bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a 3‐D Plasmapause Model With a Back‐Propagation Neural Network
Authors: Zheng Zhi‐Qi , Lei Jiuhou , Yue Xinan , Zhang Xiao‐Xin , He Fei
Published: December 2019

Several empirical models have been previously developed to study the characteristics of the global plasmasphere. A three‐dimensional solar wind‐driven global dynamic plasmapause model was developed in this study using a back‐propagation neural network based on multisatellite measurements. Our database contains 37,859 plasmapause crossing events from 4 January 1995 to 31 December 2015 covering all 24 magnetic local times (MLTs) from66° to 79° magnetic latitudes. This model is parameterized by solar wind speed, interplanetary magnetic field, SYM‐H, andindices with smooth MLTs and latitude dependence. As the first 3‐D empirical model, this model corresponds to the true plasmapause structure and is useful for observing space weather and other applications especially for predicting the shape of the plasmapause by forecasting the input parameters. Moreover, the proposed model is not only highly sensitive to these parameters, but also to their changes over days, seasons, and years; this means that the diurnal, seasonal, and annual variations of the parameters can be captured by the model. Therefore, this model can provide a more accurate plasmapause position compared with previous models and can also be used as a basic reference to develop other models such as a global plasmaspheric density model.
PPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55α/PP2A reconstitution that triggers centrosome destabilization
Authors: Zhao Ziran , Kurimchak Alison , Nikonova Anna S. , Feiser Felicity , Wasserman Jason S. , Fowle Holly , Varughese Tinsa , Connors Megan , Johnson Katherine , Makhov Petr , Lindskog Cecilia , Kolenko Vladimir M. , Golemis Erica A. , Duncan James S. , Graña Xavier
Published: December 2019

The PPP2R2A gene encodes the B55α regulatory subunit of PP2A. Here, we report that PPP2R2A is hemizygously lost in ~42% of prostate adenocarcinomas, correlating with reduced expression, poorer prognosis, and an increased incidence of hemizygous loss (>75%) in metastatic disease. Of note, PPP2R2A homozygous loss is less common (5%) and not increased at later tumor stages. Reduced expression of B55α is also seen in prostate tumor tissue and cell lines. Consistent with the possibility that complete loss of PPP2R2A is detrimental in prostate tumors, PPP2R2A deletion in cells with reduced but present B55α reduces cell proliferation by slowing progression through the cell cycle. Remarkably, B55α-low cells also appear addicted to lower B55α expression, as even moderate increases in B55α expression are toxic. Reconstitution of B55α expression in prostate cancer (PCa) cell lines with low B55α expression reduces proliferation, inhibits transformation and blocks xenograft tumorigenicity. Mechanistically, we show B55α reconstitution reduces phosphorylation of proteins essential for centrosomal maintenance, and induces centrosome collapse and chromosome segregation failure; a first reported link between B55α/PP2A and the vertebrate centrosome. These effects are dependent on a prolonged metaphase/anaphase checkpoint and are lethal to PCa cells addicted to low levels of B55α. Thus, we propose the reduction in B55α levels associated with hemizygous loss is necessary for centrosomal integrity in PCa cells, leading to selective lethality of B55α reconstitution. Such a vulnerability could be targeted therapeutically in the large pool of patients with hemizygous PPP2R2A deletions, using pharmacologic approaches that enhance PP2A/B55α activity.
Sec62 promotes early recurrence of hepatocellular carcinoma through activating integrinα/CAV1 signalling
Authors: Du Juan , Zhao Zhihao , Zhao Hetong , Liu Dong , Liu Hui , Chen Jun , Cheng Binbin , Zhai Xiaofeng , Yin Zifei , Zhang Yani , Ling Changquan
Published: December 2019

Postsurgical recurrence within 2 years is the major cause of poor survival of hepatocellular carcinoma (HCC) patients. However, the molecular mechanism underlying HCC recurrence remains unclear. Here, we distinguish the function and mechanism of Sec62 in promoting HCC recurrence. The correlation between Sec62 and early recurrence was demonstrated in 60 HCC samples from a prospective study. HCC cells with Sec62 knockdown (Sec62KD) or overexpression (Sec62OE) were used to determine the potential of Sec62 in cell migration in vitro. Microarray analysis comparing Sec62KD or Sec62OE to their control counterparts was used to explore the mechanisms of Sec62-induced recurrence. A luciferase-labelled orthotopic nude mouse model of HCC with Sec62KD or Sec62OE was used to validate the potential of Sec62 in early HCC recurrence in vivo. We found that high expression of Sec62 was positively correlated with surgical recurrence in clinical HCC samples. Multivariate analysis revealed that Sec62 was an independent prognostic factor for early recurrence in postoperative HCC patients. Moreover, Sec62 promoted migration and invasion of HCC cells in vitro and postsurgical recurrence in vivo. Mechanically, integrinα/CAV1 signalling was identified as one of the targets of Sec62 in cell movement. Overexpression of integrin α partially rescued the Sec62 knockdown-induced inhibition of cell migration. Sec62 is a potentially prognostic factor for early recurrence in postoperative HCC patients and promotes HCC metastasis through integrinα/CAV1 signalling. Sec62 might be an attractive drug target for combating HCC postsurgical recurrence.
Proteomic analysis to define predictors of treatment response to adalimumab or methotrexate in rheumatoid arthritis patients
Authors:   MATURA consortium, Ling Stephanie F. , Nair Nisha , Verstappen Suzanne M. M. , Barton Anne , Zucht Hans-Dieter , Budde Petra , Schulz-Knappe Peter , Plant Darren
Published: December 2019

Seropositivity for anti-citrullinated peptide antibodies (ACPA) in patients with rheumatoid arthritis (RA), a chronic autoimmune arthritis, is associated with worse long-term disease outcomes. ACPA is ubiquitously tested in RA patients, but other autoantibodies exist (in both citrullinated and non-citrullinated form) which may provide additional information on RA subtypes and/or treatment response. We used a multiplex bead-based assay of 376 autoantibodies to test associations between these autoantibodies and treatment response in RA patients. Clusters of patients with similar autoantibody expression were defined and cluster membership was associated with treatment response. Thirty-four autoantibodies were differentially expressed in RA patients compared with healthy controls; citrullinated vimentin was associated with treatment response. A selection of citrullinated autoantibodies was found to be associated with treatment response in a subanalysis of ACPA-negative RA patients. Finer ACPA specificities in ACPA-negative RA patients may be predictive of treatment response and could represent a rich vein of future study.
Inactivation of 3-hydroxybutyrate dehydrogenase type 2 promotes proliferation and metastasis of nasopharyngeal carcinoma by iron retention
Authors: Li Bo , Liao Zhipeng , Mo Yingxi , Zhao Weilin , Zhou Xiaohui , Xiao Xiling , Cui Wanmeng , Feng Guofei , Zhong Suhua , Liang Yushan , Du Chunping , Huang Guangwu , Li Ping , Xiao Xue , Zhou Xiaoying , Wang Rensheng , Zhang Zhe
Published: December 2019

Background

3-Hydroxybutyrate dehydrogenase type 2 (BDH2) is known to catalyse a rate-limiting step in the biogenesis of the mammalian siderophore and regulate intracellular iron metabolism. Here we aim to explore the expression and possible function of BDH2 in nasopharyngeal carcinoma (NPC).

Methods

The transcription and protein expression of BDH2 in NPC were determined by both real-time RT-PCR and immunohistochemistry staining assays. Cell proliferation, migration and invasion were evaluated by MTT assay, wound-healing assay and Transwell assay, respectively. The profile of genes regulated by restoring BDH2 expression in NPC cells was analysed by cDNA microarray. The level of iron in NPC cells was detected by iron colorimetric assay.

Results

The expression of BDH2 was significantly downregulated in NPC. Ectopic expression of BDH2 inhibited NPC cell proliferation and colony formation. Meanwhile, BDH2 suppressed the migration and invasion of NPC cells by reversing the epithelial–mesenchymal transition (EMT). In addition, a higher level of BDH2 decreased the growth and metastasis of NPC cells via reducing intracellular iron level.

Conclusions

Our findings suggest that BDH2 may be a candidate tumour-suppressor gene in NPC. Decreasing intracellular iron could be an effective therapeutic approach for NPC.
MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming
Authors: Zhang Ze , Li Tian-En , Chen Mo , Xu Da , Zhu Ying , Hu Bei-Yuan , Lin Zhi-Fei , Pan Jun-Jie , Wang Xuan , Wu Chao , Zheng Yan , Lu Lu , Jia Hu-Liang , Gao Song , Dong Qiong-Zhu , Qin Lun-Xiu
Published: December 2019

Background

Mitochondrial dynamics plays an important role in tumour progression. However, how these dynamics integrate tumour metabolism in hepatocellular carcinoma (HCC) metastasis is still unclear.

Methods

The mitochondrial fusion protein mitofusin-1 (MFN1) expression and its prognostic value are detected in HCC. The effects and underlying mechanisms of MFN1 on HCC metastasis and metabolic reprogramming are analysed both in vitro and in vivo.

Results

Mitochondrial dynamics, represented by constant fission and fusion, are found to be associated with HCC metastasis. High metastatic HCC displays excessive mitochondrial fission. Among genes involved in mitochondrial dynamics, MFN1 is identified as a leading downregulated candidate that is closely associated with HCC metastasis and poor prognosis. While promoting mitochondrial fusion, MFN1 inhibits cell proliferation, invasion and migration capacity both in vitro and in vivo. Mechanistically, disruption of mitochondrial dynamics by depletion of MFN1 triggers the epithelial-to-mesenchymal transition (EMT) of HCC. Moreover, MFN1 modulates HCC metastasis by metabolic shift from aerobic glycolysis to oxidative phosphorylation. Treatment with glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) significantly suppresses the effects induced by depletion of MFN1.

Conclusions

Our results reveal a critical involvement of mitochondrial dynamics in HCC metastasis via modulating glucose metabolic reprogramming. MFN1 may serve as a novel potential therapeutic target for HCC.
Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance
Authors: Liu Nan , Lin Xiaoli , Huang Chengying
Published: December 2019

Background

Ferroptosis is an iron-dependent, lipid peroxide-mediated cell death that may be exploited to selective elimination of damaged and malignant cells. Recent studies have identified that small-molecule erastin specifically inhibits transmembrane cystine–glutamate antiporter system xc−, prevents extracellular cystine import and ultimately causes ferroptosis in certain cancer cells. In this study, we aimed to investigate the molecular mechanism underlying erastin-induced ferroptosis resistance in ovarian cancer cells.

Methods

We treated ovarian cancer cells with erastin and examined cell viability, cellular ROS and metabolites of the transsulfuration pathway. We also depleted cystathionine β-synthase (CBS) and NRF2 to investigate the CBS and NRF2 dependency in erastin-resistant cells.

Results

We found that prolonged erastin treatment induced ferroptosis resistance. Upon exposure to erastin, cells gradually adapted to cystine deprivation via sustained activation of the reverse transsulfuration pathway, allowing the cells to bypass erastin insult. CBS, the biosynthetic enzyme for cysteine, was constantly upregulated and was critical for the resistance. Knockdown of CBS by RNAi in erastin-resistant cells caused ferroptotic cell death, while CBS overexpression conferred ferroptosis resistance. We determined that the antioxidant transcriptional factor, NRF2 was constitutively activated in erastin-resistant cells and NRF2 transcriptionally upregulated CBS. Genetically repression of NRF2 enhanced ferroptosis susceptibility.

Conclusions

Based on these results, we concluded that constitutive activation of NRF2/CBS signalling confers erastin-induced ferroptosis resistance. This study demonstrates a new mechanism underlying ferroptosis resistance, and has implications for the therapeutic response to erastin-induced ferroptosis.
Novel clinical and genetic insight into CXorf56-associated intellectual disability
Authors: Rocha Maria Eugenia , Silveira Tainá Regina Damaceno , Sasaki Erina , Sás Daíse Moreno , Lourenço Charles Marques , Kandaswamy Krishna K. , Beetz Christian , Rolfs Arndt , Bauer Peter , Reardon Willie , Bertoli-Avella Aida M.
Published: December 2019

Intellectual disability (ID) is one of most frequent reasons for genetic consultation. The complex molecular anatomy of ID ranges from complete chromosomal imbalances to single nucleotide variant changes occurring de novo, with thousands of genes identified. This extreme genetic heterogeneity challenges the molecular diagnosis, which mostly requires a genomic approach. CXorf56 is largely uncharacterized and was recently proposed as a candidate ID gene based on findings in a single Dutch family. Here, we describe nine cases (six males and three females) from three unrelated families. Exome sequencing and combined database analyses, identified family-specific CXorf56 variants (NM_022101.3:c.498_503del, p.(Glu167_Glu168del) and c.303_304delCTinsACCC, p.(Phe101Leufs*20)) that segregated with the ID phenotype. These variants are presumably leading to loss-of-function, which is the proposed disease mechanism. Clinically, CXorf56-related disease is a slowly progressive neurological disorder. The phenotype is more severe in hemizygote males, but might also manifests in heterozygote females, which showed skewed X-inactivation patterns in blood. Male patients might present previously unreported neurological features such as epilepsy, abnormal gait, tremor, and clonus, which extends the clinical spectrum of the disorder. In conclusion, we confirm the causative role of variants in CXorf56 for an X-linked form of intellectual disability with additional neurological features. The gene should be considered for molecular diagnostics of patients with ID, specifically when family history is suggestive of X-linked inheritance. Further work is needed to understand the role of this gene in neurodevelopment and intellectual disability.
Atlas of quantitative single-base-resolution N6-methyl-adenine methylomes
Authors: Koh Casslynn W. Q. , Goh Yeek Teck , Goh W. S. Sho
Published: December 2019

Various methyltransferases and demethylases catalyse methylation and demethylation of N6-methyladenosine (m6A) and N6,2′-O-dimethyladenosine (m6Am) but precise methylomes uniquely mediated by each methyltransferase/demethylase are still lacking. Here, we develop m6A-Crosslinking-Exonuclease-sequencing (m6ACE-seq) to map transcriptome-wide m6A and m6Am at quantitative single-base-resolution. This allows for the generation of a comprehensive atlas of distinct methylomes uniquely mediated by every individual known methyltransferase or demethylase. Our atlas reveals METTL16 to indirectly impact manifold methylation targets beyond its consensus target motif and highlights the importance of precision in mapping PCIF1-dependent m6Am. Rather than reverse RNA methylation, we find that both ALKBH5 and FTO instead maintain their regulated sites in an unmethylated steady-state. In FTO’s absence, anomalous m6Am disrupts snRNA interaction with nuclear export machinery, potentially causing aberrant pre-mRNA splicing events.
Electronic heat flow and thermal shot noise in quantum circuits
Authors: Sivre E. , Duprez H. , Anthore A. , Aassime A. , Parmentier F. D. , Cavanna A. , Ouerghi A. , Gennser U. , Pierre F.
Published: December 2019

When assembling individual quantum components into a mesoscopic circuit, the interplay between Coulomb interaction and charge granularity breaks down the classical laws of electrical impedance composition. Here we explore experimentally the thermal consequences, and observe an additional quantum mechanism of electronic heat transport. The investigated, broadly tunable test-bed circuit is composed of a micron-scale metallic node connected to one electronic channel and a resistance. Heating up the node with Joule dissipation, we separately determine, from complementary noise measurements, both its temperature and the thermal shot noise induced by the temperature difference across the channel. The thermal shot noise predictions are thereby directly validated, and the electronic heat flow is revealed. The latter exhibits a contribution from the channel involving the electrons’ partitioning together with the Coulomb interaction. Expanding heat current predictions to include the thermal shot noise, we find a quantitative agreement with experiments.
Deciphering protein evolution and fitness landscapes with latent space models
Authors: Ding Xinqiang , Zou Zhengting , Brooks III Charles L.
Published: December 2019

Protein sequences contain rich information about protein evolution, fitness landscapes, and stability. Here we investigate how latent space models trained using variational auto-encoders can infer these properties from sequences. Using both simulated and real sequences, we show that the low dimensional latent space representation of sequences, calculated using the encoder model, captures both evolutionary and ancestral relationships between sequences. Together with experimental fitness data and Gaussian process regression, the latent space representation also enables learning the protein fitness landscape in a continuous low dimensional space. Moreover, the model is also useful in predicting protein mutational stability landscapes and quantifying the importance of stability in shaping protein evolution. Overall, we illustrate that the latent space models learned using variational auto-encoders provide a mechanism for exploration of the rich data contained in protein sequences regarding evolution, fitness and stability and hence are well-suited to help guide protein engineering efforts.
Hyperconjugative aromaticity and protodeauration reactivity of polyaurated indoliums
Authors: Xiao Kui , Zhao Yu , Zhu Jun , Zhao Liang
Published: December 2019

Aromaticity generally describes a cyclic structure composed of sp2-hybridized carbon or hetero atoms with remarkable stability and unique reactivity. The doping of even one sp3-hybridized atom often damages the aromaticity due to the interrupted electron conjugation. Here we demonstrate the occurrence of an extended hyperconjugative aromaticity (EHA) in a metalated indole ring which contains two gem-diaurated tetrahedral carbon atoms. The EHA-involved penta-aurated indolium shows extended electron conjugation because of dual hyperconjugation. Furthermore, the EHA-induced low electron density on the indolyl nitrogen atom enables a facile protodeauration reaction for the labile Au-N bond. In contrast, the degraded tetra-aurated indolium with a single gem-dimetalated carbon atom exhibits poor bond averaging and inertness in the protodeauration reaction. The aromaticity difference in such two polyaurated indoliums is discussed in the geometrical and electronic perspectives. This work highlights the significant effect of metalation on the aromaticity of polymetalated species.
Integrative systematics and ecology of a new deep-sea family of tanaidacean crustaceans
Authors: Błażewicz Magdalena , Jóźwiak Piotr , Jennings Robert M. , Studzian Maciej , Frutos Inmaculada
Published: December 2019

A new family of paratanaoidean Tanaidacea – Paranarthrurellidae fam. nov. – is erected to accommodate two genera without family classification (Paratanaoideaincertae sedis), namelyArmatognathiaKudinova-Pasternak, 1987 andParanarthrurellaLang, 1971. Seven new species ofParanarthrurellaand two ofArmatognathiaare described from material taken in different deep-sea areas of the Atlantic and Pacific oceans. The type species ofParanarthrurella—P. caudata(Kudinova-Pasternak, 1965) — is redescribed based on the paratype. The genusCheliasetosatanaisLarsen and Araújo-Silva, 2014 originally classified within Colletteidae is synonymised withParanarthrurella, andArthrura shiinoiKudinova-Pasternak, 1973 is transferred toArmatognathia. Amended diagnoses ofArmatognathiaandParanarthrurellagenera are given. Choosing characters for distinguishing and defining both genera was supported by Principal Component Analysis. Designation of the new family is supported by molecular phylogenetic analysis of COI and 18S datasets. The distribution of all species currently included in the new family was visualised and their bathymetric distribution analysed.
Fuzhenghuayu Decoction ameliorates hepatic fibrosis by attenuating experimental sinusoidal capillarization and liver angiogenesis
Authors: Liu Hong-liang , Lv Jing , Zhao Zhi-min , Xiong An-ming , Tan Ye , Glenn Jeffrey S. , Tao Yan-yan , Weng Hong-lei , Liu Cheng-hai
Published: December 2019

Fuzhenghuayu (FZHY) is a compound extracted from natural plants. Its anti-fibrotic effect has been confirmed in experimental and clinical studies. However, precise effects and underlying mechanisms of FZHY in liver angiogenesis largely remain understood. In this study, we investigated the effects of FZHY on sinusoidal capillarization and angiogenesis with mice challenged for Carbon tetrachloride (CCl4) and dimethylnitrosamine (DMN), in vitro human hepatic sinusoidal endothelial cells (HHSEC) and Human Umbilical Vein Endothelial Cell (HUVEC) 3D fibrin gel model. Besides its anti-fibrotic effect, FZHY ameliorated CCl4 and DMN-induced sinusoidal capillarization, angiogenesis and expression of angiogenesis-associated factors, i.e. CD31, VEGF, VEGF receptor II, phosphor-ERK and HIF-1α. Consistent with the findings based on animal models, inhibitory effects of FZHY on capillarization and angiogenesis were further confirmed in HHSEC and the HUVEC 3D fibrin gel model, respectively. These data suggest that FZHY ameliorates not only liver fibrosis but also vessel remodeling in experimental models. Therefore, FZHY might be a potentially useful drug to treat liver cirrhosis in clinical practice.
The emissions of CO2 and other volatiles from the world’s subaerial volcanoes
Authors: Fischer Tobias P. , Arellano Santiago , Carn Simon , Aiuppa Alessandro , Galle Bo , Allard Patrick , Lopez Taryn , Shinohara Hiroshi , Kelly Peter , Werner Cynthia , Cardellini Carlo , Chiodini Giovanni
Published: December 2019

Volcanoes are the main pathway to the surface for volatiles that are stored within the Earth. Carbon dioxide (CO2) is of particular interest because of its potential for climate forcing. Understanding the balance of CO2 that is transferred from the Earth’s surface to the Earth’s interior, hinges on accurate quantification of the long-term emissions of volcanic CO2 to the atmosphere. Here we present an updated evaluation of the world’s volcanic CO2 emissions that takes advantage of recent improvements in satellite-based monitoring of sulfur dioxide, the establishment of ground-based networks for semi-continuous CO2-SO2 gas sensing and a new approach to estimate key volcanic gas parameters based on magma compositions. Our results reveal a global volcanic CO2 flux of 51.3 ± 5.7 Tg CO2/y (11.7 × 1011 mol CO2/y) for non-eruptive degassing and 1.8 ± 0.9 Tg/y for eruptive degassing during the period from 2005 to 2015. While lower than recent estimates, this global volcanic flux implies that a significant proportion of the surface-derived CO2 subducted into the Earth’s mantle is either stored below the arc crust, is efficiently consumed by microbial activity before entering the deeper parts of the subduction system, or becomes recycled into the deep mantle to potentially form diamonds.
Plasma metabolomics in tuberculosis patients with and without concurrent type 2 diabetes at diagnosis and during antibiotic treatment
Authors: Vrieling Frank , Alisjahbana Bachti , Sahiratmadja Edhyana , van Crevel Reinout , Harms Amy C. , Hankemeier Thomas , Ottenhoff Tom H. M. , Joosten Simone A.
Published: December 2019

Tuberculosis (TB) and type 2 diabetes mellitus (DM), a major TB risk factor, are both accompanied by marked alterations in metabolic processes. Dissecting the specific metabolic changes induced by disease through metabolomics has shown potential to improve our understanding of relevant pathophysiological mechanisms of disease, which could lead to improved treatment. Targeted tandem liquid chromatography–mass spectrometry (LC-MS/MS) was used to compare amine and acylcarnitine levels in plasma samples of patients with TB or TB-DM from Indonesia at time of diagnosis and during antibiotic treatment. Partial least squares discrimination analysis (PLS-DA) showed good separation of patient groups. Amine levels were strongly altered in both disease groups compared to healthy controls, including low concentrations of citrulline and ornithine. Several amino acid ratios discriminated TB from controls (phenylalanine/histidine; citrulline/arginine; kynurenine/tryptophan), possibly reflecting changes in indoleamine-pyrrole 2,3-dioxygenase (IDO) and nitric oxide synthase (NOS) activity. Choline, glycine, serine, threonine and homoserine levels were lower in TB-DM compared to TB, and, in contrast to other analytes, did not normalize to healthy control levels during antibiotic treatment. Our results not only provide important validation of previous studies but also identify novel biomarkers, and significantly enhance our understanding of metabolic changes in human TB and TB-DM.
The perception of time is dynamically interlocked with the facial muscle activity
Authors: Fernandes Alexandre C. , Garcia-Marques Teresa
Published: December 2019

Time perception relies on the motor system. Involves core brain regions of this system, including those associated with feelings generated from sensorimotor states. Perceptual timing is also distorted when movement occurs during timing tasks, possibly by interfering with sensorimotor afferent feedback. However, it is unknown if the perception of time is an active process associated with specific patterns of muscle activity. We explored this idea based on the phenomenon of electromyographic gradients, which consists of the dynamic increase of muscle activity during cognitive tasks that require sustained attention, a critical function in perceptual timing. We aimed to determine whether facial muscle dynamic activity indexes the subjective representation of time. We asked participants to judge stimuli durations (varying in familiarity) while we monitored the time course of the activity of the zygomaticus-major and corrugator-supercilii muscles, both associated with cognitive and affective feelings. The dynamic electromyographic activity in corrugator-supercilii over time reflected objective time and this relationship predicted subjective judgments of duration. Furthermore, the zygomaticus-major muscle signaled the bias that familiarity introduces in duration judgments. This suggests that subjective duration could be an embodiment process based in motor information changing over time and their associated feelings.
Virtual clinical trials identify effective combination therapies in ovarian cancer
Authors: Kozłowska Emilia , Vallius Tuulia , Hynninen Johanna , Hietanen Sakari , Färkkilä Anniina , Hautaniemi Sampsa
Published: December 2019

A major issue in oncology is the high failure rate of translating preclinical results in successful clinical trials. Using a virtual clinical trial simulations approach, we present a mathematical framework to estimate the added value of combinatorial treatments in ovarian cancer. This approach was applied to identify effective targeted therapies that can be combined with the platinum-taxane regimen and overcome platinum resistance in high-grade serous ovarian cancer. We modeled and evaluated the effectiveness of three drugs that target the main platinum resistance mechanisms, which have shown promising efficacy in vitro, in vivo, and early clinical trials. Our results show that drugs resensitizing chemoresistant cells are superior to those aimed at triggering apoptosis or increasing the bioavailability of platinum. Our results further show that the benefit of using biomarker stratification in clinical trials is dependent on the efficacy of the drug and tumor composition. The mathematical framework presented herein is suitable for systematically testing various drug combinations and clinical trial designs in solid cancers.
Intracellular delivery of therapeutic antibodies into specific cells using antibody-peptide fusions
Authors: Gaston Julie , Maestrali Nicolas , Lalle Guilhem , Gagnaire Marie , Masiero Alessandro , Dumas Bruno , Dabdoubi Tarik , Radošević Katarina , Berne Pierre-François
Published: December 2019

Because of their favorable properties as macromolecular drugs, antibodies are a very successful therapeutic modality for interfering with disease-relevant targets in the extracellular space or at the cell membrane. However, a large number of diseases involve cytosolic targets and designing antibodies able to efficiently reach intracellular compartments would expand the antibody-tractable conditions. Here, we genetically fused cell penetrating peptides (CPPs) at various positions to an antibody targeting cancer cells, evaluated the developability features of the resulting antibody-peptide fusions and the ability of selected constructs to reach the cytosol. We first determined positions in the IgG structure that were permissive to CPP incorporation without destabilizing the antibody. Fusing CPPs to the C-terminus of the light chain and either before or after the hinge had the least effect on antibody developability features. These constructs were further evaluated for cell penetration efficiency. Two out of five tested CPPs significantly enhanced antibody penetration into the cytosol, in particular when fused before or after the hinge. Finally, we demonstrate that specific antibody binding to the cell surface target is necessary for efficient cell penetration of the CPP-antibody fusions. This study provides a solid basis for further exploration of therapeutic antibodies for intracellular targets.
Transscleral cyclophotocoagulation and its histological effects on the conjunctiva
Authors: Tan Nicholas Y. Q. , Ang Marcus , Chan Anita S. Y. , Barathi Veluchamy A. , Tham Clement C. , Barton Keith , Sng Chelvin C. A.
Published: December 2019

Micropulse transscleral cyclophotocoagulation (MP-TCP) is increasingly being used as an initial procedure prior to conjunctival filtration surgeries. However, it is uncertain whether MP-TCP may cause inflammation and scarring of the bulbar conjunctiva. Thus, we aimed to study the histological effects of MP-TCP (compared to controls and continuous wave [CW]-TCP) on the conjunctiva. Our study included 10 Dutch Belted Rabbits that underwent TCP in their right eyes (n = 5, MP-TCP; n = 5, CW-TCP), while their left eyes served as controls. The rabbits were euthanised at 4 weeks, and their dissected globes underwent histopathological and immunohistochemical examination. We observed greater conjunctival inflammation in MP-TCP or CW-TCP-treated eyes compared to controls, but not between each other. The majority of the lymphocytic infiltrates were CD4 T-cells. Increased conjunctival fibrosis was evident in MP-TCP or CW-TCP-treated eyes, to similar extents, compared to controls. However, the increased staining for myofibroblasts was not statistically significant in TCP-treated eyes. We concluded that MP-TCP causes significantly greater overall conjunctival inflammation and scarring compared to controls, similar to CW-TCP. As these are risk-factors for fibrosis and failure of the conjunctival bleb, further studies are required to explore the effect, if any, of post-TCP conjunctival changes on future bleb morphology and survival.
Genome analysis of deep sea piezotolerant Nesiotobacter exalbescens COD22 and toluene degradation studies under high pressure condition
Authors: Ganesh Kumar A. , Mathew Noelin Chinnu , Sujitha K. , Kirubagaran R. , Dharani G.
Published: December 2019

A marine isolate, Nesiotobacter exalbescens COD22, isolated from deep sea sediment (2100 m depth) was capable of degrading aromatic hydrocarbons. The Nesiotobacter sp. grew well in the presence of toluene at 0.1 MPa and 10 MPa at a rate of 0.24 h−1 and 0.12 h−1, respectively, in custom designed high pressure reactors. Percentage of hydrocarbon degradation was found to be 87.5% at ambient pressure and it reached 92% under high pressure condition within a short retention period of 72 h. The biodegradation of hydrocarbon was confirmed by the accumulation of dicarboxylic acid, benzoic acid, benzyl alcohol and benzaldehyde which are key intermediates in toluene catabolism. The complete genome sequence consists of 4,285,402 bp with 53% GC content and contained 3969 total coding genes. The complete genome analysis revealed unique adaptation and degradation capabilities for complex aromatic compounds, biosurfactant synthesis to facilitate hydrocarbon emulsification, advanced mechanisms for chemotaxis and presence of well developed flagellar assembly. The genomic data corroborated with the results of hydrocarbon biodegradation at high pressure growth conditions and confirmed the biotechnological potential of Nesiotobacter sp. towards bioremediation of hydrocarbon polluted deep sea environments.
Enteric neuronal cell therapy reverses architectural changes in a novel diphtheria toxin-mediated model of colonic aganglionosis
Authors: Bhave Sukhada , Arciero Emily , Baker Corey , Ho Wing Lam , Stavely Rhian , Goldstein Allan M. , Hotta Ryo
Published: December 2019

Hirschsprung disease (HSCR) is characterized by absence of the enteric nervous system (ENS) in the distal bowel. Despite removal of the aganglionic segment, gastrointestinal (GI) problems persist. Cell therapy offers potential treatment but use of genetic models is limited by their poor survival. We have developed a novel model of aganglionosis in which enteric neural crest-derived cells (ENCDCs) express diphtheria toxin (DT) receptor. Local DT injection into the colon wall results in focal, specific, and sustained ENS ablation without altering GI transit or colonic contractility, allowing improved survival over other aganglionosis models. Focal ENS ablation leads to increased smooth muscle and mucosal thickness, and localized inflammation. Transplantation of ENCDCs into this region leads to engraftment, migration, and differentiation of enteric neurons and glial cells, with restoration of normal architecture of the colonic epithelium and muscle, reduction in inflammation, and improved survival.
Genetic analysis of the invasive alga Didymosphenia geminata in Southern Argentina: Evidence of a Pleistocene origin of local lineages
Authors: Jones Leandro R. , Manrique Julieta M. , Uyua Noelia M. , Whitton Brian A.
Published: December 2019

The diatom Didymosphenia geminata has gained notoriety due to the massive growths which have occurred in recent decades in temperate regions. Different explanations have been proposed for this phenomenon, including the emergence of new invasive strains, human dispersion and climate change. Despite the fact in Argentina nuisance growths began in about 2010, historical records suggest that the alga was already present before that date. In addition, preliminary genetic data revealed too high a diversity to be explained by a recent invasion. Here, we estimate the divergence times of strains from southern Argentina. We integrate new genetic data and secondary, fossil and geological calibrations into a Penalized Likelihood model used to infer 18,630 plausible chronograms. These indicate that radiation of the lineages in Argentina began during or before the Pleistocene, which is hard to reconcile with the hypothesis that a new variant is responsible for the local mass growths. Instead, this suggests that important features of present distribution could be the result of multiple recent colonizations or the expansion of formerly rare populations. The text explains how these two possibilities are compatible with the hypothesis that recent nuisance blooms may be a consequence of climate change.
One-year mortality after hip fracture surgery and prognostic factors: a prospective cohort study
Authors: Morri Mattia , Ambrosi Elisa , Chiari Paolo , Orlandi Magli Antonella , Gazineo Domenica , D’ Alessandro Fabio , Forni Cristiana
Published: December 2019

Older adult patients with hip fractures are 3–4 times more likely to die within one-year after surgery than general population. The study aimed to identify independent predictive factors associated with one-year mortality after hip fracture surgery. A prospective prognostic cohort study was performed. All patients aged ≥65 years, consecutively admitted in three Italian hospitals with a diagnosis of fragility hip fracture were included. Patients with periprosthetic or pathological fractures were excluded. Multivariate analysis was used to determine variables that significantly increased the risk of one-year mortality and Receiver operating characteristic (ROC) curve analysis to assess their predictive capacity on the outcome.1083 patients fulfilled the inclusion criteria and the one-year follow-up was reached in 728 patients. The 16.6% of patients died within one-year after surgery. At the multivariate analysis, advancing age (OR = 1.094, 95% CI = 1.057–1.132), higher baseline Charlson Index (OR = 1.257, 95% CI = 1.114–1.418) and Activities of Daily Living scores (OR = 1.259, 95% CI = 1.143–1.388), presence of hospital-acquired pressure ulcers (PUs) (OR = 1.579, 95% CI = 1.002–2.489) and lack recovery of ambulation (OR = 1.736, 95% CI = 1.115–2.703), were found to be independent predictive factors of one-year mortality after surgery. The area under the ROC curve of the model was 0.780 (CI95% 0.737–0.824) for one-year mortality in elderly hip fractures patients. Early ambulation and careful long-term follow-up, with attention to frailty in elderly people, should be promoted.
Differential Proteome Analysis of Hybrid Bamboo (Bambusa pervariabilis × Dendrocalamopsis grandis) Under Fungal Stress (Arthrinium phaeospermum)
Authors: Li Shujiang , Fang Xinmei , Han Shan , Zhu Tianhui , Zhu Hanmingyue
Published: December 2019

In this study, TMT (tandem mass tag)-labeled quantitative protein technology combined with LC–MS/MS (liquid chromatography-mass spectrometry/mass spectrometry) was used to isolate and identify the proteins of the hybrid bamboo (Bambusa pervariabilis × Dendrocalamopsis grandis) and the bamboo inoculated with the pathogenic fungi Arthrinium phaeospermum. A total of 3320 unique peptide fragments were identified after inoculation with either A. phaeospermum or sterile water, and 1791 proteins were quantified. A total of 102 differentially expressed proteins were obtained, of which 66 differential proteins were upregulated and 36 downregulated in the treatment group. Annotation and enrichment analysis of these peptides and proteins using the GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) databases with bioinformatics software showed that the differentially expressed protein functional annotation items were mainly concentrated on biological processes and cell components. The LC–PRM/MS (liquid chromatography-parallel reaction monitoring/mass spectrometry) quantitative analysis technique was used to quantitatively analyze 11 differential candidate proteins obtained by TMT combined with LC–MS/MS. The up–down trend of 10 differential proteins in the PRM results was consistent with that of the TMT quantitative analysis. The coincidence rate of the two results was 91%, which confirmed the reliability of the proteomic results. Therefore, the differentially expressed proteins and signaling pathways discovered here may be the further concern for the bamboo-pathogen interaction studies.
Synthesis of Ce-doped Mn3Gd7−xCex(SiO4)6O1.5 for the enhanced catalytic ozonation of tetracycline
Authors: Fu Jie , Liu Ning , Mei Lefu , Liao Libing , Deyneko Dina , Wang Jiayang , Bai Yaning , Lv Guocheng
Published: December 2019

A novel cerium doped compounds Mn3Gd7–xCex(SiO4)6O1.5 with an apatite structure was found and used to achieve high-efficiency degradation of tetracycline in aqueous solution. The catalysts were characterized by XRD, XPS, EDS and other techniques. The characteristic results indicated that the catalytic activity of the compound was improved due to the introduction of Ce in the structure, because Ce3+ which was stably present in the apatite structure can serve as an active site for the reaction, and in addition, there was a high presence between Ce4+ and Ce3+ on the surface of the catalyst. The redox potential and high oxygen storage capacity were also beneficial for the catalytic reaction. The results of free radical capture indicated that both superoxide radicals and hydroxyl radicals participated in the catalytic oxidation process and played an important role in the reaction. The decomposition of tetracycline followed the pseudo second-order reaction kinetics. In addition, the catalyst exhibited long-term stability and low metal leaching during the reaction, which indicated that the novel cerium-doped apatite structure material could be a promising wastewater treatment material.
Re-regeneration to reduce negative effects associated with tail loss in lizards
Authors: Barr James I. , Boisvert Catherine A. , Somaweera Ruchira , Trinajstic Kate , Bateman Philip W.
Published: December 2019

Many species of lizard use caudal autotomy, the ability to self-amputate a portion of their tail, regenerated over time, as an effective anti-predation mechanism. The importance of this tactic for survival depends on the degree of predation risk. There are, however, negative trade-offs to losing a tail, such as loss of further autotomy opportunities with the regenerated tail vertebrae being replaced by a continuous cartilaginous rod. The common consensus has been that once a tail has been autotomised and regenerated it can only be autotomised proximal to the last vertebral autotomy point, as the cartilage rod lacks autotomy planes. However, anecdotal evidence suggests that although the regenerated portion of the tail is unable to autotomise, it can re-regenerate following a physical shearing event. We assessed re-regeneration in three populations of the King’s skink (Egernia kingii), a large lizard endemic to south-west Western Australia and surrounding islands. We show that re-regeneration is present at an average of 17.2% across the three populations, and re-regenerated tissue can comprise up to 23.3% of an individual’s total tail length. The ability to re-regenerate may minimise the costs to an individual’s fitness associated with tail loss, efficiently restoring ecological functions of the tail.
D-shaped plastic optical fibre aptasensor for fast thrombin detection in nanomolar range
Authors: Cennamo Nunzio , Pasquardini Laura , Arcadio Francesco , Vanzetti Lia E. , Bossi Alessandra Maria , Zeni Luigi
Published: December 2019

The development of optical biosensors for the rapid and costless determination of clinical biomarkers is of paramount importance in medicine. Here we report a fast and low-cost biosensor based on a plasmonic D-shaped plastic optical fibre (POF) sensor derivatized with an aptamer specific for the recognition of thrombin, the target marker of blood homeostasis and coagulation cascade. In particular, we designed a functional interface based on a Self Assembled Monolayer (SAM) composed of short Poly Ethylene Glycol (PEG) chains and biotin-modified PEG thiol in ratio 8:2 mol:mol, these latter serving as baits for the binding of the aptamer through streptavidin-chemistry. The SAM was studied by X-ray Photoelectron Spectroscopy (XPS) analysis, static contact angle (CA), Surface Plasmon Resonance (SPR) in POFs, and fluorescence microscopy on gold surface. The optimized SAM composition enabled the immobilization of about 112 ng/cm2 of aptamer. The thrombin detection exploiting POF-Aptasensor occurred in short times (5–10 minutes), the reached Limit of Detection (LOD) was about 1 nM, and the detection range was 1.6–60 nM, indicating the POF-Aptasensor well addresses the needs for a low-cost, simple to use and to realize, rapid, small size and portable diagnostic platform.
A transient time window for early predispositions in newborn chicks
Authors: Versace Elisabetta , Ragusa Morgana , Vallortigara Giorgio
Published: December 2019

Neonates of different species are born with a set of predispositions that influence their early orienting responses toward the first stimuli encountered in their life. Human neonates and domestic chicks exhibit several similarities in the predisposition for attending to objects that move with speed changes, face-like stimuli and biological motion. Although early predispositions are connected to physiological development, little is known on the temporal course of early predispositions (whether they are stable or change in time) and on the associated genetic variability. To address these issues, we tested the preference for objects that change in speed vs. linear motion in three chicken breeds (Padovana, Polverara and Robusta maculata) within one day after hatching and three days after hatching. We found that the predisposition to preferentially attend to changes in speed is shared by different breeds on the first day of life and that it disappears by day three. These results indicate the existence of a short and transient time window of early predispositions that does not depend on visual experience.
The effects of surface albedo and initial lignin concentration on photodegradation of two varieties of Sorghum bicolor litter
Authors: Ruhland Christopher T. , Niere Joshua A.
Published: December 2019

Decomposition of plant litter exposed to solar radiation appears to be a significant contributor to carbon cycling in some ecosystems. One factor that may influence incident solar radiation exposure on litter is surface albedo. Snow and soils with high reflectivity may enhance photodecomposition, especially in litter that stands upright for extended periods. We examined the influence of different surface albedos on the photodegradation of two varieties of sorghum (Sorghum bicolor) litter for 200-d, in southern Minnesota using litterbags made of material with a high transmittance of ultraviolet radiation (UV; 280–400 nm). One of these cultivars was a brown-midrib double mutant (DM) which had reduced levels of lignin compared to the wild type (WT). After 200-d sorghum litter had lost > 50% of its initial mass, and litter that was exposed to a high UV/high visible surface albedo had lost 1.4 and 2.5% more mass than litter exposed to a low UV/high visible and low UV/low visible surface albedo, respectively. Mass loss patterns agreed with initial litter chemistry, as DM litter had higher initial N, neutral detergent fiber (NDF) solubles and holocellulose:lignin ratios and lower lignin:N ratios than WT litter. Mass loss appears to be related to increased loss of hemicellulose and NDF soluble concentrations and not to lignin concentrations. Our results demonstrate that surface albedo has a small but significant effect on photodecomposition of sorghum litter.