Yasushi , Fujiwara Tomoharu , Mitamura Yoshinori , Sakamoto Taiji , Sonoda Shozo
Published: April 2021

The purpose of this study was to determine the number and location of vortex vein ampullae (VVA) in normal eyes. This was an observational retrospective study. Montage images of one on-axis and two off-axis ultra-widefield images of 74 healthy eyes were enhanced, and reverse projected onto a 3D model eye. The number and distance between the optic disc to each VVA in the four sectors were compared. The significance of correlations between these values and age, sex, visual acuity, refractive error, and axial length was determined. The mean number of VVA was 8.10/eye with 1.84, 2.12, 2.19 and 1.95 in upper lateral, lower lateral, upper nasal, and lower nasal sectors, respectively. The mean number of VVA/eye was significantly greater in men at 8.43 than women at 7.76 (P = 0.025). The mean distance between the optic disc and VVA was 14.15 mm, and it was 14.04, 15.55, 13.29 and 13.66 mm in the upper lateral, lower lateral, upper nasal and lower nasal sectors, respectively (all P < 0.05). The number and location of VVA can be obtained non-invasively, and the number was significantly higher in men than women. This technique can be used to determine whether these values are altered in a retinochoroidal disease.
New approach to determine the healthy immune variations by combining clustering methods
Authors: Liefferinckx Claire , De Grève Zacharie , Toubeau Jean-François , Perée Hélène , Quertinmont Eric , Tafciu Vjola , Minsart Charlotte , Rahmouni Souad , Georges Michel , Vallée François , Franchimont Denis
Published: April 2021

Immune-mediated inflammatory diseases are characterized by variability in disease presentation and severity but studying it is a challenging task. Defining the limits of a healthy immune system is therefore a prior step to capture variability in disease conditions. The goal of this study is to characterize the global immune cell composition along with their influencing factors. Blood samples were collected from 2 independent cohorts of respectively 389 (exploratory) and 208 (replication) healthy subjects. Twelve immune cells were measured in blood together with biological parameters. Three complementary clustering approaches were used to evaluate if variability related to the immune cells could be characterized as clusters or as a continuum. Large coefficients of variation confirmed the inter-individual variability of immune cells. Considering all subset variations in an overall analysis, it appeared that the immune makeup was organized as a continuum through the two cohorts. Some intrinsic and environmental factors affected the inter-individual variability of cells but without unveiling separable groups with similar features. This study provides a framework based on complementary clustering approach for analyzing inter-individual variability of immune cells. Our analyses support the absence of clusters in our two healthy cohorts. Also, our study reports some influence of age, gender, BMI, cortisol, season and CMV infection on immune variability.
Cumulative risks of colorectal cancer in Han Chinese patients with Lynch syndrome in Taiwan
Authors: Kamiza Abram Bunya , Wang Wen-Chang , You Jeng-Fu , Tang Reiping , Chien Huei-Tzu , Lai Chih-Hsiung , Chiu Li-Ling , Lo Tsai-Ping , Hung Kuan-Yi , Hsiung Chao A. , Yeh Chih-Ching
Published: April 2021

Patients with Lynch syndrome have a high risk of colorectal cancer (CRC). In this study, we estimated the age- and sex-specific cumulative risks of CRC in Han Chinese patients with Lynch syndrome caused by the pathogenic germline mutations in MLH1 or MSH2 in Taiwan. Based on 321 mutation carriers and 419 non-mutation carriers from 75 pedigrees collected in an Amsterdam criteria family registry in Taiwan, the age- and sex-specific cumulative risks of CRC in male carriers of mutation in MLH1 and MSH2 at the age of 70 years were 60.3% (95% confidence interval (CI) = 31.1%–89.9%) and 76.7% (95% CI = 37.2%–99.0%), respectively. For females, the cumulative risks of CRC at the age of 70 were estimated to be 30.6% (95% CI = 14.3%–57.7%) and 49.3% (95% CI = 21.9%–84.5%) in the carriers of MLH1 and MSH2 germline mutations, respectively. In conclusion, the cumulative risks of CRC at the age of 70 in the Han Chinese patients is higher in mutation carriers than non-mutation carriers and male mutation carriers have a higher cumulative risk of developing CRC than the female mutation carriers.
A phantom study to contrast and compare polymer and gold fiducial markers in radiotherapy simulation imaging
Authors: Lim Joon Daryl , Smith Drew , Tacey Mark , Schneider Michal , Harris Benjamin , Ong Wee Loon , Foroudi Farshad , Jenkins Trish , Wada Morikatsu , Chao Michael , Rykers Kym , Khoo Vincent
Published: April 2021

To assess visibility and artifact characteristics of polymer fiducials compared to standard gold fiducials for radiotherapy CT and MRI simulation. Three gold and three polymer fiducials were inserted into a CT and MRI tissue-equivalent phantom that approximated the prostate cancer radiotherapy configuration. The phantom and fiducials were imaged on CT and MRI. Images were assessed in terms of fiducial visibility and artifact. ImageJ was employed to quantify the pixel gray-scale of each fiducial and artifact. Fiducial gray-scale histograms and profiles were generated for analysis. Objective measurements of the contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), and artifact index (AI) were calculated. The CT images showed that the gold fiducials are visually brighter, with greater contrast than the polymer. The higher peak values illustrate this in the line profiles. However, they produce bright radiating and dark shadowing artifacts. This is depicted by the greater width of line profiles and the disruption of phantom area profiles. Quantitatively this results in greater percentile ranges of the histograms. Furthermore, for CT, gold had a higher CNR than polymer, relative to the phantom. However, the gold CNR and SNR were degraded by the greater artifact and thus AI. Both fiducials were visible on MRI and had similar histograms and profiles that were also reflected in comparable CNR, SNR and AI. Polymer fiducials were well visualized in a phantom on CT and MR and produce less artifact than the gold fiducials. Polymer markers could enhance the quality and accuracy of radiotherapy co-registration and planning but require clinical confirmation.
Deep learning-based automated and universal bubble detection and mask extraction in complex two-phase flows
Authors: Kim Yewon , Park Hyungmin
Published: April 2021

While investigating multiphase flows experimentally, the spatiotemporal variation in the interfacial shape between different phases must be measured to analyze the transport phenomena. For this, numerous image processing techniques have been proposed, showing good performance. However, they require trial-and-error optimization of thresholding parameters, which are not universal for all experimental conditions; thus, their accuracy is highly dependent on human experience, and the overall processing cost is high. Motivated by the remarkable improvements in deep learning-based image processing, we trained the Mask R-CNN to develop an automated bubble detection and mask extraction tool that works universally in gas–liquid two-phase flows. The training dataset was rigorously optimized to improve the model performance and delay overfitting with a finite amount of data. The range of detectable bubble size (particularly smaller bubbles) could be extended using a customized weighted loss function. Validation with different bubbly flows yields promising results, with AP50 reaching 98%. Even while testing with bubble-swarm flows not included in the training set, the model detects more than 95% of the bubbles, which is equivalent or superior to conventional image processing methods. The pure processing speed for mask extraction is more than twice as fast as conventional approaches, even without counting the time required for tedious threshold parameter tuning. The present bubble detection and mask extraction tool is available online (https://github.com/ywflow/BubMask).
Competitive interactions as a mechanism for chemical diversity maintenance in Nodularia spumigena
Authors: Lage Sandra , Mazur-Marzec Hanna , Gorokhova Elena
Published: April 2021

Nodularia spumigena is a bloom-forming diazotrophic cyanobacterium inhabiting brackish waters worldwide. This species produces non-ribosomal peptides (NRPs), including the hepatotoxin nodularin, often referred to as cyanotoxin. Several known classes of NRPs have various biological activities, although their modes of action are poorly understood. In the Baltic N. spumigena, there is a high NRP chemodiversity among strains, allowing their grouping in specific chemotypes and subgroups. Therefore, it is relevant to ask whether the NRP production is affected by intraspecific interactions between the co-existing strains. Using a novel approach that combines culture technique and liquid chromatography-tandem mass spectrometry for the NRP analysis, we examined N. spumigena strains under mono- and co-culture conditions. The test strains were selected to represent N. spumigena belonging to the same or different chemotype subgroups. In this setup, we observed physiological and metabolic responses in the test strains grown without cell contact. The changes in NRP levels to co-culture conditions were conserved within a chemotype subgroup but different between the subgroups. Our results suggest that intraspecific interactions may promote a chemical diversity in N. spumigena population, with higher NRP production compared to a single-strain population. Studying allelochemical signalling in this cyanobacterium is crucial for understanding toxicity mechanisms and plankton community interactions in the Baltic Sea and other aquatic systems experiencing regular blooms.
Factors affecting resolution of subretinal fluid after selective retina therapy for central serous chorioretinopathy
Authors: Kyo Akika , Yamamoto Manabu , Hirayama Kumiko , Kohno Takeya , Theisen-Kunde Dirk , Brinkmann Ralf , Miura Yoko , Honda Shigeru
Published: April 2021

The purpose of this study was to investigate the factors of clinical outcome of selective retina therapy (SRT) for central serous chorioretinopathy (CSC). This retrospective study included 77 eyes of 77 patients, who were treated with SRT for CSC and observed at least 6 months after the treatment. SRT laser (527 nm, 1.7 µs, 100 Hz) was used for treatment. The mean best-corrected visual acuity (logMAR), central macular thickness (CMT) and central choroidal thickness were changed from baseline to at 6-months follow-up with significant difference. The multivariate analyses found that the rate of change (reduction) in CMT was associated with focal leakage type on fluorescein angiography (FA) (p = 0.03, coefficient 15.26, 95% confidence interval 1.72–28.79) and larger baseline CMT (p < 0.01, coefficient − 0.13, 95% confidence interval − 0.13 to − 0.05). Complete resolution of subretinal fluid was associated with nonsmoking history (p = 0.03, odds ratio 0.276, 95% confidence interval 0.086–0.887) and focal leakage type on FA (p < 0.01, odds ratio 0.136, 95% confidence interval 0.042–0.437). These results may be useful for predicting the therapeutic effectiveness of SRT.
Compressions of magnetorheological fluids under instantaneous magnetic field and constant area
Authors: Wang Hongyun , Bi Cheng , Zhang Yongju , Zhang Li , Zhou Fenfen
Published: April 2021

Compressions of magnetorheological (MR) fluids have been carried out under instantaneous magnetic fields. The yield strength of the MR fluid in compressive mode has been derived by assuming that it was a transformed shear flow in Bi-visous model. The compressive stresses have experimentally studied under different magnetic fields, different initial gap distances and different compressive velocities. The nominal yield shear stresses of the compressed MR fluid under different influential factors have been calculated. The compressive stress increased in a power law as the applied magnetic field increased, while it decreased as the initial gap distance and the compressive velocity increased. With the increase of magnetic field, the difference between the nominal yield shear stress curves increased, and the exponents of the power law increased with the increase of the magnetic field strengths. A larger initial gap distance and a lower compressive velocity resulted in a higher nominal yield shear stress under the same instantaneous magnetic field. The achieved results of the nominal yield shear stress with magnetic field seemed to deviate from the prediction of dipole model, and the chain structure aggregation effect, the sealing effect and the friction effect by compression should be considered.
A phase 2a clinical study on the safety and efficacy of individualized dosed mebendazole in patients with advanced gastrointestinal cancer
Authors: Mansoori S. , Fryknäs M. , Alvfors C. , Loskog A. , Larsson R. , Nygren P.
Published: April 2021

Mebendazole is used extensively for treatment of local gut helminthic and invasive echinococcus infections. Anticancer effects of mebendazole have been shown in experimental cancer models and in case studies in patients with advanced cancer. Given these observations, the aims of this study were to investigate safety and efficacy of individualized dosed mebendazole in the cancer indication. Patients with treatment refractory gastrointestinal cancer were treated with individualized dose adjusted mebendazole up to 4 g/day to target a serum concentration of 300 ng/ml. Efficacy and safety were assessed by CT-scans, clinical surveillance and blood sampling. Eleven patients were included in the study and 10 started the treatment phase. Two patients stopped treatment prior to and the remaining eight after tumour evaluation by CT-scan at 8 weeks, all due to progressive disease. Four patients also fulfilled criteria suggested for hyperprogression. Only five patients reached the target serum-mebendazole concentration. No severe adverse effects were observed. Individualized dose adjusted mebendazole is safe and well tolerated in patients with advanced cancer but all patients experienced rapid progressive disease. New approaches such as prodrug development and combination with other anticancer drugs seem needed for further exploration of mebendazole as an anticancer drug.
Recurrent somatic mutations and low germline predisposition mutations in Korean ALL patients
Authors: Shin Sang-Yong , Lee Hyeonah , Lee Seung-Tae , Choi Jong Rak , Jung Chul Won , Koo Hong Hoe , Kim Sun-Hee
Published: April 2021

In addition to somatic mutations, germline genetic predisposition to hematologic malignancies is currently emerging as an area attracting high research interest. In this study, we investigated genetic alterations in Korean acute lymphoblastic leukemia/lymphoma (ALL) patients using targeted gene panel sequencing. To this end, a gene panel consisting of 81 genes that are known to be associated with 23 predisposition syndromes was investigated. In addition to sequence variants, gene-level copy number variations (CNVs) were investigated as well. We identified 197 somatic sequence variants and 223 somatic CNVs. The IKZF1 alteration was found to have an adverse effect on overall survival (OS) and relapse-free survival (RFS) in childhood ALL. We found recurrent somatic alterations in Korean ALL patients similar to previous studies on both prevalence and prognostic impact. Six patients were found to be carriers of variants in six genes associated with primary immunodeficiency disorder (PID). Of the 81 genes associated with 23 predisposition syndromes, this study found only one predisposition germline mutation (TP53) (1.1%). Altogether, our study demonstrated a low probability of germline mutation predisposition to ALL in Korean ALL patients.
The synergistic effect of Canady Helios cold atmospheric plasma and a FOLFIRINOX regimen for the treatment of cholangiocarcinoma in vitro
Authors: Jones Olivia , Cheng Xiaoqian , Murthy Saravana R. K. , Ly Lawan , Zhuang Taisen , Basadonna Giacomo , Keidar Michael , Canady Jerome
Published: April 2021

Cholangiocarcinoma (CCA) is a rare biliary tract cancer with a low five-year survival rate and high recurrence rate after surgical resection. Currently treatment approaches include systemic chemotherapeutics such as FOLFIRINOX, a chemotherapy regimen is a possible treatment for severe CCA cases. A limitation of this chemotherapy regimen is its toxicity to patients and adverse events. There exists a need for therapies to alleviate the toxicity of a FOLFIRINOX regimen while enhancing or not altering its anticancer properties. Cold atmospheric plasma (CAP) is a technology with a promising future as a selective cancer treatment. It is critical to know the potential interactions between CAP and adjuvant chemotherapeutics. In this study the aim is to characterize the efficacy of FOLFIRINOX and CAP in combination to understand potential synergetic effect on CCA cells. FOLFIRINOX treatment alone at the highest dose tested (53.8 µM fluorouracil, 13.7 µM Leucovorin, 5.1 µM Irinotecan, and 3.7 µM Oxaliplatin) reduced CCA cell viability to below 20% while CAP treatment alone for 7 min reduced viability to 3% (p < 0.05). An analysis of cell viability, proliferation, and cell cycle demonstrated that CAP in combination with FOLFIRINOX is more effective than either treatment alone at a lower FOLFIRINOX dose of 6.7 µM fluorouracil, 1.7 µM leucovorin, 0.6 µM irinotecan, and 0.5 µM oxaliplatin and a shorter CAP treatment of 1, 3, or 5 min. In conclusion, CAP has the potential to reduce the toxicity burden of FOLFIRINOX and warrants further investigation as an adjuvant therapy.
Population-based serology reveals risk factors for RSV infection in children younger than 5 years
Authors: Andeweg Stijn P. , Schepp Rutger M. , van de Kassteele Jan , Mollema Liesbeth , Berbers Guy A. M. , van Boven Michiel
Published: April 2021

Respiratory syncytial virus (RSV) infection is a leading cause of hospitalization in infants. Underlying risk factors for RSV infection in the general population are not well understood, as previous work has focused on severe outcomes of infection in a clinical setting. Here we use RSV-specific IgG and IgA antibody measurements from two population-based cross-sectional serosurveys carried out in the Netherlands (n = 682) to classify children up to 5 years as seronegative or seropositive. We employ a generalized additive model to estimate the probability of prior RSV infection as function of age, date of birth within the year, and other risk factors. The analyses show that the majority of children have experienced a RSV infection before the age of 2 years. Age and birthdate are strong predictors of RSV infection in the first years of life, and children born in summer have higher estimated probability of infection than those born in winter [e.g., 0.56 (95% CI 0.45–0.66) vs. 0.32 (0.21–0.45) at age 1 year]. Our analyses reveal that the mean age at infection depends on date of birth, which has implications for the design of vaccination programmes and prioritisation schemes for the prophylactic use of monoclonal antibodies.
Investigation of water bonding status of normal and psoriatic skin in vivo using diffuse reflectance spectroscopy
Authors: Yang Chao-Chun , Yen Yun-Yo , Hsu Chao-Kai , Cheng Nan-Yu , Tzeng Shih-Yu , Chou Shih-Jay , Chang Jun-Ming , Tseng Sheng-Hao
Published: April 2021

Psoriasis affects more than 125 million people worldwide, and the diagnosis and treatment efficacy evaluation of the disease mainly rely on clinical assessments that could be subjective. Our previous study showed that the skin erythema level could be quantified using diffuse reflectance spectroscopy (DRS), and the hemoglobin concentration of most psoriatic lesion was higher than that of its adjacent uninvolved skin. While the compromised epidermal barrier function has been taken as the major cause of clinical manifestation of skin dryness and inflammation of psoriasis, very few methods can be used to effectively evaluate this function. In this study, we investigate the near infrared spectroscopic features of psoriatic (n = 21) and normal (n = 21) skin that could link to the epidermal barrier function. From the DRS measurements, it was found that the water bonding status and light scattering properties of psoriasis are significantly different from those of uninvolved or normal skin. The connection between these parameters to the epidermal barrier function and morphology will be discussed. Our results suggest that objective evaluation of epidermal barrier function of psoriasis could be achieved using a simple DRS system.
SARS-CoV-2 does not have a strong effect on the nasopharyngeal microbial composition
Authors: Braun Tzipi , Halevi Shiraz , Hadar Rotem , Efroni Gilate , Glick Saar Efrat , Keller Natahan , Amir Amnon , Amit Sharon , Haberman Yael
Published: April 2021

The coronavirus disease 2019 (COVID-19) has rapidly spread around the world, impacting the lives of many individuals. Growing evidence suggests that the nasopharyngeal and respiratory tract microbiome are influenced by various health and disease conditions, including the presence and the severity of different viral disease. To evaluate the potential interactions between Severe Acute Respiratory Syndrome Corona 2 (SARS-CoV-2) and the nasopharyngeal microbiome. Microbial composition of nasopharyngeal swab samples submitted to the clinical microbiology lab for suspected SARS-CoV-2 infections was assessed using 16S amplicon sequencing. The study included a total of 55 nasopharyngeal samples from 33 subjects, with longitudinal sampling available for 12 out of the 33 subjects. 21 of the 33 subjects had at least one positive COVID-19 PCR results as determined by the clinical microbiology lab. Inter-personal variation was the strongest factor explaining > 75% of the microbial variation, irrespective of the SARS-CoV-2 status. No significant effect of SARS-CoV-2 on the nasopharyngeal microbial community was observed using multiple analysis methods. These results indicate that unlike some other viruses, for which an effect on the microbial composition was noted, SARS-CoV-2 does not have a strong effect on the nasopharynx microbial habitants.
Improved parallel magnetic resonance imaging reconstruction with multiple variable density sampling
Authors: Sheng Jinhua , Shi Yuchen , Zhang Qiao
Published: April 2021

Generalized auto-calibrating partially parallel acquisitions (GRAPPA) and other parallel Magnetic Resonance Imaging (pMRI) methods restore the unacquired data in k-space by linearly calculating the undersampled data around the missing points. In order to obtain the weight of the linear calculation, a small number of auto-calibration signal (ACS) lines need to be sampled at the center of the k-space. Therefore, the sampling pattern used in this type of method is to full sample data in the middle area and undersample in the outer k-space with nominal reduction factors. In this paper, we propose a novel reconstruction method with a multiple variable density sampling (MVDS) that is different from traditional sampling patterns. Our method can significantly improve the image quality using multiple reduction factors with fewer ACS lines. Specifically, the traditional sampling pattern only uses a single reduction factor to uniformly undersample data in the region outside the ACS, but we use multiple reduction factors. When sampling the k-space data, we keep the ACS lines unchanged, use a smaller reduction factor for undersampling data near the ACS lines and a larger reduction factor for the outermost part of k-space. The error is lower after reconstruction of this region by undersampled data with a smaller reduction factor. The experimental results show that with the same amount of data sampled, using NL-GRAPPA to reconstruct the k-space data sampled by our method can result in lower noise and fewer artifacts than traditional methods. In particular, our method is extremely effective when the number of ACS lines is small.
Suppression of human T cell activation by derivatives of glycerol monolaurate
Authors: Fosdick Micaela G. , Chheda Pratik Rajesh , Tran Phuong M. , Wolff Alex , Peralta Ronal , Zhang Michael Y. , Kerns Robert , Houtman Jon C. D.
Published: April 2021

Glycerol monolaurate (GML), a naturally occurring monoglyceride, is widely used commercially for its antimicrobial properties. Interestingly, several studies have shown that GML not only has antimicrobial properties but is also an anti-inflammatory agent. GML inhibits peripheral blood mononuclear cell proliferation and inhibits T cell receptor (TCR)-induced signaling events. In this study, we perform an extensive structure activity relationship analysis to investigate the structural components of GML necessary for its suppression of human T cell activation. Human T cells were treated with analogs of GML, differing in acyl chain length, head group, linkage of acyl chain, and number of laurate groups. Treated cells were then tested for changes in membrane dynamics, LAT clustering, calcium signaling, and cytokine production. We found that an acyl chain with 12–14 carbons, a polar head group, an ester linkage, and a single laurate group at any position are all necessary for GML to inhibit protein clustering, calcium signaling, and cytokine production. Removing the glycerol head group or replacing the ester linkage with a nitrogen prevented derivative-mediated inhibition of protein cluster formation and calcium signaling, while still inhibiting TCR-induced cytokine production. These findings expand our current understanding of the mechanisms of action of GML and the of GML needed to function as a novel immunosuppressant.
Non-autoimmune diabetes mellitus and the risk of virus infections: a systematic review and meta-analysis of case-control and cohort studies
Authors: Lontchi-Yimagou Eric , Feutseu Charly , Kenmoe Sebastien , Djomkam Zune Alexandra Lindsey , Kinyuy Ekali Solange Fai , Nguewa Jean Louis , Choukem Siméon Pierre , Mbanya Jean Claude , Gautier Jean Francois , Sobngwi Eugene
Published: April 2021

A significant number of studies invoked diabetes as a risk factor for virus infections, but the issue remains controversial. We aimed to examine whether non-autoimmune diabetes mellitus enhances the risk of virus infections compared with the risk in healthy individuals without non-autoimmune diabetes mellitus. In this systematic review and meta-analysis, we assessed case-control and cohort studies on the association between non-autoimmune diabetes and viruses. We searched PubMed, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Web of Science with no language restriction, to identify articles published until February 15, 2021. The main outcome assessment was the risk of virus infection in individuals with non-autoimmune diabetes. We used a random-effects model to pool individual studies and assessed heterogeneity (I2) using the χ2 test on Cochrane’s Q statistic. This study is registered with PROSPERO, number CRD42019134142. Out of 3136 articles identified, we included 68 articles (90 studies, as the number of virus and or diabetes phenotype varied between included articles). The summary OR between non-autoimmune diabetes and virus infections risk were, 10.8(95% CI: 10.3–11.4; 1-study) for SARS-CoV-2; 3.6(95%CI: 2.7–4.9,I2 = 91.7%; 43-studies) for HCV; 2.7(95% CI: 1.3–5.4,I2 = 89.9%, 8-studies;) for HHV8; 2.1(95% CI: 1.7–2.5; 1-study) for H1N1 virus; 1.6(95% CI: 1.2–2.13,I2 = 98.3%, 27-studies) for HBV; 1.5(95% CI: 1.1–2.0; 1-study) for HSV1; 3.5(95% CI: 0.6–18.3 ,I2 = 83.9%, 5-studies) for CMV; 2.9(95% CI: 1–8.7, 1-study) for TTV; 2.6(95% CI: 0.7–9.1, 1-study) for Parvovirus B19; 0.7(95% CI: 0.3–1.5 , 1-study) for coxsackie B virus; and 0.2(95% CI: 0–6.2; 1-study) for HGV. Our findings suggest that, non-autoimmune diabetes is associated with increased susceptibility to viruses especially SARS-CoV-2, HCV, HHV8, H1N1 virus, HBV and HSV1. Thus, these viruses deserve more attention from diabetes health-care providers, researchers, policy makers, and stakeholders for improved detection, overall proper management, and efficient control of viruses in people with non-autoimmune diabetes.
Serum correlation, demographic differentiation, and seasonality of blubber testosterone in common bottlenose dolphins, Tursiops truncatus, in Sarasota Bay, FL
Authors: Sherman Kathryn K. , Beaulieu-McCoy Nicole E. , Wurster Elyse L. , Wells Randall S. , Smith Cynthia R. , Barleycorn Aaron A. , Allen Jason B. , Kellar Nicholas M.
Published: April 2021

Blubber and serum testosterone levels were compared among 55 individual common bottlenose dolphins,Tursiops truncatus, in Sarasota Bay, FL during 2011–2019. A significant positive relationship between the matrices was found in male testosterone concentrations in 29 paired samples (r2 = 0.932). Mature males (n = 17) had 300 times greater mean testosterone concentration in serum than immature males (n = 17). A comparison of blubber samples, including 12 females, 24 immature males, and 19 mature males, revealed significant differences in mean blubber testosterone values among all three demographics. Immature males had greater than 6 times the average blubber testosterone concentration of females and mature males had almost 100 times that of immature males. Estimated testis volume was highly correlated with blubber testosterone concentration and mature males had 60 times greater average testis volume than immature males. We observed seasonal variation in blubber testosterone in mature males, consistent with known reproductive patterns. These data suggest males can be distinguished from females and designated as mature or immature via blubber testosterone concentrations, an observation that validates dart biopsy sampling as a means of obtaining demographic data.
Fine mapping of the major QTLs for biochemical variation of sulforaphane in broccoli florets using a DH population
Authors: Li Zhansheng , Liu Yumei , Yuan Suxia , Han Fengqing , Fang Zhiyuan , Yang Limei , Zhuang Mu , Zhang Yangyong , Lv Honghao , Wang Yong , Ji Jialei
Published: April 2021

Glucoraphanin is a major secondary metabolite found in Brassicaceae vegetables, especially broccoli, and its degradation product sulforaphane plays an essential role in anticancer. The fine mapping of sulforaphane metabolism quantitative trait loci (QTLs) in broccoli florets is necessary for future marker-assisted selection strategies. In this study, we utilized a doubled haploid population consisting of 176 lines derived from two inbred lines (86,101 and 90,196) with significant differences in sulforaphane content, coupled with extensive genotypic and phenotypic data from two independent environments. A linkage map consisting of 438 simple sequence repeats markers was constructed, covering a length of 1168.26 cM. A total of 18 QTLs for sulforaphane metabolism in broccoli florets were detected, 10 were detected in 2017, and the other 8 were detected in 2018. The LOD values of all QTLs ranged from 3.06 to 14.47, explaining 1.74–7.03% of the biochemical variation between two years. Finally, 6 QTLs (qSF-C3-1, qSF-C3-2, qSF-C3-3, qSF-C3-5, qSF-C3-6 and qSF-C7) were stably detected in more than one environment, each accounting for 4.54–7.03% of the phenotypic variation explained (PVE) and a total of 30.88–34.86% of PVE. Our study provides new insights into sulforaphane metabolism in broccoli florets and marker-assisted selection breeding in Brassica oleracea crops.
Two-dimensional palladium diselenide for the oxygen reduction reaction
Authors: Koh See Wee , Hu Jie , Hwang Jeemin , Yu Peng , Sun Zixu , Liu Qiunan , Hong Wei , Ge Junyu , Fei Jipeng , Han Byungchan , Liu Zheng , Li Hong
Published: April 2021

In situ lithiation-delithiation treatment enables high oxygen reduction activity in palladium selenide without serious structural or phase change; resulting in an optimum balance of catalytic activity and stability.
Design, synthesis and evaluation of novel indole-2-carboxamides for growth inhibition of Mycobacterium tuberculosis and paediatric brain tumour cells
Authors: Alsayed Shahinda S. R. , Lun Shichun , Bailey Anders W. , Suri Amreena , Huang Chiang-Ching , Mocerino Mauro , Payne Alan , Sredni Simone Treiger , Bishai William R. , Gunosewoyo Hendra
Published: April 2021

In this study, we demonstrated that an indoleamide scaffold can be fine-tuned to confer a set of derivatives with selective antitubercular and/or antitumour activities.
Investigation of the dislocation structure in Czochralski germanium crystals grown in [211] and [110] growth directions
Authors: Gradwohl Kevin-P. , Roder Melissa , Danilewsky Andreas N. , Sumathi R. Radhakrishnan
Published: April 2021

X-ray topography of the [211] Ge crystal grown by the Cz-method shows that dislocations can be confined within the (1̄11) glide plane.
Structure optimization of lipopeptide assemblies for aldol reactions in an aqueous medium
Authors: Soares Bruna M. , Sodré Pedro T. , Aguilar Andrea M. , Gerbelli Barbara B. , Pelin Juliane N. B. D. , Argüello Karina B. , Silva Emerson R. , de Farias Marcelo A. , Portugal Rodrigo V. , Schmuck Carsten , Coutinho-Neto Maurício D. , Alves Wendel A.
Published: April 2021

Guanidiniocarbonyl pyrrole (GCP) conjugated lipopeptides improve aldol reaction catalysis by enhanced the molecules packing parameter, as shown by SAXS data and molecular dynamics simulations.
Pimenta dioica and Pimenta racemosa: GC-based metabolomics for the assessment of seasonal and organ variation in their volatile components, in silico and in vitro cytotoxic activity estimation
Authors: Youssef Fadia S. , Labib Rola M. , Gad Haidy A. , Eid SafaaY. , Ashour Mohamed L. , Eid Hanaa H.
Published: April 2021

Volatile constituents from Pimenta dioica and Pimenta racemosa leaves and stems using Gas Chromatography analyses, their in silico and in vitro cytotoxic effect.