bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced hippocampal type II theta activity AND altered theta architecture in mice lacking the Cav3.2 T-type voltage-gated calcium channel
Authors: Arshaad Muhammad Imran , Siwek Magdalena Elisabeth , Henseler Christina , Daubner Johanna , Ehninger Dan , Hescheler Jürgen , Sachinidis Agapios , Broich Karl , Papazoglou Anna , Weiergräber Marco
Published: January 2021

T-type Ca2+ channels are assumed to contribute to hippocampal theta oscillations. We used implantable video-EEG radiotelemetry and qPCR to unravel the role of Cav3.2 Ca2+ channels in hippocampal theta genesis. Frequency analysis of spontaneous long-term recordings in controls and Cav3.2−/− mice revealed robust increase in relative power in the theta (4–8 Hz) and theta-alpha (4–12 Hz) ranges, which was most prominent during the inactive stages of the dark cycles. Urethane injection experiments also showed enhanced type II theta activity and altered theta architecture following Cav3.2 ablation. Next, gene candidates from hippocampal transcriptome analysis of control and Cav3.2−/− mice were evaluated using qPCR. Dynein light chain Tctex-Type 1 (Dynlt1b) was significantly reduced in Cav3.2−/− mice. Furthermore, a significant reduction of GABA A receptor δ subunits and GABA B1 receptor subunits was observed in the septohippocampal GABAergic system. Our results demonstrate that ablation of Cav3.2 significantly alters type II theta activity and theta architecture. Transcriptional changes in synaptic transporter proteins and GABA receptors might be functionally linked to the electrophysiological phenotype.
Effects of aging on brain networks during swallowing: general linear model and independent component analyses
Authors: Tae Woo-Suk , Lee Sekwang , Choi Sunyoung , Pyun Sung-Bom
Published: January 2021

Swallowing disorders occur more frequently in older adults. However, the effects of the aging process on neural activation when swallowing are unclear. We aimed to identify neural regions activated during swallowing and evaluate changes in neural activation and neural networks with aging. Using a general linear model (GLM) and independent component (IC) analyses, blood oxygen level-dependent (BOLD) signals were observed in the lateral precentral gyrus, postcentral gyrus, anterior insular cortices, supramarginal gyri, and medial frontal gyrus during swallowing. The right thalamus and anterior cingulate gyri were found to be active areas by GLM and IC analyses, respectively. In the correlational analyses, age was negatively correlated with BOLD signals of the lateral precentral gyri, postcentral gyri, and insular cortices in swallowing tasks. Additionally, correlation analyses between ICs of all participants and age revealed negative correlations in the right supramarginal gyrus, both anterior cingulate cortices, putamen, and cerebellum. In the network analysis, the BOLD signal positively correlated with age in the default mode network (DMN), and was negatively correlated in the lateral precentral gyri, postcentral gyri, and insular cortices. The amplitude of low-frequency fluctuations was significantly decreased in the DMN and increased in swallowing-related areas during swallowing tasks. These results suggest that aging has negative effects on the activation of swallowing-related regions and task-induced deactivation of the DMN. These changes may be used to detect early functional decline during swallowing.
RETRACTED ARTICLE: Monitoring of production of blood components by attribute control chart under indeterminacy
Authors: Khan Nasrullah , Aslam Muhammad , Jeyadurga P. , Balamurali S.
Published: January 2021

The existing control chart for monitoring the blood components by attribute is designed using classical statistics. The existing attribute control chart can be applied only when the experimenter is sure about the proportion of defective or all the observations in the sample are determined. In this paper, new attribute control charts for monitoring the blood components under the neutrosophic statistics will be presented. The design of the proposed control chart is given under the neutrosophic statistical interval method. The applications of these control charts demonstrate that the proposed control charts are quite effective, adequate, flexible, and informative for monitoring the blood components under uncertain environment.
Simulation of leaf curl disease dynamics in chili for strategic management options
Authors: Roy Buddhadeb , Dubey Shailja , Ghosh Amalendu , Shukla Shalu Misra , Mandal Bikash , Sinha Parimal
Published: January 2021

Leaf curl, a whitefly-borne begomovirus disease, is the cause of frequent epidemic in chili. In the present study, transmission parameters involved in tripartite interaction are estimated to simulate disease dynamics in a population dynamics model framework. Epidemic is characterized by a rapid conversion rate of healthy host population into infectious type. Infection rate as basic reproduction number, R0 = 13.54, has indicated a high rate of virus transmission. Equilibrium population of infectious host and viruliferous vector are observed to be sensitive to the immigration parameter. A small increase in immigration rate of viruliferous vector increased the population of both infectious host and viruliferous vector. Migrant viruliferous vectors, acquisition, and transmission rates as major parameters in the model indicate leaf curl epidemic is predominantly a vector -mediated process. Based on underlying principles of temperature influence on vector population abundance and transmission parameters, spatio-temporal pattern of disease risk predicted is noted to correspond with leaf curl distribution pattern in India. Temperature in the range of 15–35 °C plays an important role in epidemic as both vector population and virus transmission are influenced by temperature. Assessment of leaf curl dynamics would be a useful guide to crop planning and evolution of efficient management strategies.
Joint modelling of colorectal cancer recurrence and death after resection using multi-state model with cured fraction
Authors: Alafchi Behnaz , Roshanaei Ghodratollah , Tapak Leili , Abbasi Mohammad , Mahjub Hossein
Published: January 2021

Curing of colorectal cancer (CRC) occurs at the time of resection but it is not immediately observable. If the cancer is not completely eliminated, the patient will not be cured of cancer and will experience recurrence as the tumor has regrown to a detectable size. The main propose of the present study was to assess the effects of different covariates on the probability of being cured as well as the time-to-recurrence, and time-to-death in CRC patients by using multi-state cure model. The information of 283 patients with CRC, who underwent resection, from 2000 to 2015 in Imam Khomeini Hospital of Hamadan, Iran, were analyzed. The results of multi-state cure model reveal that females and who experience metastasis were more likely to be apparently cured. It has been shown that sex has a significant effect on the time-to-recurrence given patient was in the not cured group. The survival time of patients of the not cured group was affected by the stage of disease. However, the survival of the apparently cured patients were affected by age at diagnosis and metastasis status. The multi-state cure model provided a flexible framework to study the effects of prognostic factors simultaneously on the transition between different states and the probability of being apparently cured of CRC.
Enhanced oncolytic adenoviral production by downregulation of death-domain associated protein and overexpression of precursor terminal protein
Authors: Lee Jihyun , Oh Geun-Hyeok , Hong Jeong A. , Choi Soojin , Choi Hye Jin , Song Jae J.
Published: January 2021

Adequate viral replication in tumor cells is the key to improving the anti-cancer effects of oncolytic adenovirus therapy. In this study, we introduced short hairpin RNAs against death-domain associated protein (Daxx), a repressor of adenoviral replication, and precursor terminal protein (pTP), an initiator of adenoviral genome replication, into adenoviral constructs to determine their contributions to viral replication. Both Daxx downregulation and pTP overexpression increased viral production in variety of human cancer cell lines, and the enhanced production of virus progeny resulted in more cell lysis in vitro, and tumor regression in vivo. We confirmed that increased virus production by Daxx silencing, or pTP overexpression, occurred using different mechanisms by analyzing levels of adenoviral protein expression and virus production. Specifically, Daxx downregulation promoted both virus replication and oncolysis in a consecutive manner by optimizing IVa2-based packaging efficiency, while pTP overexpression by increasing both infectious and total virus particles but their contribution to increased viral production may have been damaged to some extent by their another contribution to apoptosis and autophagy. Therefore, introducing both Daxx shRNA and pTP in virotherapy may be a suitable strategy to increase apoptotic tumor-cell death and to overcome poor viral replication, leading to meaningful reductions in tumor growth in vivo.
Beta-blockers have no impact on survival in pancreatic ductal adenocarcinoma prior to cancer diagnosis
Authors: Yang Anthony , Zylberberg Haley M. , Rustgi Sheila D. , Amin Sunil P. , Bar-Mashiah Ariel , Boffetta Paolo , Lucas Aimee L.
Published: January 2021

Previous studies have suggested that β-adrenergic signaling may regulate the growth of various cancers. The aim of our study is to investigate the association between the incidental use of beta-blockers for various conditions on the overall survival of patients with pancreatic ductal adenocarcinoma (PDAC). Patients with histologically-confirmed PDAC between 2007 and 2011 were extracted from Surveillance, Epidemiology, and End Results registry (SEER)-Medicare linked database. Kaplan Meier and multivariable Cox Proportional-Hazard models were used to examine the association between beta-blocker usage before diagnosis and overall survival adjusting for appropriate confounders. As an additional analysis we also examined continuous beta-blocker use before and after diagnosis. From 2007 to 2011, 13,731 patients were diagnosed with PDAC. Of these, 7130 patients had Medicare Part D coverage in the 6-month period before diagnosis, with 2564 (36%) of these patients using beta-blockers in this period. Patients receiving beta-blockers had a mean survival time of 5.1 months compared to 6 months for non-users (p < 0.01). In multivariable analysis, beta-blockers usage was not associated with improved survival (Hazard Ratio (HR) 1.04, 95%, Confidence Interval (CI) 0.98–1.1, p = 0.2). When patients were stratified by conditions with indications for beta-blocker usage, such as hypertension, coronary artery disease and cardiac arrhythmia, differences in survival were insignificant compared to non-users in all groups (p > 0.05). After stratification by receptor selectivity, this lack of association with survival persisted (p > 0.05 for all). As a subgroup analysis, looking at patients with continuous Medicare Part D coverage who used beta-blockers in the 6-month period before and after cancer diagnosis, we identified 7085 patients, of which 1750 (24.7%) had continuous beta blocker use. In multivariable analysis, continuous beta-blockers usage was associated with improved survival (Hazard Ratio (HR) 0.86, 95%, Confidence Interval (CI) 0.8–0.9, p < 0.01). Beta-blocker usage before diagnosis does not confer a survival advantage in patients with PDAC, though continuous use before and after diagnosis did confer a survival advantage. Prospective studies into the mechanism for this advantage are needed.
High cut-off dialysis mitigates pro-calcific effects of plasma on vascular progenitor cells
Authors: Schaub Theres , Janke Daniel , Zickler Daniel , Lange Claudia , Girndt Matthias , Schindler Ralf , Dragun Duska , Hegner Björn
Published: January 2021

Mortality of patients with end-stage renal disease tremendously exceeds that of the general population due to excess cardiovascular morbidity. Large middle-sized molecules (LMM) including pro-inflammatory cytokines are major drivers of uremic cardiovascular toxicity and cannot be removed sufficiently by conventional high-flux (HFL) hemodialysis. We tested the ability of plasma from 19 hemodialysis patients participating in a trial comparing HFL with high cut-off (HCO) membranes facilitating removal of LMM to induce calcification in mesenchymal stromal cells (MSC) functioning as vascular progenitors. HCO dialysis favorably changed plasma composition resulting in reduced pro-calcific activity. LMM were removed more effectively by HCO dialysis including FGF23, a typical LMM we found to promote osteoblastic differentiation of MSC. Protein-bound uremic retention solutes with known cardiovascular toxicity but not LMM inhibited proliferation of MSC without direct toxicity in screening experiments. We could not attribute the effect of HCO dialysis on MSC calcification to distinct mediators. However, we found evidence of sustained reduced inflammation that might parallel other anti-calcifying mechanisms such as altered generation of extracellular vesicles. Our findings imply protection of MSC from dysfunctional differentiation by novel dialysis techniques targeted at removal of LMM. HCO dialysis might preserve their physiologic role in vascular regeneration and improve outcomes in dialysis patients.
Culex quinquefasciatus carrying Wolbachia is less susceptible to entomopathogenic bacteria
Authors: Díaz-Nieto Leonardo M. , Gil M. Florencia , Lazarte J. Nicolás , Perotti M. Alejandra , Berón Corina M.
Published: January 2021

In an attempt to evaluate the susceptibility of the mosquitoCulex quinquefasciatusto bacterial agents, a population naturally infected with aWolbachia pipientis wPipSJ native strain was tested against the action of three bacterial mosquitocides,Bacillus thuringiensissubsp.israelensis,Bacillus wiedmanniibiovarthuringiensisandLysinibacillus sphaericus.Tests were carried out on mosquito larvae with and withoutWolbachia(controls).Cx. quinquefasciatusnaturally infected with the nativewPipSJ strain proved to be more resistant to the pathogenic action of the three mosquitocidal bacterial strains. Additionally,wPipSJ was fully characterised using metagenome-assembled genomics, PCR–RFLP (PCR-Restriction Fragment Length Polymorphism) and MLST (MultiLocus Sequence Typing) analyses. ThisWolbachiastrainwPipSJ belongs to haplotype I, groupwPip-III and supergroup B, clustering with other mosquitowPip strains, such aswPip PEL,wPip JHB,wPip Mol, andwAlbB; showing the southernmost distribution in America. The cytoplasmic incompatibility phenotype of this strain was revealed via crosses between wildtype (Wolbachia+) and antibiotic treated mosquito populations. The results of the tests with the bacterial agents suggest thatCx. quinquefasciatusnaturally infected withwPipSJ is less susceptible to the pathogenic action of mosquitocidal bacterial strains when compared with the antibiotic-treated mosquito isoline, and is more susceptible toB. thuringiensissubsp.israelensisthan to the other two mosquitocidal agents.
Haptic communication optimises joint decisions and affords implicit confidence sharing
Authors: Pezzulo Giovanni , Roche Lucas , Saint-Bauzel Ludovic
Published: January 2021

Group decisions can outperform the choices of the best individual group members. Previous research suggested that optimal group decisions require individuals to communicate explicitly (e.g., verbally) their confidence levels. Our study addresses the untested hypothesis that implicit communication using a sensorimotor channel—haptic coupling—may afford optimal group decisions, too. We report that haptically coupled dyads solve a perceptual discrimination task more accurately than their best individual members; and five times faster than dyads using explicit communication. Furthermore, our computational analyses indicate that the haptic channel affords implicit confidence sharing. We found that dyads take leadership over the choice and communicate their confidence in it by modulating both the timing and the force of their movements. Our findings may pave the way to negotiation technologies using fast sensorimotor communication to solve problems in groups.
Foveal avascular zone segmentation in optical coherence tomography angiography images using a deep learning approach
Authors: Mirshahi Reza , Anvari Pasha , Riazi-Esfahani Hamid , Sardarinia Mahsa , Naseripour Masood , Falavarjani Khalil Ghasemi
Published: January 2021

The purpose of this study was to introduce a new deep learning (DL) model for segmentation of the fovea avascular zone (FAZ) in en face optical coherence tomography angiography (OCTA) and compare the results with those of the device’s built-in software and manual measurements in healthy subjects and diabetic patients. In this retrospective study, FAZ borders were delineated in the inner retinal slab of 3 × 3 enface OCTA images of 131 eyes of 88 diabetic patients and 32 eyes of 18 healthy subjects. To train a deep convolutional neural network (CNN) model, 126 enface OCTA images (104 eyes with diabetic retinopathy and 22 normal eyes) were used as training/validation dataset. Then, the accuracy of the model was evaluated using a dataset consisting of OCTA images of 10 normal eyes and 27 eyes with diabetic retinopathy. The CNN model was based on Detectron2, an open-source modular object detection library. In addition, automated FAZ measurements were conducted using the device’s built-in commercial software, and manual FAZ delineation was performed using ImageJ software. Bland–Altman analysis was used to show 95% limit of agreement (95% LoA) between different methods. The mean dice similarity coefficient of the DL model was 0.94 ± 0.04 in the testing dataset. There was excellent agreement between automated, DL model and manual measurements of FAZ in healthy subjects (95% LoA of − 0.005 to 0.026 mm2 between automated and manual measurement and 0.000 to 0.009 mm2 between DL and manual FAZ area). In diabetic eyes, the agreement between DL and manual measurements was excellent (95% LoA of − 0.063 to 0.095), however, there was a poor agreement between the automated and manual method (95% LoA of − 0.186 to 0.331). The presence of diabetic macular edema and intraretinal cysts at the fovea were associated with erroneous FAZ measurements by the device’s built-in software. In conclusion, the DL model showed an excellent accuracy in detection of FAZ border in enfaces OCTA images of both diabetic patients and healthy subjects. The DL and manual measurements outperformed the automated measurements of the built-in software.
Thermoplastic polyurethane flexible capacitive proximity sensor reinforced by CNTs for applications in the creative industries
Authors: Moheimani Reza , Aliahmad Nojan , Aliheidari Nahal , Agarwal Mangilal , Dalir Hamid
Published: January 2021

Wearable sensing platforms have been rapidly advanced over recent years, thanks to numerous achievements in a variety of sensor fabrication techniques. However, the development of a flexible proximity sensor that can perform in a large range of object mobility remains a challenge. Here, a polymer-based sensor that utilizes a nanostructure composite as the sensing element has been presented for forthcoming usage in healthcare and automotive applications. Thermoplastic Polyurethane (TPU)/Carbon Nanotubes (CNTs) composites are capable of detecting presence of an external object in a wide range of distance. The proximity sensor exhibits an unprecedented detection distance of 120 mm with a resolution of 0.3%/mm. The architecture and manufacturing procedures of TPU/CNTs sensor are straightforward and performance of the proximity sensor shows robustness to reproducibility as well as excellent electrical and mechanical flexibility under different bending radii and over hundreds of bending cycles with variation of 4.7% and 4.2%, respectively. Tunneling and fringing effects are addressed as the sensing mechanism to explain significant capacitance changes. Percolation threshold analysis of different TPU/CNT contents indicated that nanocomposites having 2 wt% carbon nanotubes are exhibiting excellent sensing capabilities to achieve maximum detection accuracy and least noise among others. Fringing capacitance effect of the structure has been systematically analyzed by ANSYS Maxwell (Ansoft) simulation, as the experiments precisely supports the sensitivity trend in simulation. Our results introduce a new mainstream platform to realize an ultrasensitive perception of objects, presenting a promising prototype for application in wearable proximity sensors for motion analysis and artificial electronic skin.
Evaluation of in-service speed performance improvement by means of FDR-AF (frictional drag reducing anti-fouling) marine coating based on ISO19030 standard
Authors: Cho Yurim , Jeon Kyung Hwan , Lee Sang Bong , Park Hyun , Lee Inwon
Published: January 2021

In previous reports by the authors, the drag reduction performance of a novel frictional drag reduction self-polishing copolymer (FDR-SPC) was presented. The drag-reducing functional compound polyethylene glycol methacrylate (PEGMA) was used in the synthesis process, thereby allowing the release of polyethylene glycol (PEG) into seawater by a hydrolysis reaction. In a laboratory skin friction measurement, a low-friction antifouling (AF) coating based on FDR-SPC was found to provide a 25% skin friction reduction compared with a conventional AF coating. This coating was then applied to the entire underwater surface of a 176 k DWT bulk carrier during dry docking in December 2015. The propulsion performance of the present vessel as well as the weather conditions were recorded over five years from November 2014 to December 2019. It was imperative that the hull coating performance be evaluated without being affected by the additional resistance component associated with weather conditions such as wind and waves. ISO 19,030 is proposed as a new international standard for that purpose. Based on this standard, in-service navigation data collected from the 176 k DWT bulk carrier, which amounts to 5.7 million data points, are analyzed to assess the speed improvement performance of the present frictional drag reduction antifouling (FDR-AF) coating. The analysis results indicate that the present coating leads to a speed increase of 3.72% over the conventional AF coating. The speed improvement effect is equivalent to power (fuel) saving of 11.7%.
Genetic diversity associated with natural rubber quality in elite genotypes of the rubber tree
Authors: Sant’Anna Isabela de Castro , Gouvêa Ligia Regina Lima , Martins Maria Alice , Scaloppi Junior Erivaldo José , de Freitas Rogério Soares , Gonçalves Paulo de Souza
Published: January 2021

The objective of this study was to evaluate the genetic variability of natural rubber latex traits among 44 elite genotypes of the rubber tree [Hevea brasiliensis (Willd. ex Adr. de Juss.) Müell. Arg.]. Multivariate analysis and machine learning techniques were used, targeting the selection of parents that demonstrate superior characters. We analyzed traits related to technological or physicochemical properties of natural rubber latex, such as Wallace plasticity (P0), the plasticity retention index [PRI (%)], Mooney viscosity (VR), ash percentage (Ash), acetone extract percentage (AE), and nitrogen percentage (N), to study genetic diversity. Multivariate [unweighted pair group method with arithmetic means (UPGMA) and Tocher)] and machine learning techniques [K-means and Kohonen’s self-organizing maps (SOMs)] were employed. The genotypes showed high genetic variability for some of the evaluated traits. The traits PRI, Ash, and PO contributed the most to genetic diversity. The genotypes were classified into six clusters by the UPGMA method, and the results were consistent with the Tocher, K-means and SOM results. PRI can be used to improve the industrial potential of clones. The clones IAC 418 and PB 326 were the most divergent, followed by IAC 404 and IAC 56. These genotypes and others from the IAC 500 and 400 series could be used to start a breeding program. These combinations offer greater heterotic potential than the others, which can be used to improve components of rubber latex quality. Thus, it is important to consider the quality of rubber latex in the early stage of breeding programs.
Variation in size and shape of toxin glands among cane toads from native-range and invasive populations
Authors: Hudson Cameron M. , Brown Gregory P. , Blennerhassett Ryann A. , Shine Richard
Published: January 2021

If optimal investment in anti-predator defences depends on predation risk, invading new regions (and thus, encountering different predators) may favour shifts in that investment. Cane toads offer an ideal system to test this prediction: expensive anti-predator toxins are stored mainly in parotoid glands whose dimensions are easy to measure, and toad invasions have changed the suites of predators they encounter. Although plasticity may influence parotoid morphology, comparisons between parents and progeny revealed that gland dimensions were highly heritable. That heritability supports the plausibility of an evolved basis to variation in gland dimensions. Measurements of 3779 adult toads show that females have larger glands than males, invasive populations have larger glands than in the native-range, and that parotoid sexual size dimorphism varies strongly among invaded areas. Geographic variation in parotoid morphology may be driven by predation risk to both adult toads and offspring (provisioned with toxins by their mother), with toxins allocated to eggs exacerbating the risk of cannibalism but reducing the risk of interspecific predation. Investment into chemical defences has evolved rapidly during the cane toad’s international diaspora, consistent with the hypothesis that organisms flexibly adjust resource allocation to anti-predator tactics in response to novel challenges.
Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6
Authors: Padash Barmchi Mojgan , Thomas Miranda , Thatte Jayashree V. , Vats Arushi , Zhang Bing , Cagan Ross L. , Banks Lawrence
Published: January 2021

Human papillomavirus (HPV) is the leading cause of cervical cancer and has been implicated in several other cancer types including vaginal, vulvar, penile, and oropharyngeal cancers. Despite the recent availability of a vaccine, there are still over 310,000 deaths each year worldwide. Current treatments for HPV-mediated cancers show limited efficacy, and would benefit from improved understanding of disease mechanisms. Recently, we developed a Drosophila ‘HPV 18 E6’ model that displayed loss of cellular morphology and polarity, junctional disorganization, and degradation of the major E6 target Magi; we further provided evidence that mechanisms underlying HPV E6-induced cellular abnormalities are conserved between humans and flies. Here, we report a functional genetic screen of the Drosophila kinome that identified IKK$$\beta$$
β
—a regulator of NF-κB—as an enhancer of E6-induced cellular defects. We demonstrate that inhibition of IKK$$\beta$$
β
reduces Magi degradation and that this effect correlates with hyperphosphorylation of E6. Further, the reduction in IKK$$\beta$$
β
suppressed the cellular transformation caused by the cooperative action of HPVE6 and the oncogenic Ras. Finally, we demonstrate that the interaction between IKK$$\beta$$
β
and E6 is conserved in human cells: inhibition of IKK$$\beta$$
β
blocked the growth of cervical cancer cells, suggesting that IKK$$\beta$$
β
may serve as a novel therapeutic target for HPV-mediated cancers.
Geographical influences on thyroid abnormalities in adult population from iodine-replete regions: a cross-sectional study
Authors: Wang Xiaofeng , Mo Zhe , Mao Guangming , Zhu Wenming , Xing Mingluan , Li Xueqing , Wang Yuanyang , Wang Zhifang , Lou Xiaoming
Published: January 2021

The studies on the increasing incidence of thyroid abnormalities are scarce. The aim of this current study was to ascertain the effects of geographical region on thyroid abnormalities under the context of universal salt iodization (USI). We randomly selected 1255 participants residing in inland and 1248 in coast, with the determination of urinary iodine concentration (UIC) and functional and morphological abnormalities of thyroid gland. The median UIC was significantly higher for the inland participants (188.5 μg/L) than the coastal participants (128.5 μg/L; p < 0.001), indicating iodine sufficiency in both populations according to the recommended assessment criteria by the World Health Organization. However, the spectrum of thyroid abnormalities varied between regions, with hypothyroidism prevalent in inland and thyroid nodules in coast. The associations between region and thyroid abnormalities via binary logistic regression models showed that the coastal participants were at a higher risk of total thyroid abnormalities than those from the inland (OR 1.216, 95% CI 1.020–1.449), after the adjustment of ten confounders (demographical characteristics, smoking status, metabolism syndrome, and hyperuricemia). These results indicated that further investigations of the adverse effects of hypothyroidism and thyroid nodules on health burden is urgently needed to sustain USI program.
Cloning, characterization, and functional analysis of acetyl-CoA C-acetyltransferase and 3-hydroxy-3-methylglutaryl-CoA synthase genes in Santalum album
Authors: Niu Meiyun , Yan Haifeng , Xiong Yuping , Zhang Yueya , Zhang Xinhua , Li Yuan , da Silva Jaime A. Teixeira , Ma Guohua
Published: January 2021

Sandalwood (Santalum album L.) is famous for its unique fragrance derived from the essential oil of heartwood, whose major components are santalols. To understand the mechanism underlying the biosynthesis of santalols, in this study, we cloned two related genes involved in the mevalonate pathway in S. album coding for acetyl-CoA C-acetyl transferase (AACT) and 3-hydroxy-3-methyglutary-CoA synthase (HMGS). These genes were characterized and functionally analyzed, and their expression profiles were also assessed. An AACT gene designated as SaAACT (GenBank accession No. MH018694) and a HMGS gene designated as SaHMGS (GenBank accession No. MH018695) were successfully cloned from S. album. The deduced SaAACT and SaHMGS proteins contain 415 and 470 amino acids, and the corresponding size of their open-reading frames is 1538 bp and 1807 bp, respectively. Phylogenetic trees showed that the SaAACT protein had the closest relationship with AACT from Hevea brasiliensis and the SaHMGS proteins had the highest homology with HMGS from Siraitia grosvenorii. Functional complementation of SaAACT and SaHMGS in a mutant yeast strain deficient in these proteins confirmed that SaAACT and SaHMGS cDNA encodes functional SaAACT and SaHMGS that mediate mevalonate biosynthesis in yeast. Tissue-specific expression analysis revealed that both genes were constitutively expressed in all examined tissues (roots, sapwood, heartwood, young leaves, mature leaves and shoots) of S. album, both genes showing highest expression in roots. After S. album seedlings were treated with 100 μM methyl jasmonate, the expression levels of SaAACT and SaHMGS genes increased, suggesting that these genes were responsive to this elicitor. These studies provide insight that would allow further analysis of the role of genes related to the sandalwood mevalonate pathway in the regulation of biosynthesis of sandalwood terpenoids and a deeper understanding of the molecular mechanism of santalol biosynthesis.
Molecular mechanism of the anti-inflammatory effects of Sophorae Flavescentis Aiton identified by network pharmacology
Authors: Zhu Naiqiang , Hou Jingyi
Published: January 2021

Inflammation, a protective response against infection and injury, involves a variety of biological processes. Sophorae Flavescentis (Kushen) is a promising Traditional Chinese Medicine (TCM) for treating inflammation, but the pharmacological mechanism of Kushen’s anti-inflammatory effect has not been fully elucidated. The bioactive compounds, predicted targets, and inflammation-related targets of Kushen were obtained from open source databases. The “Component-Target” network and protein–protein interaction (PPI) network were constructed, and hub genes were screened out by topological analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on genes in the PPI network. Furthermore, nitric oxide (NO) production analysis, RT-PCR, and western blot were performed to detect the mRNA and protein expression of hub genes in LPS-induced RAW264.7 cells. An immunofluorescence assay found that NF-κB p65 is translocated. A total of 24 bioactive compounds, 465 predicted targets, and 433 inflammation-related targets were identified and used to construct “Component-Targets” and PPI networks. Then, the five hub genes with the highest values-IL-6, IL-1β, VEGFA, TNF-α, and PTGS2 (COX-2)- were screened out. Enrichment analysis results suggested mainly involved in the NF-κB signaling pathway. Moreover, experiments were performed to verify the predicted results. Kushen may mediate inflammation mainly through the IL-6, IL-1β, VEGFA, TNF-α, and PTGS2 (COX-2), and the NF-κB signaling pathways. This finding will provide clinical guidance for further research on the use of Kushen to treat inflammation.
Intermittent hypoxia inhibits mandibular cartilage growth with reduced TGF-β and SOX9 expressions in neonatal rats
Authors: Lekvijittada Kochakorn , Hosomichi Jun , Maeda Hideyuki , Hong Haixin , Changsiripun Chidsanu , Kuma Yo-ichiro , Oishi Shuji , Suzuki Jun-ichi , Yoshida Ken-ichi , Ono Takashi
Published: January 2021

Intermittent hypoxia (IH) has been associated with skeletal growth. However, the influence of IH on cartilage growth and metabolism is unknown. We compared the effects of IH on chondrocyte proliferation and maturation in the mandibular condyle fibrocartilage and tibial hyaline cartilage of 1-week-old male Sprague–Dawley rats. The rats were exposed to normoxic air (n = 9) or IH at 20 cycles/h (nadir, 4% O2; peak, 21% O2; 0% CO2) (n = 9) for 8 h each day. IH impeded body weight gain, but not tibial elongation. IH also increased cancellous bone mineral and volumetric bone mineral densities in the mandibular condylar head. The mandibular condylar became thinner, but the tibial cartilage did not. IH reduced maturative and increased hypertrophic chondrocytic layers of the middle and posterior mandibular cartilage. PCR showed that IH shifted proliferation and maturation in mandibular condyle fibrocartilage toward hypertrophic differentiation and ossification by downregulating TGF-β and SOX9, and upregulating collagen X. These effects were absent in the tibial growth plate hyaline cartilage. Our results showed that neonatal rats exposed to IH displayed underdeveloped mandibular ramus/condyles, while suppression of chondrogenesis marker expression was detected in the growth-restricted condylar cartilage.
Neural correlates of affective contributions to lexical decisions in children and adults
Authors: Sylvester Teresa , Liebig Johanna , Jacobs Arthur M.
Published: January 2021

The goal of the present study was to investigate whether 6–9-year old children and adults show similar neural responses to affective words. An event-related neuroimaging paradigm was used in which both age cohorts performed the same auditory lexical decision task (LDT). The results show similarities in (auditory) lexico-semantic network activation as well as in areas associated with affective information. In both age cohorts’ activations were stronger for positive than for negative words, thus exhibiting a positivity superiority effect. Children showed less activation in areas associated with affective information in response to all three valence categories than adults. Our results are discussed in the light of computational models of word recognition, and previous findings of affective contributions to LDT in adults.
Implicit Theory of Mind under realistic social circumstances measured with mobile eye-tracking
Authors: Kulke Louisa , Hinrichs Max Andreas Bosse
Published: January 2021

Recently, there has been a debate whether implicit Theory of Mind can be reliably measured using anticipatory looking tasks. Previous anticipatory looking paradigms used video stimuli to measure implicit Theory of Mind; however, numerous replications of these paradigms were unsuccessful. This lack of replications may be due to video stimuli not being sufficiently engaging. As Theory of Mind is an inherently social phenomenon, robust evidence might only be observed in a real social situation. Therefore, the current preregistered study aimed to test anticipatory looking with real-life social stimuli. A mobile eye-tracker was used to measure gaze patterns indicative of Theory of Mind while participants observed a real-life interaction of an experimenter and a confederate. The realistic scenario did not provide clear evidence for implicit Theory of Mind. Furthermore, anticipatory looking behavior did not reliably occur during familiarization trials, in line with previous research. However, looking patterns were slightly more in line with belief tracking than in some more controlled studies using video stimuli. In general, implicit Theory of Mind was not reliably reflected in anticipatory looking patterns even if they were measured in realistic social situations. This questions the suitability of anticipatory looking measures for implicit Theory of Mind.
Maternal tadalafil therapy for fetal growth restriction prevents non-alcoholic fatty liver disease and adipocyte hypertrophy in the offspring
Authors: Kawamura Takuya , Tanaka Hiroaki , Tachibana Ryota , Yoshikawa Kento , Maki Shintaro , Toriyabe Kuniaki , Takeuchi Hiroki , Katsuragi Shinji , Tanaka Kayo , Ikeda Tomoaki
Published: January 2021

We aimed to investigate the effects of maternal tadalafil therapy on fetal programming of metabolic function in a mouse model of fetal growth restriction (FGR). Pregnant C57BL6 mice were divided into the control, L-NG-nitroarginine methyl ester (L-NAME), and tadalafil + L-NAME groups. Six weeks after birth, the male pups in each group were given a high-fat diet. A glucose tolerance test (GTT) was performed at 15 weeks and the pups were euthanized at 20 weeks. We then assessed the histological changes in the liver and adipose tissue, and the adipocytokine production. We found that the non-alcoholic fatty liver disease activity score was higher in the L-NAME group than in the control group (p < 0.05). Although the M1 macrophage numbers were significantly higher in the L-NAME/high-fat diet group (p < 0.001), maternal tadalafil administration prevented this change. Moreover, the epididymal adipocyte size was significantly larger in the L-NAME group than in the control group. This was also improved by maternal tadalafil administration (p < 0.05). Further, we found that resistin levels were significantly lower in the L-NAME group compared to the control group (p < 0.05). The combination of exposure to maternal L-NAME and a high-fat diet induced glucose impairment and non-alcoholic fatty liver disease. However, maternal tadalafil administration prevented these complications. Thus, deleterious fetal programming caused by FGR might be modified by in utero intervention with tadalafil.
Functional connectome differences in individuals with hallucinations across the psychosis continuum
Authors: Schutte Maya J. L. , Bohlken Marc M. , Collin Guusje , Abramovic Lucija , Boks Marco P. M. , Cahn Wiepke , Dauwan Meenakshi , van Dellen Edwin , van Haren Neeltje E. M. , Hugdahl Kenneth , Koops Sanne , Mandl René C. W. , Sommer Iris E. C.
Published: January 2021

Hallucinations may arise from an imbalance between sensory and higher cognitive brain regions, reflected by alterations in functional connectivity. It is unknown whether hallucinations across the psychosis continuum exhibit similar alterations in functional connectivity, suggesting a common neural mechanism, or whether different mechanisms link to hallucinations across phenotypes. We acquired resting-state functional MRI scans of 483 participants, including 40 non-clinical individuals with hallucinations, 99 schizophrenia patients with hallucinations, 74 bipolar-I disorder patients with hallucinations, 42 bipolar-I disorder patients without hallucinations, and 228 healthy controls. The weighted connectivity matrices were compared using network-based statistics. Non-clinical individuals with hallucinations and schizophrenia patients with hallucinations exhibited increased connectivity, mainly among fronto-temporal and fronto-insula/cingulate areas compared to controls (P < 0.001 adjusted). Differential effects were observed for bipolar-I disorder patients with hallucinations versus controls, mainly characterized by decreased connectivity between fronto-temporal and fronto-striatal areas (P = 0.012 adjusted). No connectivity alterations were found between bipolar-I disorder patients without hallucinations and controls. Our results support the notion that hallucinations in non-clinical individuals and schizophrenia patients are related to altered interactions between sensory and higher-order cognitive brain regions. However, a different dysconnectivity pattern was observed for bipolar-I disorder patients with hallucinations, which implies a different neural mechanism across the psychosis continuum.
Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation
Authors: Heinzelmann Germano , Gilson Michael K.
Published: January 2021

Absolute binding free energy calculations with explicit solvent molecular simulations can provide estimates of protein-ligand affinities, and thus reduce the time and costs needed to find new drug candidates. However, these calculations can be complex to implement and perform. Here, we introduce the software BAT.py, a Python tool that invokes the AMBER simulation package to automate the calculation of binding free energies for a protein with a series of ligands. The software supports the attach-pull-release (APR) and double decoupling (DD) binding free energy methods, as well as the simultaneous decoupling-recoupling (SDR) method, a variant of double decoupling that avoids numerical artifacts associated with charged ligands. We report encouraging initial test applications of this software both to re-rank docked poses and to estimate overall binding free energies. We also show that it is practical to carry out these calculations cheaply by using graphical processing units in common machines that can be built for this purpose. The combination of automation and low cost positions this procedure to be applied in a relatively high-throughput mode and thus stands to enable new applications in early-stage drug discovery.
Functional constipation induces bladder overactivity associated with upregulations of Htr2 and Trpv2 pathways
Authors: Iguchi Nao , Carrasco Alonso , Xie Alison X. , Pineda Ricardo H. , Malykhina Anna P. , Wilcox Duncan T.
Published: January 2021

Bladder and bowel dysfunction (BBD) is a common yet underdiagnosed paediatric entity that describes lower urinary tract symptoms (LUTS) accompanied by abnormal bowel patterns manifested as constipation and/or encopresis. LUTS usually manifest as urgency, urinary frequency, incontinence, and urinary tract infections (UTI). Despite increasing recognition of BBD as a risk factor for long-term urinary tract problems including recurrent UTI, vesicoureteral reflux, and renal scarring, the mechanisms underlying BBD have been unclear, and treatment remains empirical. We investigated how constipation affects the lower urinary tract function using a juvenile murine model of functional constipation. Following four days of functional constipation, animals developed LUTS including urinary frequency and detrusor overactivity evaluated by awake cystometry. Physiological examination of detrusor function in vitro using isolated bladder strips, demonstrated a significant increase in spontaneous contractions without affecting contractile force in response to electrical field stimulation, carbachol, and KCl. A significant upregulation of serotonin receptors, Htr2a and Htr2c, was observed in the bladders from mice with constipation, paralleled with augmented spontaneous contractions after pre-incubation of the bladder strips with 0.5 µM of serotonin. These results suggest that constipation induced detrusor overactivity and increased excitatory serotonin receptor activation in the urinary bladder, which contributes to the development of BBD.
Faint trace of a particle in a noisy Vaidman three-path interferometer
Authors: Dajka Jerzy
Published: January 2021

We study weak traces of particle passing Vaidman’s nested Mach–Zehnder interferometer. We investigate an effect of decoherence caused by an environment coupled to internal degree of freedom (a spin) of a travelling particle. We consider two models: pure decoherence leading to exact results and weak coupling Davies approximation allowing to include dissipative effects. We show that potentially anomalous discontinuity of particle paths survives an effect of decoherence unless it affects internal part of the nested interferometer.
A combination of CMC and α-MSH inhibited ROS activated NLRP3 inflammasome in hyperosmolarity stressed HCECs and scopolamine-induced dry eye rats
Authors: Lv Ying , Chu Chenchen , Liu Ke , Ru Yusha , Zhang Yan , Lu Xiaoxiao , Gao Yichen , Zhang Caijie , Zhao Shaozhen
Published: January 2021

An important mechanism involved in dry eye (DE) is the association between tear hyperosmolarity and inflammation severity. Inflammation in DE might be mediated by the NLRP3 inflammasome, which activated by exposure to reactive oxygen species (ROS). A combination of carboxymethylcellulose (CMC) and α-melanocyte stimulating hormone (α-MSH) may influence DE through this mechanism, thus avoiding defects of signal drug. In this study, we assessed whether treatment comprising CMC combined with α-MSH could ameliorate ocular surface function; we found that it promoted tear secretion, reduced the density of fluorescein sodium staining, enhanced the number of conjunctival goblet cells, and reduced the number of corneal apoptotic cells. Investigation of the underlying mechanism suggested that the synergistic effect of combined treatment alleviated DE inflammation through reduction of ROS level and inhibition of the NLRP3 inflammasome in human corneal epithelial cells. These findings indicate that combined CMC + α-MSH treatment could ameliorate lesions and restore ocular surface function in patients with DE through reduction of ROS level and inhibition of NLRP3 signalling.
Effect of SSRI exposure on the proliferation rate and glucose uptake in breast and ovary cancer cell lines
Authors: Stapel Britta , Melzer Catharina , von der Ohe Juliane , Hillemanns Peter , Bleich Stefan , Kahl Kai G. , Hass Ralf
Published: January 2021

Breast cancer is the most prevalent malignancy amongst women worldwide while ovarian cancer represents the leading cause of death among gynecological malignancies. Women suffering from these cancers displayed heightened rates of major depressive disorder, and antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs) is frequently recommended. Recently, narrative reviews and meta-analyses showed increased recurrence risks and mortality rates in SSRI-treated women with breast and ovarian cancer. We therefore examined whether three commonly prescribed SSRIs, fluoxetine, sertraline and citalopram, affect proliferation or glucose uptake of human breast and ovarian cancer cell lines characterized by different malignancies and metastatic potential. SSRI treatment or serotonin stimulation with therapeutically relevant concentrations over various time periods revealed no consistent dose- or time-dependent effect on proliferation rates. A marginal, but significant increase in glucose uptake was observed in SK-OV-3 ovarian cancer cells upon fluoxetine or sertraline, but not citalopram treatment. In three breast cancer cell lines and in two additional ovarian cancer cell lines no significant effect of SSRIs on glucose uptake was observed. Our data suggest that the observed increase in recurrence- and mortality rates in SSRI-treated cancer patients is unlikely to be linked to antidepressant therapies.