bluuebunny/crossref_metadata_2025 huggingface dataset:
EOMES is essential for antitumor activity of CD8+ T cells in chronic lymphocytic leukemia
Authors: Llaó-Cid Laura , Roessner Philipp M. , Chapaprieta Vicente , Öztürk Selcen , Roider Tobias , Bordas Marie , Izcue Ana , Colomer Dolors , Dietrich Sascha , Stilgenbauer Stephan , Hanna Bola , Martín-Subero José Ignacio , Seiffert Martina
Published: March 2021

Genome-wide association studies identified a single-nucleotide polymorphism (SNP) affecting the transcription factor Eomesodermin (EOMES) associated with a significantly increased risk to develop chronic lymphocytic leukemia (CLL). Epigenetic analyses, RNA sequencing, and flow cytometry revealed that EOMES is not expressed in CLL cells, but in CD8+ T cells for which EOMES is a known master regulator. We thus hypothesized that the increased CLL risk associated with the EOMES SNP might be explained by its negative impact on CD8+ T-cell-mediated immune control of CLL. Flow cytometry analyses revealed a higher EOMES expression in CD8+ T cells of CLL patients compared to healthy individuals, and an accumulation of PD-1+ EOMES+ CD8+ T cells in lymph nodes rather than blood or bone marrow in CLL. This was in line with an observed expansion of EOMES+ CD8+ T cells in the spleen of leukemic Eµ-TCL1 mice. As EOMES expression was highest in CD8+ T cells that express inhibitory receptors, an involvement of EOMES in T-cell exhaustion and dysfunction seems likely. Interestingly, Eomes-deficiency in CD8+ T cells resulted in their impaired expansion associated with decreased CLL control in mice. Overall, these observations suggest that EOMES is essential for CD8+ T-cell expansion and/or maintenance, and therefore involved in adaptive immune control of CLL.
Portable and wearable self-powered systems based on emerging energy harvesting technology
Authors: Xu Chen , Song Yu , Han Mengdi , Zhang Haixia
Published: March 2021

A self-powered system based on energy harvesting technology can be a potential candidate for solving the problem of supplying power to electronic devices. In this review, we focus on portable and wearable self-powered systems, starting with typical energy harvesting technology, and introduce portable and wearable self-powered systems with sensing functions. In addition, we demonstrate the potential of self-powered systems in actuation functions and the development of self-powered systems toward intelligent functions under the support of information processing and artificial intelligence technologies.
Tumor-secreted exosomal Wnt2B activates fibroblasts to promote cervical cancer progression
Authors: Liang Luo-Jiao , Yang Yang , Wei Wen-Fei , Wu Xiang-Guang , Yan Rui-Ming , Zhou Chen-Fei , Chen Xiao-Jing , Wu Sha , Wang Wei , Fan Liang-Sheng
Published: March 2021

The activation of stromal fibroblasts into cancer-associated fibroblasts (CAFs) has been suggested to promote primary tumor growth and progression; however, the mechanisms underlying the crosstalk between tumors and fibroblasts that drives stromal heterogeneity remain unknown. Here, we show that high Wnt2B levels were positively correlated with the number of CAFs in cervical cancer (CC). More importantly, Wnt2B was characteristically enriched in CC cell-secreted exosomes and transferred into fibroblasts to promote fibroblast activation via Wnt/β-catenin signaling, and inhibiting exosomal release or the Wnt/β-catenin signaling pathway diminished the activation induced by exosomal Wnt2B. Moreover, circulating exosomal Wnt2B also promoted CAF conversion in vitro and its expression was significantly higher in CC patients. In conclusion, our findings indicate that CC cell-derived Wnt2B can induce the activation of fibroblasts into CAFs, mainly via exosome-dependent secretion, thus providing directions for the development of diagnostic and therapeutic targets for CC progression.
C20orf204, a hepatocellular carcinoma-specific protein interacts with nucleolin and promotes cell proliferation
Authors: Burbano De Lara Sebastian , Tran Doan Duy Hai , Allister Aldrige Bernardus , Polenkowski Mareike , Nashan Björn , Koch Martina , Tamura Teruko
Published: March 2021

In most human cancers, a large number of proteins with driver mutations are involved in tumor development, implying that multiple fine tuners are involved in cancer formation and/or maintenance. A useful strategy for cancer therapy may therefore be to target multiple cancer type-specific fine tuners. Furthermore, genome-wide association studies of tumor samples have identified a large number of long noncoding (lnc)RNA associated with various types of tumor. In this context we have previously found that C20orf204 (a splice variant of Linc00176) RNA contains a 189 amino acid (AA) long open reading frame (C20orf204-189AA) that is expressed predominantly in hepatocellular carcinoma (HCC). We report here that a protein, C20orf204-189AA, was detected in the nucleus of 14 out of 20 primary HCC, but not in control livers. Strikingly, overexpression of C20orf204-189AA enhanced cell proliferation and ribosomal RNA transcription. C20orf204-189AA is co-localized, and interacted with nucleolin via the C-terminal and with ribosomal RNA via the N-terminal domain. Furthermore, the expression of C20orf204-189AA upregulates the protein level of nucleolin. Nucleolin and C20orf204 mRNA levels in HCC are correlated with tumor differentiation grade and patient survival, suggesting that C20orf204-189AA is a cancer type-specific fine tuner in some HCC that presents itself for potential targeting therapy and cancer biomarker. Thus, cancer cells exhibit remarkable transcriptome alterations partly by adopting cancer-specific splicing isoforms of noncoding RNAs and may participate in tumor development.
BNST specific mGlu5 receptor knockdown regulates sex-dependent expression of negative affect produced by adolescent ethanol exposure and adult stress
Authors: Kasten Chelsea R. , Holmgren Eleanor B. , Lerner Mollie R. , Wills Tiffany A.
Published: March 2021

Adolescent alcohol use is one of the strongest predictors for the development of an alcohol use disorder (AUD). Notably, this period of risk coincides with the development of affective disorders, which disproportionately impact and drive problematic drinking behavior in women. Stress is a particularly salient factor that drives relapse during periods of abstinence. Previous work in our lab has shown that adolescent intermittent ethanol vapor (AIE) produces sex-dependent changes in glutamatergic activity in the bed nucleus of the stria terminalis (BNST) and behavioral outcomes following acute restraint stress in adulthood. In females, AIE disrupts group 1 metabotropic glutamate (mGlu1/5) receptor activity and enhances anhedonia-like behavior. The current study site-specifically knocked down mGlu5 receptors in the BNST of male and female Grm5loxp mice, exposed them to AIE, and observed the interaction of AIE and stress on negative affect-like behaviors in adulthood. These negative affect-like behaviors included the novelty-induced hypophagia task following acute restraint stress, open field activity, and contextual fear conditioning. Overall, we replicated our previous findings that AIE enhanced anhedonia-like activity in the novelty-induced hypophagia task in females and fear acquisition in males. The primary effect of BNST-mGlu5 receptor knockdown was that it independently enhanced anhedonia-like activity in females. Correlation analyses revealed that behavior in these paradigms showed poor interdependence. These results indicate that preclinical models of negative affective-like states encompass distinct features that may have independent, clinically relevant mechanisms. Further, modulating mGlu5 receptors is a prospective treatment target for females experiencing anhedonic-like states that make them susceptible to alcohol relapse.
Prioritization of schizophrenia risk genes from GWAS results by integrating multi-omics data
Authors: He Dan , Fan Cong , Qi Mengling , Yang Yuedong , Cooper David N. , Zhao Huiying
Published: March 2021

Schizophrenia (SCZ) is a polygenic disease with a heritability approaching 80%. Over 100 SCZ-related loci have so far been identified by genome-wide association studies (GWAS). However, the risk genes associated with these loci often remain unknown. We present a new risk gene predictor, rGAT-omics, that integrates multi-omics data under a Bayesian framework by combining the Hotelling and Box–Cox transformations. The Bayesian framework was constructed using gene ontology, tissue-specific protein–protein networks, and multi-omics data including differentially expressed genes in SCZ and controls, distance from genes to the index single-nucleotide polymorphisms (SNPs), and de novo mutations. The application of rGAT-omics to the 108 loci identified by a recent GWAS study of SCZ predicted 103 high-risk genes (HRGs) that explain a high proportion of SCZ heritability (Enrichment = 43.44 and $$p = 9.30 \times 10^{ - 9}$$

p
=
9.30
×
1

0

−
9

). HRGs were shown to be significantly ($$p_{\mathrm{adj}} = 5.35 \times 10^{ - 7}$$

p

adj

=
5.35
×
1

0

−
7

) enriched in genes associated with neurological activities, and more likely to be expressed in brain tissues and SCZ-associated cell types than background genes. The predicted HRGs included 16 novel genes not present in any existing databases of SCZ-associated genes or previously predicted to be SCZ risk genes by any other method. More importantly, 13 of these 16 genes were not the nearest to the index SNP markers, and them would have been difficult to identify as risk genes by conventional approaches while ten out of the 16 genes are associated with neurological functions that make them prime candidates for pathological involvement in SCZ. Therefore, rGAT-omics has revealed novel insights into the molecular mechanisms underlying SCZ and could provide potential clues to future therapies.
Anomalous brain gyrification patterns in major psychiatric disorders: a systematic review and transdiagnostic integration
Authors: Sasabayashi Daiki , Takahashi Tsutomu , Takayanagi Yoichiro , Suzuki Michio
Published: March 2021

Anomalous patterns of brain gyrification have been reported in major psychiatric disorders, presumably reflecting their neurodevelopmental pathology. However, previous reports presented conflicting results of patients having hyper-, hypo-, or normal gyrification patterns and lacking in transdiagnostic consideration. In this article, we systematically review previous magnetic resonance imaging studies of brain gyrification in schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder at varying illness stages, highlighting the gyral pattern trajectory for each disorder. Patients with each psychiatric disorder may exhibit deviated primary gyri formation under neurodevelopmental genetic control in their fetal life and infancy, and then exhibit higher-order gyral changes due to mechanical stress from active brain changes (e.g., progressive reduction of gray matter volume and white matter integrity) thereafter, representing diversely altered pattern trajectories from those of healthy controls. Based on the patterns of local connectivity and changes in neurodevelopmental gene expression in major psychiatric disorders, we propose an overarching model that spans the diagnoses to explain how deviated gyral pattern trajectories map onto clinical manifestations (e.g., psychosis, mood dysregulation, and cognitive impairments), focusing on the common and distinct gyral pattern changes across the disorders in addition to their correlations with specific clinical features. This comprehensive understanding of the role of brain gyrification pattern on the pathophysiology may help to optimize the prediction and diagnosis of psychiatric disorders using objective biomarkers, as well as provide a novel nosology informed by neural circuits beyond the current descriptive diagnostics.
Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition
Authors: Masood Ashiq , Christ Trevor , Asif Samia , Rajakumar Priya , Gustafson Beth A. , Shune Leyla O. , Salahudeen Ameen , Nedvad Drew , Nanua Suparna , Paner Agne , Kuzel Timothy M. , Levy Mia , Subramanian Janakiraman , Raza Shahzad
Published: March 2021

Non-secretory multiple myeloma (NSMM) constitutes a distinct entity of multiple myeloma characterized by the absence of detectable monoclonal protein and rarely an absence of free light chains in the serum and urine. Given its rarity, the genomic landscape, clinical course, and prognosis of NSSM are not well characterized. Here, we report a case of a patient with relapsed and refractory NSMM with brain metastasis harboring a TFG-ALK fusion showing a dramatic and durable (over two years) response to commercially available anaplastic lymphoma kinase (ALK) inhibitors. The case emphasizes the beneficial role of molecular profiling in this target-poor disease.
Sensorized tissue analogues enabled by a 3D-printed conductive organogel
Authors: Crump Michael R. , Bidinger Sophia L. , Pavinatto Felippe J. , Gong Alex T. , Sweet Robert M. , MacKenzie J. Devin
Published: March 2021

State-of-the-art tissue analogues used in high-fidelity, hands-on medical simulation modules can deliver lifelike appearance and feel but lack the capability to provide quantified, real-time assessment of practitioner performance. The monolithic fabrication of hybrid printed/textile piezoresistive strain sensors in a realistic Y/V plasty suture training pad is demonstrated. A class of 3D-printable organogels comprised of inexpensive and nonhazardous feedstocks is used as the sensing medium, and conductive composite threads are used as the electrodes. These organogels are comprised of a glycol-based deep-eutectic solvent (DES) serving as the ionic conductor and 3-trimethoxysilylmethacrylate-capped fumed silica particles serving as the gelating agent. Rheology measurements reveal the influence of fumed silica particle capping group on the mixture rheology. Freestanding strain sensors demonstrate a maximum strain amplitude of 300%, negligible signal drift, a monotonic sensor response, a low degree of hysteresis, and excellent cyclic stability. The increased contact resistance of the conductive thread electrodes used in place of wire electrodes do not make a significant impact on sensor performance. This work showcases the potential of these organogels utilized in sensorized tissue analogues and freestanding strain sensors for widespread applications in medical simulation and education.
Renal Dnase1 expression is regulated by FGF23 but loss of Dnase1 does not alter renal phosphate handling
Authors: Egli-Spichtig Daniela , Zhang Martin Y. H. , Li Alfred , Pastor Arroyo Eva Maria , Hernando Nati , Wagner Carsten A. , Chang Wenhan , Perwad Farzana
Published: March 2021

Fibroblast growth factor 23 (FGF23) is a bone-derived endocrine hormone that regulates phosphate and vitamin D metabolism. In models of FGF23 excess, renal deoxyribonuclease 1 (Dnase1) mRNA expression is downregulated. Dnase-1 is an endonuclease which binds monomeric actin. We investigated whether FGF23 suppresses renal Dnase-1 expression to facilitate endocytic retrieval of renal sodium dependent phosphate co-transporters (NaPi-IIa/c) from the brush border membrane by promoting actin polymerization. We showed that wild type mice on low phosphate diet andFgf23−/−mice with hyperphosphatemia have increased renalDnase1mRNA expression while inHypmice with FGF23 excess and hypophosphatemia,Dnase1mRNA expression is decreased. Administration of FGF23 in wild type andFgf23−/−mice loweredDnase1expression. Taken together, our data shows thatDnase1is regulated by FGF23. In 6-week-oldDnase1−/−mice, plasma phosphate and renal NaPi-IIa protein were significantly lower compared to wild-type mice. However, these changes were transient, normalized by 12 weeks of age and had no impact on bone morphology. Adaptation to low and high phosphate diet were similar inDnase1−/−andDnase1+/+mice, and loss ofDnase1gene expression did not rescue hyperphosphatemia inFgf23−/−mice. We conclude that Dnase-1 does not mediate FGF23-induced inhibition of renal tubular phosphate reabsorption.
Standing on unstable surface challenges postural control of tracking tasks and modulates neuromuscular adjustments specific to task complexity
Authors: Mademli Lida , Mavridi Dimitra , Bohm Sebastian , Patikas Dimitrios A. , Santuz Alessandro , Arampatzis Adamantios
Published: March 2021

Understanding the modulations of motor control in the presence of perturbations in task conditions of varying complexity is a key element towards the design of effective perturbation-based balance exercise programs. In this study we investigated the effect of mechanical perturbations, induced by an unstable surface, on muscle activation and visuo-postural coupling, when actively tracking target motion cues of different complexity. Four postural tasks following a visual oscillating target of varying target complexity (periodic-sinusoidal vs. chaotic-Lorenz) and surface (stable-floor vs. unstable-foam) were performed. The electromyographic activity of the main plantarflexor and dorsiflexor muscles was captured. The coupling between sway and target was assessed through spectral analysis and the system’s local dynamic stability through the short-term maximum Lyapunov exponent. We found that external perturbations increased local instability and deteriorated visuo-motor coupling. Visuo-motor deterioration was greater for the chaotic target, implying that the effect of the induced perturbations depends on target complexity. There was a modulation of the neuromotor system towards amplification of muscle activity and coactivation to compensate surface-related perturbations and to ensure robust motor control. Our findings provide evidence that, in the presence of perturbations, target complexity induces specific modulations in the neuromotor system while controlling balance and posture.
Looking for a proxy of the ionospheric turbulence with Swarm data
Authors: De Michelis Paola , Consolini Giuseppe , Pignalberi Alessio , Tozzi Roberta , Coco Igino , Giannattasio Fabio , Pezzopane Michael , Balasis Georgios
Published: March 2021

The present work focuses on the analysis of the scaling features of electron density fluctuations in the mid- and high-latitude topside ionosphere under different conditions of geomagnetic activity. The aim is to understand whether it is possible to identify a proxy that may provide information on the properties of electron density fluctuations and on the possible physical mechanisms at their origin, as for instance, turbulence phenomena. So, we selected about 4 years (April 2014–February 2018) of 1 Hz electron density measurements recorded on-board ESA Swarm A satellite. Using the Auroral Electrojet (AE) index, we identified two different geomagnetic conditions: quiet (AE < 50 nT) and active (AE > 300 nT). For both datasets, we evaluated the first- and second-order scaling exponents and an intermittency coefficient associated with the electron density fluctuations. Then, the joint probability distribution between each of these quantities and the rate of change of electron density index was also evaluated. We identified two families of plasma density fluctuations characterized by different mean values of both the scaling exponents and the considered ionospheric index, suggesting that different mechanisms (instabilities/turbulent processes) can be responsible for the observed scaling features. Furthermore, a clear different localization of the two families in the magnetic latitude—magnetic local time plane is found and its dependence on geomagnetic activity levels is analyzed. These results may well have a bearing about the capability of recognizing the turbulent character of irregularities using a typical ionospheric plasma irregularity index as a proxy.
Assessment of clinical radiosensitivity in patients with head-neck squamous cell carcinoma from pre-treatment quantitative ultrasound radiomics
Authors: Osapoetra Laurentius Oscar , Dasgupta Archya , DiCenzo Daniel , Fatima Kashuf , Quiaoit Karina , Saifuddin Murtuza , Karam Irene , Poon Ian , Husain Zain , Tran William T. , Sannachi Lakshmanan , Czarnota Gregory J.
Published: March 2021

To investigate the role of quantitative ultrasound (QUS) radiomics to predict treatment response in patients with head and neck squamous cell carcinoma (HNSCC) treated with radical radiotherapy (RT). Five spectral parameters, 20 texture, and 80 texture-derivative features were extracted from the index lymph node before treatment. Response was assessed initially at 3 months with complete responders labelled as early responders (ER). Patients with residual disease were followed to classify them as either late responders (LR) or patients with persistent/progressive disease (PD). Machine learning classifiers with leave-one-out cross-validation was used for the development of a binary response-prediction radiomics model. A total of 59 patients were included in the study (22 ER, 29 LR, and 8 PD). A support vector machine (SVM) classifier led to the best performance with accuracy and area under curve (AUC) of 92% and 0.91, responsively to define the response at 3 months (ER vs. LR/PD). The 2-year recurrence-free survival for predicted-ER, LR, PD using an SVM-model was 91%, 78%, and 27%, respectively (p < 0.01). Pretreatment QUS-radiomics using texture derivatives in HNSCC can predict the response to RT with an accuracy of more than 90% with a strong influence on the survival.

Clinical trial registration: clinicaltrials.gov.in identifier NCT03908684.
A high-throughput screening to identify small molecules that suppress huntingtin promoter activity or activate huntingtin-antisense promoter activity
Authors: Khaled Houda G. , Feng Hongxuan , Hu Xin , Sun Xin , Zheng Wang , Li Pan P. , Rudnicki Dobrila D. , Ye Wenjuan , Chen Yu-Chi , Southall Noel , Marugan Juan , Ross Christopher A. , Ferrer Marc , Henderson Mark J. , Margolis Russell L.
Published: March 2021

Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of huntingtin (HTT). While there are currently no disease-modifying treatments for HD, recent efforts have focused on the development of nucleotide-based therapeutics to lower HTT expression. As an alternative to siRNA or oligonucleotide methods, we hypothesized that suppression of HTT expression might be accomplished by small molecules that either (1) directly decrease HTT expression by suppressing HTT promoter activity or (2) indirectly decrease HTT expression by increasing the promoter activity of HTT-AS, the gene antisense to HTT that appears to inhibit expression of HTT. We developed and employed a high-throughput screen for modifiers of HTT and HTT-AS promoter activity using luminescent reporter HEK293 cells; of the 52,041 compounds tested, we identified 898 replicable hits. We used a rigorous stepwise approach to assess compound toxicity and the capacity of the compounds to specifically lower huntingtin protein in 5 different cell lines, including HEK293 cells, HD lymphoblastoid cells, mouse primary neurons, HD iPSCs differentiated into cortical-like neurons, and HD hESCs. We found no compounds which were able to lower huntingtin without lowering cell viability in all assays, though the potential efficacy of a few compounds at non-toxic doses could not be excluded. Our results suggest that more specific targets may facilitate a small molecule approach to HTT suppression.
Comparison of three qPCR-based commercial tests for detection of periodontal pathogens
Authors: Van der Weijden Fridus , Rijnen Mirella , Valkenburg Cees
Published: March 2021

In periodontal practice microbial results of periodontal test kits for identification of key pathogens are an aid in the treatment planning. Information on the performance of commercially available test kits is therefore essential for the clinician. In this retrospective analysis three commercially available qPCR kits for detection and quantification of selected periodontal bacterial species were compared, using 100 clinical samples from patients with untreated periodontitis. The analysis involved two separate comparisons in which kit A (LabOral Diagnostics, The Netherlands) was compared with kit B (Advanced Dental Diagnostics, The Netherlands), and with kit C (OralDent diagnostics, The Netherlands). Analytic procedures for detection and quantification of selected periodontal bacterial species were carried out according to the instructions of the laboratories. Kit A detected target species more often, and absolute numbers of bacterial cells were higher than with kit B. A high degree of similarity was found between the test outcomes by kit A and kit C. All three kits performed satisfactory but small and significant differences exist between kits.
d-Aspartate consumption selectively promotes intermediate-term spatial memory and the expression of hippocampal NMDA receptor subunits
Authors: Zachar Gergely , Kemecsei Róbert , Papp Szilvia Márta , Wéber Katalin , Kisparti Tamás , Tyler Teadora , Gáspár Gábor , Balázsa Tamás , Csillag András
Published: March 2021

d-Aspartate (d-Asp) and d-serine (d-Ser) have been proposed to promote early-phase LTP in vitro and to enhance spatial memory in vivo. Here, we investigated the behavioural effects of chronic consumption of d-Asp and d-Ser on spatial learning of mice together with the expression of NMDA receptors. We also studied the alterations of neurogenesis by morphometric analysis of bromo-deoxyuridine incorporating and doublecortin expressing cells in the hippocampus. Our results specify a time period (3–4 h post-training), within which the animals exposed to d-Asp (but not d-Ser) show a more stable memory during retrieval. The cognitive improvement is due to elimination of transient bouts of destabilization and reconsolidation of memory, rather than to enhanced acquisition. d-Asp also protracted reversal learning probably due to reduced plasticity. Expression of GluN1 and GluN2A subunits was elevated in the hippocampus of d-Asp (but not d-Ser) treated mice. d-Asp or d-Ser did not alter the proliferation of neuronal progenitor cells in the hippocampus. The observed learning-related changes evoked by d-Asp are unlikely to be due to enhanced proliferation and recruitment of new neurones. Rather, they are likely associated with an upregulation of NMDA receptors, as well as a reorganization of receptor subunit assemblies in existing hippocampal/dentate neurons.
Repetitive transcranial magnetic stimulation restores altered functional connectivity of central poststroke pain model monkeys
Authors: Kadono Yoshinori , Koguchi Keigo , Okada Ken-ichi , Hosomi Koichi , Hiraishi Motoki , Ueguchi Takashi , Kida Ikuhiro , Shah Adnan , Liu Guoxiang , Saitoh Youichi
Published: March 2021

Central poststroke pain (CPSP) develops after a stroke around the somatosensory pathway. CPSP is hypothesized to be caused by maladaptive reorganization between various brain regions. The treatment for CPSP has not been established; however, repetitive transcranial magnetic stimulation (rTMS) to the primary motor cortex has a clinical effect. To verify the functional reorganization hypothesis for CPSP development and rTMS therapeutic mechanism, we longitudinally pursued the structural and functional changes of the brain by using two male CPSP model monkeys (Macaca fuscata) developed by unilateral hemorrhage in the ventral posterolateral nucleus of the thalamus. Application of rTMS to the ipsilesional primary motor cortex relieved the induced pain of the model monkeys. A tractography analysis revealed a decrease in the structural connectivity in the ipsilesional thalamocortical tract, and rTMS had no effect on the structural connectivity. A region of interest analysis using resting-state functional magnetic resonance imaging revealed inappropriately strengthened functional connectivity between the ipsilesional mediodorsal nucleus of the thalamus and the amygdala, which are regions associated with emotion and memory, suggesting that this may be the cause of CPSP development. Moreover, rTMS normalizes this strengthened connectivity, which may be a possible therapeutic mechanism of rTMS for CPSP.
Temperate conditions restrict Japanese encephalitis virus infection to the mid-gut and prevents systemic dissemination in Culex pipiens mosquitoes
Authors: Folly Arran J. , Dorey-Robinson Daniel , Hernández-Triana Luis M. , Ackroyd Stuart , Vidana Beatriz , Lean Fabian Z. X. , Hicks Daniel , Nuñez Alejandro , Johnson Nicholas
Published: March 2021

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is the main cause of viral encephalitis in Asia. However, with changing climate JEV has the potential to emerge in novel temperate regions. Here, we have assessed the vector competence of the temperate mosquito Culex pipiens f. pipiens to vector JEV genotype III at temperatures representative of those experienced, or predicted in the future during the summer months, in the United Kingdom. Our results show that Cx. pipiens is susceptible to JEV infection at both temperatures. In addition, at 25 °C, JEV disseminated from the midgut and was recovered in saliva samples, indicating the potential for transmission. At a lower temperature, 20 °C, following an incubation period of fourteen days, there were reduced levels of JEV dissemination and virus was not detected in saliva samples. The virus present in the bodies of these mosquitoes was restricted to the posterior midgut as determined by microscopy and viable virus was successfully recovered. Apart from the influence on virus dissemination, mosquito mortality was significantly increased at the higher temperature. Overall, our results suggest that temperature is a critical factor for JEV vector competence and infected-mosquito survival. This may in turn influence the vectorial capacity of Cx. pipiens to vector JEV genotype III in temperate areas.
Semi-automatic liver segmentation based on probabilistic models and anatomical constraints
Authors: Le Doan Cong , Chinnasarn Krisana , Chansangrat Jirapa , Keeratibharat Nattawut , Horkaew Paramate
Published: March 2021

Segmenting a liver and its peripherals from abdominal computed tomography is a crucial step toward computer aided diagnosis and therapeutic intervention. Despite the recent advances in computing methods, faithfully segmenting the liver has remained a challenging task, due to indefinite boundary, intensity inhomogeneity, and anatomical variations across subjects. In this paper, a semi-automatic segmentation method based on multivariable normal distribution of liver tissues and graph-cut sub-division is presented. Although it is not fully automated, the method minimally involves human interactions. Specifically, it consists of three main stages. Firstly, a subject specific probabilistic model was built from an interior patch, surrounding a seed point specified by the user. Secondly, an iterative assignment of pixel labels was applied to gradually update the probabilistic map of the tissues based on spatio-contextual information. Finally, the graph-cut model was optimized to extract the 3D liver from the image. During post-processing, overly segmented nodal regions due to fuzzy tissue separation were removed, maintaining its correct anatomy by using robust bottleneck detection with adjacent contour constraint. The proposed system was implemented and validated on the MICCAI SLIVER07 dataset. The experimental results were benchmarked against the state-of-the-art methods, based on major clinically relevant metrics. Both visual and numerical assessments reported herein indicated that the proposed system could improve the accuracy and reliability of asymptomatic liver segmentation.
Benchmarking DNA isolation kits used in analyses of the urinary microbiome
Authors: Karstens Lisa , Siddiqui Nazema Y. , Zaza Tamara , Barstad Alecsander , Amundsen Cindy L. , Sysoeva Tatyana A.
Published: March 2021

The urinary microbiome has been increasingly characterized using next-generation sequencing. However, many of the technical methods have not yet been specifically optimized for urine. We sought to compare the performance of several DNA isolation kits used in urinary microbiome studies. A total of 11 voided urine samples and one buffer control were divided into 5 equal aliquots and processed in parallel using five commercial DNA isolation kits. DNA was quantified and the V4 segment of the 16S rRNA gene was sequenced. Data were processed to identify the microbial composition and to assess alpha and beta diversity of the samples. Tested DNA isolation kits result in significantly different DNA yields from urine samples. DNA extracted with the Qiagen Biostic Bacteremia and DNeasy Blood & Tissue kits showed the fewest technical issues in downstream analyses, with the DNeasy Blood & Tissue kit also demonstrating the highest DNA yield. Nevertheless, all five kits provided good quality DNA for high throughput sequencing with non-significant differences in the number of reads recovered, alpha, or beta diversity.
Elucidation of the core betalain biosynthesis pathway in Amaranthus tricolor
Authors: Chang Yu-Cheng , Chiu Yi-Ching , Tsao Nai-Wen , Chou Yuan-Lin , Tan Choon-Meng , Chiang Yi-Hsuan , Liao Pei-Chi , Lee Ya-Chien , Hsieh Li-Ching , Wang Sheng-Yang , Yang Jun-Yi
Published: March 2021

Amaranthus tricolor L., a vegetable Amaranthus species, is an economically important crop containing large amounts of betalains. Betalains are natural antioxidants and can be classified into betacyanins and betaxanthins, with red and yellow colors, respectively. A. tricolor cultivars with varying betalain contents, leading to striking red to green coloration, have been commercially produced. However, the molecular differences underlying betalain biosynthesis in various cultivars of A. tricolor remain largely unknown. In this study, A. tricolor cultivars with different colors were chosen for comparative transcriptome analysis. The elevated expression of AmCYP76AD1 in a red-leaf cultivar of A. tricolor was proposed to play a key role in producing red betalain pigments. The functions of AmCYP76AD1, AmDODAα1, AmDODAα2, and AmcDOPA5GT were also characterized through the heterologous engineering of betalain pigments in Nicotiana benthamiana. Moreover, high and low L-DOPA 4,5-dioxygenase activities of AmDODAα1 and AmDODAα2, respectively, were confirmed through in vitro enzymatic assays. Thus, comparative transcriptome analysis combined with functional and enzymatic studies allowed the construction of a core betalain biosynthesis pathway of A. tricolor. These results not only provide novel insights into betalain biosynthesis and evolution in A. tricolor but also provide a basal framework for examining genes related to betalain biosynthesis among different species of Amaranthaceae.
Effect of earthworms on mycorrhization, root morphology and biomass of silver fir seedlings inoculated with black summer truffle (Tuber aestivum Vittad.)
Authors: Nahberger Tina Unuk , Benucci Gian Maria Niccolò , Kraigher Hojka , Grebenc Tine
Published: March 2021

Species of the genusTuberhave gained a lot of attention in recent decades due to their aromatic hypogenous fruitbodies, which can bring high prices on the market. The tendency in truffle production is to infect oak, hazel, beech, etc. in greenhouse conditions. We aimed to show whether silver fir (Abies albaMill.) can be an appropriate host partner for commercial mycorrhization with truffles, and how earthworms in the inoculation substrate would affect the mycorrhization dynamics. Silver fir seedlings inoculated withTuber. aestivumwere analyzed for root system parameters and mycorrhization, how earthworms affect the bare root system, and if mycorrhization parameters change when earthworms are added to the inoculation substrate. Seedlings were analyzed 6 and 12 months after spore inoculation. Mycorrhization with or without earthworms revealed contrasting effects on fine root biomass and morphology of silver fir seedlings. Only a few of the assessed fine root parameters showed statistically significant response, namely higher fine root biomass and fine root tip density in inoculated seedlings without earthworms 6 months after inoculation, lower fine root tip density when earthworms were added, the specific root tip density increased in inoculated seedlings without earthworms 12 months after inoculation, and general negative effect of earthworm on branching density. Silver fir was confirmed as a suitable host partner for commercial mycorrhization with truffles, with 6% and 35% mycorrhization 6 months after inoculation and between 36% and 55% mycorrhization 12 months after inoculation. The effect of earthworms on mycorrhization of silver fir withTuber aestivumwas positive only after 6 months of mycorrhization, while this effect disappeared and turned insignificantly negative after 12 months due to the secondary effect of grazing on ectomycorrhizal root tips.
Bacterial metabolites trimethylamine N-oxide and butyrate as surrogates of small intestinal bacterial overgrowth in patients with a recent decompensated heart failure
Authors: Mollar Anna , Marrachelli Vannina G. , Núñez Eduardo , Monleon Daniel , Bodí Vicent , Sanchis Juan , Navarro David , Núñez Julio
Published: March 2021

In patients with heart failure (HF), the exhaled concentrations of hydrogen after a breath test—a non-invasive assessment of small intestinal overgrowth- has been related to HF severity and higher risk of adverse outcomes. Indeed, two intestinal bacterial metabolites—blood Trimethylamine N-Oxide (TMAO) and butyrate—have been related to a worse prognosis in HF. However, the relationship between the exhaled concentrations of hydrogen after a breath test and these two metabolites remains unknown. Thus, in this post-hoc analysis, we sought to evaluate whether these two metabolites are associated with the exhaled concentrations of hydrogen after a breath test in patients with a recent admission for HF. We included 60 patients with a recent hospitalization for HF. Cumulative hydrogen over time was integrated into a single measurement by the area under the concentration curve (AUC-H2). A linear regression multivariable analysis was used to evaluate the associations. A 2-sided p-value < 0.05 was considered to be statistically significant. The median (p25–p75) amino-terminal pro-brain natriuretic peptide, AUC-H2, TMAO, and Butyrate were 4789 pg/ml (1956–11149), 1615 (700–2585), 0.68 (0.42–1.12), and 0.22 ± 13, respectively. After multivariate adjustment, TMAO and butyrate were significantly associated with AUC-H2 (p = 0.027 and p = 0.009, respectively). For TMAO, this association was positive and for butyrate, negative. Bacterial-origin metabolites TMAO and Butyrate were independently related to AUC-H2 in patients with a recent hospitalization for acute HF.
Normal weight obesity and the risk of diabetes in Chinese people: a 9-year population-based cohort study
Authors: Xu Shaoyong , Ming Jie , Jia Aihua , Yu Xinwen , Cai Jing , Jing Ce , Liu Chun , Ji Qiuhe
Published: March 2021

We evaluated the risk of developing diabetes in Chinese individuals with normal weight obesity (NWO). This 9-year population-based cohort study was based on the China National Diabetes and Metabolic Disorders Survey. A total of 1128 subjects without diabetes were included. Body fat percentage (BF%) was assessed by electrical bioimpedance. NWO was defined as subjects with a normal BMI (< 24 kg/m2) and an excess BF% (≥ 24% in men; ≥ 33% in women). Of 1128 individuals, 528 individuals were normal weight non-obese (NWNO), 118 (10.5%) were normal weight obese (NWO), 63 were overweight non-obese (OWNO), and 419 were overweight obese (OWO). During a follow-up of 9.0 years (interquartile range: 8.9–9.3), 113 (10.0%) individuals developed diabetes. The incidence rates of diabetes in NWNO, NWO, OWNO and OWO people were 5.69 (27 cases), 11.30 (12 cases), 3.53 (2 cases) and 19.09 (72 cases) per 1000 person-years, respectively. Cox regression analyses indicated multivariate-adjusted hazard ratios of diabetes in NWO, OWNO and OWO people were 2.110 (95% CI 1.026–4.337, p = 0.025), 0.441 (95% CI 0.101–1.928, p = 0.232) and 3.465 (95% CI 2.163–5.551, p < 0.001), respectively, relative to NWNO people. Chinese people with NWO are at increased risk of developing diabetes. We strongly suggest the incorporation of BF% measurement into the regular physical examination in Chinese medical practice.
Composition of receptor tyrosine kinase-mediated lipid micro-domains controlled by adaptor protein interaction
Authors: Rohwedder Arndt , Knipp Sabine , Roberts Lee D. , Ladbury John E.
Published: March 2021

Receptor tyrosine kinases (RTKs) are highly regulated, single pass transmembrane proteins, fundamental to cellular function and survival. Aberrancies in regulation lead to corruption of signal transduction and a range of pathological outcomes. Although control mechanisms associated with the receptors and their ligands are well understood, little is known with respect to the impact of lipid/lipid and lipid/protein interactions in the proximal plasma membrane environment. Given that the transmembrane regions of RTKs change in response to extracellular ligand binding, the lipid interactions have important consequences in influencing signal transduction. Fibroblast growth factor receptor 2 (FGFR2) is a highly regulated RTK, including under basal conditions. Binding of the adaptor protein, growth factor receptor-bound protein 2 (GRB2) to FGFR2 prevents full activation and recruitment of downstream signalling effector proteins in the absence of extracellular stimulation. Here we demonstrate that the FGFR2-GRB2 complex is sustained in a defined lipid environment. Dissociation of GRB2 from this complex due to ligand binding, or reduced GRB2 expression, facilitates the dispersion of FGFR2 into detergent-resistant membrane (DRM) micro-domains. This modification of the plasma membrane proximal to FGFR2 provides a further regulatory checkpoint which controls receptor degradation, recycling and recruitment of intracellular signalling proteins.
Genomic signatures of drift and selection driven by predation and human pressure in an insular lizard
Authors: Bassitta Marta , Brown Richard P. , Pérez-Cembranos Ana , Pérez-Mellado Valentín , Castro José A. , Picornell Antònia , Ramon Cori
Published: March 2021

Genomic divergence was studied in 10 small insular populations of the endangered Balearic Islands lizard (Podarcis lilfordi) using double digest restriction-site associated DNA sequencing. The objectives were to establish levels of divergence among populations, investigate the impact of population size on genetic variability and to evaluate the role of different environmental factors on local adaptation. Analyses of 72,846 SNPs supported a highly differentiated genetic structure, being the populations with the lowest population size (Porros, Foradada and Esclatasang islets) the most divergent, indicative of greater genetic drift. Outlier tests identified ~ 2% of loci as candidates for selection. Genomic divergence-Enviroment Association analyses were performed using redundancy analyses based on SNPs putatively under selection, detecting predation and human pressure as the environmental variables with the greatest explanatory power. Geographical distributions of populations and environmental factors appear to be fundamental drivers of divergence. These results support the combined role of genetic drift and divergent selection in shaping the genetic structure of these endemic island lizard populations.
New thermodynamic activity-based approach allows predicting the feasibility of glycolysis
Authors: Greinert Thorsten , Vogel Kristina , Maskow Thomas , Held Christoph
Published: March 2021

Thermodynamic feasibility analyses help evaluating the feasibility of metabolic pathways. This is an important information used to develop new biotechnological processes and to understand metabolic processes in cells. However, literature standard data are uncertain for most biochemical reactions yielding wrong statements concerning their feasibility. In this article we present activity-based equilibrium constants for all the ten glycolytic reactions, accompanied by the standard reaction data (standard Gibbs energy of reaction and standard enthalpy of reaction). We further developed a thermodynamic activity-based approach that allows to correctly determine the feasibility of glycolysis under different chosen conditions. The results show for the first time that the feasibility of glycolysis can be explained by thermodynamics only if (1) correct standard data are used and if (2) the conditions in the cell at non-equilibrium states are accounted for in the analyses. The results here will help to determine the feasibility of other metabolisms and to understand metabolic processes in cells in the future.
Detecting the effects of predator-induced stress on the global metabolism of an ungulate prey using fecal metabolomic fingerprinting
Authors: Valerio Azzurra , Borrego C. Steven , Boitani Luigi , Casadei Luca , Giuliani Alessandro , Wielgus Robert B. , Simek Stephanie L. , Valerio Mariacristina
Published: March 2021

Few field tests have assessed the effects of predator-induced stress on prey fitness, particularly in large carnivore-ungulate systems. Because traditional measures of stress present limitations when applied to free-ranging animals, new strategies and systemic methodologies are needed. Recent studies have shown that stress and anxiety related behaviors can influence the metabolic activity of the gut microbiome in mammal hosts, and these metabolic alterations may aid in identification of stress. In this study, we used NMR-based fecal metabolomic fingerprinting to compare the fecal metabolome, a functional readout of the gut microbiome, of cattle herds grazing in low vs. high wolf-impacted areas within three wolf pack territories. Additionally, we evaluated if other factors (e.g., cattle nutritional state, climate, landscape) besides wolf presence were related to the variation in cattle metabolism. By collecting longitudinal fecal samples from GPS-collared cattle, we found relevant metabolic differences between cattle herds in areas where the probability of wolf pack interaction was higher. Moreover, cattle distance to GPS-collared wolves was the factor most correlated with this difference in cattle metabolism, potentially reflecting the variation in wolf predation risk. We further validated our results through a regression model that reconstructed cattle distances to GPS-collared wolves based on the metabolic difference between cattle herds. Although further research is needed to explore if similar patterns also hold at a finer scale, our results suggests that fecal metabolomic fingerprinting is a promising tool for assessing the physiological responses of prey to predation risk. This novel approach will help improve our knowledge of the consequences of predators beyond the direct effect of predation.
The correlations between dimensions of the normal tendon and tendinopathy changed Achilles tendon in routine magnetic resonance imaging
Authors: Szaro Pawel , Ghali Gataa Khaldun
Published: March 2021

This comparative study aimed to investigate how tendinopathy-related lesions change correlations in the dimensions of the Achilles tendon. Our experimental group included 74 patients. The mean age was 52.9 ± 10.4 years. The control group included 81 patients with a mean age was 35.2 ± 13.6 years, p < .001. The most significant difference in correlation was the thickness of the tendon and the midportion's width, which was more significant in the tendinopathy (r = .49 vs. r = .01, p < .001). The correlation was positive between width and length of the insertion but negative in normal tendons (r = .21 vs. r = − .23, p < .001). The correlation was between the midportions width in tendinopathy and the tendon's length but negative in the normal tendon (r = .16 vs. r = − .23, p < .001). The average thickness of the midportion in tendinopathy was 11.2 ± 3.3 mm, and 4.9 ± 0.5 mm in the control group, p < .001. The average width of the midportion and insertion was more extensive in the experimental group, 17.2 ± 3.1 mm vs. 14.7 ± 1.8 mm for the midportion and 31.0 ± 3.9 mm vs. 25.7 ± 3.0 mm for insertion, respectively, p < .001. The tendon's average length was longer in tendinopathy (83.5 ± 19.3 mm vs. 61.5 ± 14.4 mm, p < .001). The dimensions correlations in normal Achilles tendon and tendinopathic tendon differ significantly.