bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of transport electrification on critical metal sustainability with a focus on the heavy-duty segment
Authors: Hao Han , Geng Yong , Tate James E. , Liu Feiqi , Chen Kangda , Sun Xin , Liu Zongwei , Zhao Fuquan
Published: November 2019

The majority of transport electrification studies, examining the demand and sustainability of critical metals, have focused on light-duty vehicles. Heavy-duty vehicles have often been excluded from the research scope due to their smaller vehicle stock and slower pace of electrification. This study fills this research gap by evaluating the lithium resource impacts from electrification of the heavy-duty segment at the global level. Our results show that a mass electrification of the heavy-duty segment on top of the light-duty segment would substantially increase the lithium demand and impose further strain on the global lithium supply. The significant impact is attributed to the large single-vehicle battery capacity required by heavy-duty vehicles and the expected battery replacement needed within the lifetime of heavy-duty vehicles. We suggest that the ambition of mass electrification in the heavy-duty segment should be treated with cautions for both policy makers and entrepreneurs.
Release factor-dependent ribosome rescue by BrfA in the Gram-positive bacterium Bacillus subtilis
Authors: Shimokawa-Chiba Naomi , Müller Claudia , Fujiwara Keigo , Beckert Bertrand , Ito Koreaki , Wilson Daniel N. , Chiba Shinobu
Published: November 2019

Rescue of the ribosomes from dead-end translation complexes, such as those on truncated (non-stop) mRNA, is essential for the cell. Whereas bacteria use trans-translation for ribosome rescue, some Gram-negative species possess alternative and release factor (RF)-dependent rescue factors, which enable an RF to catalyze stop-codon-independent polypeptide release. We now discover that the Gram-positive Bacillus subtilis has an evolutionarily distinct ribosome rescue factor named BrfA. Genetic analysis shows that B. subtilis requires the function of either trans-translation or BrfA for growth, even in the absence of proteotoxic stresses. Biochemical and cryo-electron microscopy (cryo-EM) characterization demonstrates that BrfA binds to non-stop stalled ribosomes, recruits homologous RF2, but not RF1, and induces its transition into an open active conformation. Although BrfA is distinct from E. coli ArfA, they use convergent strategies in terms of mode of action and expression regulation, indicating that many bacteria may have evolved as yet unidentified ribosome rescue systems.
Applications of the European Parkinson’s Disease Association sponsored Parkinson’s Disease Composite Scale (PDCS)
Authors: Balestrino Roberta , Hurtado-Gonzalez Carlos Alberto , Stocchi Fabrizio , Radicati Fabiana Giada , Chaudhuri K. Ray , Rodriguez-Blazquez Carmen , Martinez-Martin Pablo ,   The PDCS European Study Group, Adarmes Astrid D. , Méndez-del-Barrio Carlota , Ariadne Vakirli , Aschermann Zsuzsanna , Juhász Annamária , Harmat Márk , Bostantjopoulou Sevasti , Corbo Massimo , Grassi Andrea , Dellaporta Dionysia , Falup-Pecurariu Cristian , Diaconu Ştefania , Giagkou Nikolaos , Guekht Alla , Popov Georgy , Gurevich Tanya , Johansson Anders , Sundgren Mathias , Kefalopoulou Zinovia , Ellul John , Kostić Vladimir S. , Kovacs Norbert , Marti Maria J. , Planelles Lluis , Migirov-Sanderovich Angel , Ezra Adi , Minar Michal , Mir Pablo , Jan Necpal  , Popovici Maria , Simitsi Athima , Stefanis Leonidas , Simu Mihaela , Rosca Cecilia , Skorvanek Matej , Stefani Alessandro , Cerroni Rocco , Stamelou Maria , Tsolaki Magda , Vuletic Vladimira , Katsarou Zoe
Published: November 2019

This study was addressed to determine the presence of Parkinson disease (PD) manifestations, their distribution according to motor subtypes, and the relationships with health-related quality of life (QoL) using the recently validated European Parkinson’s Disease Association sponsored Parkinson’s Disease Composite Scale (PDCS). Frequency of symptoms was determined by the scores of items (present if >0). Using ROC analysis and Youden method, MDS-UPDRS motor subtypes were projected on the PDCS to achieve a comparable classification based on the PDCS scores. The same method was used to estimate severity levels from other measures in the study. The association between the PDCS and QoL (PDQ-39) was analyzed by correlation and multiple linear regression. The sample consisted of 776 PD patients. We found that the frequency of PD manifestations with PDCS and MDS-UPDRS were overlapping, the average difference between scales being 5.5% only. Using the MDS-UPDRS subtyping, 215 patients (27.7%) were assigned as Tremor Dominant (TD), 60 (7.7%) Indeterminate, and 501 (64.6%) Postural Instability and Gait Difficulty (PIGD) in this cohort. With this classification as criterion, the analogous PDCS-based ratio provided these cut-off values: TD subtype, ≥1.06; Indeterminate, <1.06 but >0.65; and PIGD, <0.65. The agreement between the two scales on this classification was substantial (87.6%; kappa = 0.69). PDCS total score cut-offs for PD severity were: 23/24 for mild/moderate and 41/42 for moderate/severe. Moderate to high correlations (r = 0.35–0.80) between PDCS and PDQ-39 were obtained, and the four PDCS domains showed a significant independent influence on QoL. The conclusions are: (1) the PDCS assessed the frequency of PD symptoms analogous to the MDS-UPDRS; (2) motor subtypes and severity levels can be determined with the PDCS; (3) a significant association between PDCS and QoL scores exists.
IL-23 induces regulatory T cell plasticity with implications for inflammatory skin diseases
Authors: Kannan Arun K. , Su Zhi , Gauvin Donna M. , Paulsboe Stephanie E. , Duggan Ryan , Lasko Loren M. , Honore Prisca , Kort Michael E. , McGaraughty Steve P. , Scott Victoria E. , Gauld Stephen B.
Published: November 2019

Foxp3+ regulatory T cells (Tregs) represent a major fraction of skin resident T cells. Although normally protective, Tregs have been shown to produce pro-inflammatory cytokines in human diseases, including psoriasis. A significant hurdle in the Treg field has been the identification, or development, of model systems to study this Treg plasticity. To overcome this gap, we analyzed skin resident Tregs in a mouse model of IL-23 mediated psoriasiform dermatitis. Our results demonstrate that IL-23 drove the accumulation of Tregs; including a subpopulation that co-expressed RORγt and produced IL-17A. Genesis of this population was attenuated by a RORγt inverse agonist compound and clinically relevant therapeutics. In vitro, IL-23 drove the generation of CD4+Foxp3+RORγt+IL-17A+ cells from Treg cells. Collectively, our data shows that IL-23 drives Treg plasticity by inducing a population of CD4+Foxp3+RORγt+IL-17A+ cells that could play a role in the disease pathogenesis. Through this work, we define an in vitro system and a pre-clinical in vivo mouse model that can be used to further study Treg homeostasis and plasticity in the context of psoriasis.
Projected impacts of climate change on functional diversity of frugivorous birds along a tropical elevational gradient
Authors: Bender Irene M. A. , Kissling W. Daniel , Böhning-Gaese Katrin , Hensen Isabell , Kühn Ingolf , Nowak Larissa , Töpfer Till , Wiegand Thorsten , Dehling D. Matthias , Schleuning Matthias
Published: November 2019

Climate change forces many species to move their ranges to higher latitudes or elevations. Resulting immigration or emigration of species might lead to functional changes,e.g., in the trait distribution and composition of ecological assemblages. Here, we combined approaches from biogeography (species distribution models; SDMs) and community ecology (functional diversity) to investigate potential effects of climate-driven range changes on frugivorous bird assemblages along a 3000 m elevational gradient in the tropical Andes. We used SDMs to model current and projected future occurrence probabilities of frugivorous bird species from the lowlands to the tree line. SDM-derived probabilities of occurrence were combined with traits relevant for seed dispersal of fleshy-fruited plants to calculate functional dispersion (FDis; a measure of functional diversity) for current and future bird assemblages. Comparisons of FDis between current and projected future assemblages showed consistent results across four dispersal scenarios, five climate models and two representative concentration pathways. Projections indicated a decrease of FDis in the lowlands, an increase of FDis at lower mid-elevations and little changes at high elevations. This suggests that functional dispersion responds differently to global warming at different elevational levels, likely modifying avian seed dispersal functions and plant regeneration in forest ecosystems along tropical mountains.
Organic Molecule Detection Based on SERS in Microfluidics
Authors: Zhang Xin , Zhang Haiyan , Yan Sheng , Zeng Zugang , Huang Anshou , Liu Anping , Yuan Yuan , Huang Yingzhou
Published: November 2019

Sensitive in situ detection of organic molecules is highly demanded in environmental monitoring. In this work, the surface enhanced Raman spectroscopy (SERS) is adopted in microfluidics to detect the organic molecules with high accuracy and high sensitivity. Here the SERS substrate in microchannel consists of Ag nanoparticles synthesized by chemical reduction. The data indicates the fabrication conditions have great influence on the sizes and distributions of Ag nanoparticles, which play an important role on the SERS enhancement. This result is further confirmed by the simulation of electromagnetic field distributions based on finite difference time domain (FDTD) method. Furthermore, the SERS spectra of organic molecule (methylene blue) obtained in this plasmonic microfluidic system exhibit good reproducibility with high sensitivity. By a combination of SERS and microfluidics, our work not only explores the research field of plasmonics but also has broad application prospects in environmental monitoring.
Nanoscopic and Macro-Porous Carbon Nano-foam Electrodes with Improved Mass Transport for Vanadium Redox Flow Batteries
Authors: Mustafa Ibrahim , Susantyoko Rahmat , Wu Chieh-Han , Ahmed Fatima , Hashaikeh Raed , Almarzooqi Faisal , Almheiri Saif
Published: November 2019

Although free-standing sheets of multiwalled carbon nanotubes (MWCNT) can provide interesting electrochemical and physical properties as electrodes for redox flow batteries, the full potential of this class of materials has not been accessible as of yet. The conventional fabrication methods produce sheets with micro-porous and meso-porous structures, which significantly resist mass transport of the electrolyte during high-current flow-cell operation. Herein, we developed a method to fabricate high performance macro-porous carbon nano-foam free standing sheets (Puffy Fibers, PF), by implementing a freeze-drying step into our low cost and scalable surface-engineered tape-casting (SETC) fabrication method, and we show the improvement in the performance attained as compared with a MWCNT sheet lacking any macro pores (Tape-cast, TC). We attribute the higher performance attained by our in-lab fabricated PF papers to the presence of macro pores which provided channels that acted as pathways for electrolytic transport within the bulk of the electrode. Moreover, we propose an electrolytic transport mechanism to relate ion diffusivity to different pore sizes to explain the different modes of charge transfer in the negative and the positive electrolytes. Overall, the PF papers had a high wettability, high porosity, and a large surface area, resulting in improved electrochemical and flow-cell performances.
Sarcopenia for predicting falls and hospitalization in community-dwelling older adults: EWGSOP versus EWGSOP2
Authors: Yang Ming , Liu Ying , Zuo Yun , Tang Huairong
Published: November 2019

The European Working Group on Sarcopenia in Older People (EWGSOP) recently published an updated version (EWGSOP2). We aimed to compare the predictive values of EWGSOP-defined and EWGSOP2-defined sarcopenia for the incidence of falls and hospitalization in older adults. We defined sarcopenia according to the EWGSOP and the EWGSOP2. We further modified the cut-off points of the EWGSOP and EWGSOP2 according to the lowest quintile values of the gender-specific distribution of our study population, named “modified EWGSOP” and “modified EWGSOP2”, respectively. We included 384 participants. During the follow-up, 98 participants (26.5%) and 51 participants (13.8%) had at least one fall or hospitalization, respectively. EWGSOP2-defined sarcopenia (hazard ratio [HR] 1.86, 95% confidence interval [CI] 1.22–1.84) and modified EWGSOP2-defined sarcopenia (HR 2.09, 95% CI 1.23–3.55) were significantly associated with an increased incidence of falls, respectively. EWGSOP-defined sarcopenia and modified EWGSOP-defined sarcopenia also have a trend to be associated with the incidence of falls, but the results were not statistically significant. Only modified EWGSOP2-defined sarcopenia (HR 2.07, 95% CI 1.01–4.27) was significantly related to an increased incidence of hospitalization. In conclusion, EWGSOP2-defined sarcopenia performed more sensitive than EWGSOP-defined sarcopenia for predicting the incidence of falls or hospitalization, especially when using the modified cutoffs.
Evaluation of reference genes for gene expression analysis by real-time quantitative PCR (qPCR) in three stingless bee species (Hymenoptera: Apidae: Meliponini)
Authors: Freitas Flávia C. P. , Depintor Thiago S. , Agostini Lucas T. , Luna-Lucena Danielle , Nunes Francis M. F. , Bitondi Márcia M. G. , Simões Zilá L. P. , Lourenço Anete P.
Published: November 2019

Stingless bees are generalist pollinators distributed through the pantropical region. There is growing evidence that their wild populations are experiencing substantial decline in response to habitat degradation and pesticides. Policies for conservation of endangered species will benefit from studies focusing on genetic and molecular aspects of their development and behavior. The most common method for looking at gene expression is real-time quantitative polymerase chain reaction preceded by reverse transcription (RT-qPCR) of the mRNA of interest. This method requires the identification of reliable reference genes to correctly estimate fluctuations in transcript levels. To contribute to molecular studies on stingless bees, we used Frieseomelitta varia, Melipona quadrifasciata, and Scaptotrigona bipunctata species to test the expression stability of eight reference genes (act, ef1-α, gapdh, rpl32, rps5, rps18, tbp, and tbp-af) in RT-qPCR procedures in five physiological and experimental conditions (development, sex, tissues, bacteria injection, and pesticide exposure). In general, the rpl32, rps5 and rps18 ribosomal protein genes and tpb-af gene showed the highest stability, thus being identified as suitable reference genes for the three stingless bee species and defined conditions. Our results also emphasized the need to evaluate the stability of candidate genes for any designed experimental condition and stingless bee species.
Cooperative update of beliefs and state-transition functions in human reinforcement learning
Authors: Higashi Hiroshi , Minami Tetsuto , Nakauchi Shigeki
Published: November 2019

It is widely known that reinforcement learning systems in the brain contribute to learning via interactions with the environment. These systems are capable of solving multidimensional problems, in which some dimensions are relevant to a reward, while others are not. To solve these problems, computational models use Bayesian learning, a strategy supported by behavioral and neural evidence in human. Bayesian learning takes into account beliefs, which represent a learner’s confidence in a particular dimension being relevant to the reward. Beliefs are given as a posterior probability of the state-transition (reward) function that maps the optimal actions to the states in each dimension. However, when it comes to implementing this learning strategy, the order in which beliefs and state-transition functions update remains unclear. The present study investigates this update order using a trial-by-trial analysis of human behavior and electroencephalography signals during a task in which learners have to identify the reward-relevant dimension. Our behavioral and neural results reveal a cooperative update—within 300 ms after the outcome feedback, the state-transition functions are updated, followed by the beliefs for each dimension.
A Plant Growth-Promoting Microbial Soil Amendment Dynamically Alters the Strawberry Root Bacterial Microbiome
Authors: Deng Siwen , Wipf Heidi M.-L. , Pierroz Grady , Raab Ted K. , Khanna Rajnish , Coleman-Derr Devin
Published: November 2019

Despite growing interest in utilizing microbial-based methods for improving crop growth, much work still remains in elucidating how beneficial plant-microbe associations are established, and what role soil amendments play in shaping these interactions. Here, we describe a set of experiments that test the effect of a commercially available soil amendment, VESTA, on the soil and strawberry (Fragaria x ananassaMonterey) root bacterial microbiome. The bacterial communities of the soil, rhizosphere, and root from amendment-treated and untreated fields were profiled at four time points across the strawberry growing season using 16S rRNA gene amplicon sequencing on the Illumina MiSeq platform. In all sample types, bacterial community composition and relative abundance were significantly altered with amendment application. Importantly, time point effects on composition are more pronounced in the root and rhizosphere, suggesting an interaction between plant development and treatment effect. Surprisingly, there was slight overlap between the taxa within the amendment and those enriched in plant and soil following treatment, suggesting that VESTA may act to rewire existing networks of organisms through an, as of yet, uncharacterized mechanism. These findings demonstrate that a commercial microbial soil amendment can impact the bacterial community structure of both roots and the surrounding environment.
Fault-controlled deep hydrothermal flow in a back-arc tectonic setting, SE Tyrrhenian Sea
Authors: Loreto Maria Filomena , Düşünür-Doğan Doğa , Üner Serkan , İşcan-Alp Yeliz , Ocakoğlu Neslihan , Cocchi Luca , Muccini Filippo , Giordano Patrizia , Ligi Marco
Published: November 2019

Understanding magmatic systems and deep hydrothermal circulation beneath arc-volcanoes provides insights into deep processes associated with slab-subduction and mantle-wedge partial melting. Here we analyze hydrothermal flow below a structural high (Capo Vaticano Ridge, CVR) located offshore Capo Vaticano (western Calabria) and affected by magmatic intrusions generated from above the Ionian subducting-slab. In order to explain observations, we combine geophysical and numerical modelling results. Fluid-flow modelling shows that temperature distribution and geothermal gradient are controlled mainly by hydrothermal circulation, in turn affected by heat source, fault pattern, rock permeability, basement topography and sediment thickness. Two main faults, shaping the structural high and fracturing intensely the continental crust, enable deep hydrothermal circulation and shallow fluid discharge. Distribution of seismicity at depth supports the hypothesis of a slab below Capo Vaticano, deep enough to enable mantle-wedge partial melting above the subduction zone. Melt migration at shallow levels forms the magmatic intrusions inferred by magnetic anomalies and by δ3He enrichment in the discharged fluids at the CVR summit. Our results add new insights on the southern Tyrrhenian Sea arc-related magmatism and on the Calabrian inner-arc tectonic setting dissected by seismogenic faults able to trigger high-destructive earthquakes.
Selective synthesis of substituted amino-quinoline derivatives by C-H activation and fluorescence evaluation of their lipophilicity-responsive properties
Authors: Fuchi Yasufumi , Sakuma Masaomi , Ohyama Kohei , Hagihara Ryusuke , Kohno Minaki , Hamada Koichi , Mizutani Akihiro , Karasawa Satoru
Published: November 2019

Push-pull type fluorescent amino-quinoline derivatives (TFMAQ) bearing phenyl aromatic groups in the 8-position (TFMAQ-8Ar series) were synthesized via palladium-catalyzed C-H activation reaction in short steps. The N-arylation or C-H activation reactions were selectively controlled with high yield by combinations of palladium and phosphine ligands. The TFMAQ-8Ar analogues exhibited fluorescent solvatochromism in non-polar and polar solvents. In non-polar solvent, the absolute fluorescence quantum yield was high, wheareas the fluorescence was almost quenched in polar solvent. The TFMAQ-8Ar derivatives also showed high fluorescence emission at solid state owing to the planar structure between the quinoline ring and phenyl ring at the 7-amino group, as demonstrated by X-ray crystal structure analysis. The fluorescence imaging of 3T3-L1 cell using TFMAQ-8Ar derivatives was performed by confocal laser microscopy. Strong and specific emissions at lipid droplets were observed owing to the accumulation of TFMAQ-8Ar derivatives. Therefore, we propose that the TFMAQ-8Ar derivatives should become a versatile fluorescence probe for the live imaging of lipid droplets.
Intrinsic energy spread and bunch length growth in plasma-based accelerators due to betatron motion
Authors: Ferran Pousa Angel , Martinez de la Ossa Alberto , Assmann Ralph W.
Published: November 2019

Plasma-based accelerators (PBAs), having demonstrated the production of GeV electron beams in only centimetre scales, offer a path towards a new generation of highly compact and cost-effective particle accelerators. However, achieving the required beam quality, particularly on the energy spread for applications such as free-electron lasers, remains a challenge. Here we investigate fundamental sources of energy spread and bunch length in PBAs which arise from the betatron motion of beam electrons. We present an analytical theory, validated against particle-in-cell simulations, which accurately describes these phenomena. Significant impact on the beam quality is predicted for certain configurations, explaining previously observed limitations on the achievable bunch length and energy spread. Guidelines for mitigating these contributions towards high-quality beams are deduced.
Cromolyn sodium delays disease onset and is neuroprotective in the SOD1G93A Mouse Model of amyotrophic lateral sclerosis
Authors: Granucci Eric J. , Griciuc Ana , Mueller Kaly A. , Mills Alexandra N. , Le Hoang , Dios Amanda M. , McGinty Danielle , Pereira Joao , Elmaleh David , Berry James D. , Paganoni Sabrina , Cudkowicz Merit E. , Tanzi Rudolph E. , Sadri-Vakili Ghazaleh
Published: November 2019

Accumulating evidence suggests that neuroinflammatory processes are implicated in the initiation and progression of amyotrophic lateral sclerosis (ALS). Previous reports have demonstrated an increase in microgliosis and astrogliosis in the lumbar spinal cord of SOD1G93Atransgenic mice before the onset of symptoms, a neuroinflammatory response which correlated with disease progression. Importantly, early stage homeostatic microglia enhanced motor neuron survival, while pro-inflammatory microglia were toxic to motor neurons in the SOD1G93Amice. Recent studies from our group have demonstrated that cromolyn sodium, an FDA approved compound, exerts neuroprotective effects in mouse models of Alzheimer’s disease by altering microglial cell activation. Here, we tested the neuroprotective and anti-inflammatory effects of cromolyn sodium in the SOD1G93Amouse model of ALS. Our results indicate that cromolyn sodium treatment significantly delayed the onset of neurological symptoms, and improved deficits in PaGE performance in both male and female mice, however, there was only an effect on survival in female mice. Furthermore, there was a significant increase in motor neuron survival in the lumbar spinal cord as well as a significant decrease in the denervation of the neuromuscular junction of the tibialis anterior muscle in cromolyn treated transgenic SOD1G93Amice. Lastly, cromolyn treatment decreased the expression of pro-inflammatory cytokines/chemokines in the lumbar spinal cord and plasma and decreased mast cell degranulation in the tibialis anterior muscle of transgenic SOD1G93Amice. Together, these findings suggest that cromolyn sodium provides neuroprotection in the SOD1G93Amice by decreasing the inflammatory response.
Pre-diagnosing and managing patients with GM1 gangliosidosis and related disorders by the evaluation of GM1 ganglioside content
Authors: Tonin Rodolfo , Caciotti Anna , Procopio Elena , Fischetto Rita , Deodato Federica , Mancardi Maria Margherita , Di Rocco Maja , Ardissone Anna , Salviati Alessandro , Marangi Antonio , Strisciuglio Pietro , Mangone Giusi , Casini Arianna , Ricci Silvia , Fiumara Agata , Parini Rossella , Pavone Francesco Saverio , Guerrini Renzo , Calamai Martino , Morrone Amelia
Published: November 2019

GM1 ganglioside, a monosialic glycosphingolipid and a crucial component of plasma membranes, accumulates in lysosomal storage disorders, primarily in GM1 gangliosidosis. The development of biomarkers for simplifying diagnosis, monitoring disease progression and evaluating drug therapies is an important objective in research into neurodegenerative lysosomal disorders. With this in mind, we established fluorescent imaging and flow-cytometric methods to track changes in GM1 ganglioside levels in patients with GM1 gangliosidosis and in control cells. We also evaluated GM1 ganglioside content in patients’ cells treated with the commercially available Miglustat, a substrate inhibitor potentially suitable for the treatment of late-onset GM1 gangliosidosis. The flow-cytometric method proved to be sensitive, unbiased, and rapid in determining variations in GM1 ganglioside content in human lymphocytes derived from small amounts of fresh blood. We detected a strong correlation between GM1 ganglioside content and the clinical severity of GM1 gangliosidosis. We confirm the ability of Miglustat to act as a substrate reduction agent in the patients’ treated cells. As well as being suitable for diagnosing and managing patients with GM1 gangliosidosis this method could be useful in the diagnosis and management of other lysosomal diseases, such as galactosialidosis, Type C Niemann-Pick, and any other disease with pathologic variations of GM1 ganglioside.
Characterizing renal involvement in Hermansky-Pudlak Syndrome in a zebrafish model
Authors: Schenk H. , Müller-Deile J. , Schroder P. , Bolaños-Palmieri P. , Beverly-Staggs L. , White R. , Bräsen J. H. , Haller H. , Schiffer M.
Published: November 2019

Hermansky-Pudlak Syndrome (HPS) is a rare disease caused by mutations in the genes coding for various HPS proteins. HPS proteins are part of multi-subunit complexes involved in the biogenesis of organelles from the lysosomal-endosomal-system. In humans, this syndrome is characterized by the presence of albinism, platelet dysfunction and pulmonary fibrosis. The renal component to the disease remains unstudied and untreated in patients with HPS. Here we demonstrate that in humans, HPS proteins have a high renal expression with active transcription of HPS1, 3, 4 and 5 in human podocyte cell culture, suggesting that impaired function of HPS proteins could directly impact renal function. Therefore, we developed a zebrafish model to study the renal involvement of HPS proteins in proteinuric kidney disease. Remarkably, knockdown of HPS genes in zebrafish causes glomerular injury with edema, proteinuria and structural changes of the glomerular filtration barrier. Moreover, reduced expression of HPS proteins in zebrafish recapitulates other important disease hallmarks, like hypopigmentation and accumulation of intracellular debris characteristic of lysosomal disorders. In conclusion, we present a valid zebrafish model that highlights the previously underestimated relevance of renal disease in HPS. This draws attention to the therapeutic options available to manage this component of the syndrome.
The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells
Authors: Silva Matheus Molina , Rocha Clarissa Ribeiro Reily , Kinker Gabriela Sarti , Pelegrini Alessandra Luiza , Menck Carlos Frederico Martins
Published: November 2019

Lung cancer patients face a dismal prognosis mainly due to the low efficacy of current available treatments. Cisplatin is the first-line chemotherapy treatment for those patients, however, resistance to this drug is a common and yet not fully understood phenomenon. Aiming to shed new light into this puzzle, we used established normal and malignant lung cell lines displaying different sensitivity towards cisplatin treatment. We observed a negative correlation between cell viability and DNA damage induction upon cisplatin treatment. Interestingly, drug sensitivity in those cell lines was not due to either difference on DNA repair capacity, or in the amount of membrane ion channel commonly used for cisplatin uptake. Also, we noted that glutathione intracellular levels, and expression and activity of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) were determinant for cisplatin cytotoxicity. Remarkably, analysis of gene expression in non-small cell lung cancer patients of the TCGA data bank revealed that there is a significant lower overall survival rate in the subset of patients bearing tumors with unbalanced levels of NRF2/KEAP1 and, as consequence, increased expression of NRF2 target genes. Thus, the results indicate that NRF2 and glutathione levels figure as important cisplatin resistance biomarkers in lung cancer.
Unraveling the selective antibacterial activity and chemical composition of citrus essential oils
Authors: Ambrosio Carmen M. S. , Ikeda Natália Y. , Miano Alberto C. , Saldaña Erick , Moreno Andrea M. , Stashenko Elena , Contreras-Castillo Carmen J. , Da Gloria Eduardo M.
Published: November 2019

Post-weaning diarrhea (PWD) is an often disease affecting piglets. It is caused mainly by enterotoxigenic Escherichia coli (ETEC) colonization in pig gut. Antibiotics has been used to prevent, combat and control PWD and its negative impact on the productivity of pig breeding sector. Nonetheless, antibiotics due to their wide antibacterial spectrum also can reach beneficial gut bacteria, such as Lactobacillus. Lately, essential oils (EOs) have emerged as a potential alternative to using antibiotics in animal breeding because of their effect on bacterial growth. Commonly, citrus EOs are by-products of food industry and the availability of these EOs in the worldwide market is huge. Thus, six commercials citrus EOs were evaluated on ETEC strains, as model of pathogenic bacteria, and on Lactobacillus species, as models of beneficial bacteria. In overall, citrus EOs exhibited a selective antibacterial activity with higher effect on pathogenic bacteria (ETECs) than beneficial bacteria (Lactobacillus). Brazilian orange terpenes (BOT) oil presented the highest selective performance and caused higher disturbances on the normal growth kinetic of ETEC than on Lactobacillus rhamnosus. The action was dose-dependent on the maximal culture density (A) and the lag phase duration (λ) of the ETEC. The highest sub-inhibitory concentration (0.925 mg/mL) extended the λ duration to ETEC eight times (14.6 h) and reduced A in 55.9%. For L. rhamnosus, the λ duration was only extended 1.6 times. Despite the fact that limonene was detected as the major compound, the selective antibacterial activity of the citrus EOs could not be exclusively attributed to limonene since the presence of minor compounds could be implicated in conferring this feature.
Changes in C-reactive protein, neopterin and lactoferrin differ after conservative and surgical weight loss in individuals with morbid obesity
Authors: Aasbrenn Martin , Farup Per G. , Videm Vibeke
Published: November 2019

C-reactive protein, neopterin and lactoferrin are biomarkers of atherosclerotic disease. We aimed to assess changes in these biomarkers after conservative and surgical weight loss interventions in individuals with morbid obesity, to evaluate associations between biomarker changes and changes in body mass index and HbA1c, and to study associations between changes in the biomarkers. C-reactive protein, neopterin and lactoferrin were measured before and after conservative weight loss intervention and bariatric surgery. Data were analysed with mixed models. 137 individuals (mean age 43 years) were included. Body mass index decreased from 42.1 kg/m2 to 38.9 kg/m2 after the conservative intervention, and further to 30.5 kg/m2 after bariatric surgery. All biomarkers decreased after the conservative weight loss intervention. C-reactive protein and lactoferrin continued to decrease following bariatric surgery whereas neopterin remained stable. After adjustments for change in body mass index and HbA1c, all biomarkers decreased significantly after the conservative weight loss intervention, whereas none changed after bariatric surgery. There were no consistent correlations between changes in C-reactive protein, neopterin and lactoferrin. In conclusion, biomarkers of atherosclerosis decreased after weight loss interventions but had different trajectories. Neopterin, a marker related to atherosclerotic plaque stability, decreased after conservative weight loss but not following bariatric surgery.
A cellular automaton model for spheroid response to radiation and hyperthermia treatments
Authors: Brüningk Sarah C. , Ziegenhein Peter , Rivens Ian , Oelfke Uwe , Haar Gail ter
Published: November 2019

Thermo-radiosensitisation is a promising approach for treatment of radio-resistant tumours such as those containing hypoxic subregions. Response prediction and treatment planning should account for tumour response heterogeneity, e.g. due to microenvironmental factors, and quantification of the biological effects induced. 3D tumour spheroids provide a physiological in vitro model of tumour response and a systems oncology framework for simulating spheroid response to radiation and hyperthermia is presented. Using a cellular automaton model, 3D oxygen diffusion, delivery of radiation and/or hyperthermia were simulated for many ($${\bf{1}}{{\bf{0}}}^{{\bf{4}}}{\boldsymbol{-}}{\bf{1}}{{\bf{0}}}^{{\bf{7}}}$$
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) individual cells forming a spheroid. The iterative oxygen diffusion model was compared to an analytical oxygenation model and simulations were calibrated and validated against experimental data for irradiated (0–10 Gy) and/or heated (0–240 CEM43) HCT116 spheroids. Despite comparable clonogenic survival, spheroid growth differed significantly following radiation or hyperthermia. This dynamic response was described well by the simulation ($${{\bf{R}}}^{{\bf{2}}}$$

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 > 0.85). Heat-induced cell death was implemented as a fast, proliferation-independent process, allowing reoxygenation and repopulation, whereas radiation was modelled as proliferation-dependent mitotic catastrophe. This framework stands out both through its experimental validation and its novel ability to predict spheroid response to multimodality treatment. It provides a good description of response where biological dose-weighting based on clonogenic survival alone was insufficient.
High efficacy full allelic CRISPR/Cas9 gene editing in tetraploid potato
Authors: Johansen Ida Elisabeth , Liu Ying , Jørgensen Bodil , Bennett Eric Paul , Andreasson Erik , Nielsen Kåre L. , Blennow Andreas , Petersen Bent Larsen
Published: November 2019

CRISPR/Cas9 editing efficacies in tetraploid potato were highly improved through the use of endogenous potato U6 promoters. Highly increased editing efficiencies in the Granular Bound Starch Synthase gene at the protoplast level were obtained by replacement of the Arabidopsis U6 promotor, driving expression of the CRISPR component, with endogenous potato U6 promotors. This translated at the ex-plant level into 35% full allelic gene editing. Indel Detection Amplicon Analysis was established as an efficient tool for fast assessment of gene editing in complex genomes, such as potato. Together, this warrants significant reduction of laborious cell culturing, ex-plant regeneration and screening procedures of plants with high complexity genomes.
The complete mitochondrial genome of Harpago chiragra and Lambis lambis (Gastropoda: Stromboidea): implications on the Littorinimorpha phylogeny
Authors: Jiang Dianhang , Zheng Xiaodong , Zeng Xiaoqi , Kong Lingfeng , Li Qi
Published: November 2019

The complete mitochondrial genomes ofHarpago chiragraandLambis lambis(Strombidae) were determined with the size of 15,460 bp and 15,481 bp, respectively, and both sequences contained 13 protein-coding genes, 22 tRNAs, and two rRNAs.H. chiragraandL. lambishave similar mitochondrial features, corresponding to typical gastropod mitochondrial genomes, such as the conserved gene order, a high A + T content (66.22% forH. chiragraand 66.10% forL. lambis), and preference for A + T-rich codons. The start or termination codon of same protein-coding gene inH. chiragrawas consistent with that inL. lambis, except for the termination codon ofcox1gene (TAG forH. chiragraand TAA forL. lambis) and the start codon ofnad4(GTG forH. chiragraand ATG forL. lambis). Pairwise sequence alignments detected different degrees of variations inH. chiragraandL. lambismitochondrial genomes; and the two species had lower levels of genetic distance (0.202 for nucleotide sequence) and closest relationships as compared toStrombus gigasandOncomelania hupensis. The 13 partitioned nucleotide sequences of protein coding genes ofH. chiragraandL. lambiswere aligned with representatives of the main lineages of gastropods and their phylogenetic relationships were inferred.H. chiragraandL. lambisshare the same gene order as Littorinimorpha species, except Vermetoidea, which demonstrate a gene rearrangement in species. The reconstructed phylogeny supports three major clades within Littorinimorpha: 1) Stromboidea, Tonnoidea, Littorinoidea, and Naticoidea, 2) Rissooidea and Truncatelloidea, and 3) Vermetoidea. In addition, a relaxed molecular clock calibrated with fossils dated the diversification of Strombidae near 112 (44–206) Mya and a possible radiation is detected to occur between 45–75 Mya, providing implications to understand the Cenozoic replacement event (65–135 Mya) of Aporrhaidae by Strombidae.
Compound Specific Carbon Isotope Analysis in Sake by LC/IRMS and Brewers’ Alcohol Proportion
Authors: Suto Momoka , Kawashima Hiroto
Published: November 2019

Sake is a traditional Japanese alcohol. Nowadays, the consumption for Sake is increasing in worldwide and its popularity is growing. However, there are act of fraudulence by additional brewers’ alcohol and sugar. Therefore, a method is needed to find illegal fraud on label. In this work, we analyzed the δ13C values of the ethanol (δ13Ceth) and glucose (δ13Cglu) in Sake by liquid chromatography combined with isotope ratio mass spectrometry for the first time. Further, we developed the criteria using δ13Ceth and δ13Cglu to check brewers’ alcohol and sugar. In addition, there are some sake categories (Ginjyo and Futsu-shu) allowed to additional brewers’ alcohol up to legally determined percentage. The experimental additions of brewers’ alcohol from a C4 plant were conducted to Junmai, as sake by C3 plants. There was a strong correlation (R = 0.98, P < 0.05) between the percentage of added brewers’ alcohol and the δ13C values. We developed the method using the relationship for calculating percentage of brewers’ alcohol for the first time and estimated the percentage for commercial sake. Further, the price of sake was found to be inversely related to the percentage of brewers’ alcohol in the sake.
Effect of Different Insulin Therapies on Obstetric-Fetal Outcomes
Authors: López-Tinoco Cristina , Jiménez-Blázquez José Luis , Larrán-Escandón Laura , Roca-Rodríguez María del Mar , Bugatto Fernando , Aguilar-Diosdado Manuel
Published: November 2019

To evaluate the effectiveness of the different insulin therapies on obstetrics-fetal outcomes in women with pregestational diabetes mellitus. We enrolled 147 pregnant women with pre-existing type 1 or 2 diabetes mellitus. Clinical and biochemical parameters were analysed in relation to obstetric and fetal outcomes. 14.2% received treatment with Neutral Protamine Hagedorn insulin and short-acting insulin analogues; 19% with premixed human insulin; 40.1% with insulin glargine and lispro, 6.2% with detemir and aspart and 20% with continuous subcutaneous insulin infusion. All 5 types of treatment achieved a reduction of the mean HbA1c during pregnancy (p = 0.01). Pre-pregnancy care was carried out for 48% of patients. We found no statistically significant differences between the different insulin therapies and the obstetric-fetal outcomes. In conclusión, the different insulin therapies used in patients with pregestational diabetes mellitus does not seem to affect obstetric-fetal outcomes.
Palindromic sequence-targeted (PST) PCR: a rapid and efficient method for high-throughput gene characterization and genome walking
Authors: Kalendar Ruslan , Shustov Alexandr V. , Seppänen Mervi M. , Schulman Alan H. , Stoddard Frederick L.
Published: November 2019

Genome walking (GW) refers to the capture and sequencing of unknown regions in a long DNA molecule that are adjacent to a region with a known sequence. A novel PCR-based method, palindromic sequence-targeted PCR (PST-PCR), was developed. PST-PCR is based on a distinctive design of walking primers and special thermal cycling conditions. The walking primers (PST primers) match palindromic sequences (PST sites) that are randomly distributed in natural DNA. The PST primers have palindromic sequences at their 3′-ends. Upstream of the palindromes there is a degenerate sequence (8–12 nucleotides long); defined adapters are present at the 5′-termini. The thermal cycling profile has a linear amplification phase and an exponential amplification phase differing in annealing temperature. Changing the annealing temperature to switch the amplification phases at a defined cycle controls the balance between sensitivity and specificity. In contrast to traditional genome walking methods, PST-PCR is rapid (two to three hours to produce GW fragments) as it uses only one or two PCR rounds. Using PST-PCR, previously unknown regions (the promoter and intron 1) of the VRN1 gene of Timothy-grass (Phleum pratense L.) were captured for sequencing. In our experience, PST-PCR had higher throughput and greater convenience in comparison to other GW methods.
A diarylamine derived from anthranilic acid inhibits ZIKV replication
Authors: Silva Suely , Shimizu Jacqueline Farinha , Oliveira Débora Moraes de , Assis Leticia Ribeiro de , Bittar Cintia , Mottin Melina , Sousa Bruna Katiele de Paula , Mesquita Nathalya Cristina de Moraes Roso , Regasini Luis Octávio , Rahal Paula , Oliva Glaucius , Perryman Alexander Luke , Ekins Sean , Andrade Carolina Horta , Goulart Luiz Ricardo , Sabino-Silva Robinson , Merits Andres , Harris Mark , Jardim Ana Carolina Gomes
Published: November 2019

Zika virus (ZIKV) is a mosquito-transmitted Flavivirus, originally identified in Uganda in 1947 and recently associated with a large outbreak in South America. Despite extensive efforts there are currently no approved antiviral compounds for treatment of ZIKV infection. Here we describe the antiviral activity of diarylamines derived from anthranilic acid (FAMs) against ZIKV. A synthetic FAM (E3) demonstrated anti-ZIKV potential by reducing viral replication up to 86%. We analyzed the possible mechanisms of action of FAM E3 by evaluating the intercalation of this compound into the viral dsRNA and its interaction with the RNA polymerase of bacteriophage SP6. However, FAM E3 did not act by these mechanisms.In silicoresults predicted that FAM E3 might bind to the ZIKV NS3 helicase suggesting that this protein could be one possible target of this compound. To test this, the thermal stability and the ATPase activity of the ZIKV NS3 helicase domain (NS3Hel) were investigatedin vitroand we demonstrated that FAM E3 could indeed bind to and stabilize NS3Hel.
Zn2+ stimulates salivary secretions via metabotropic zinc receptor ZnR/GPR39 in human salivary gland cells
Authors: Kim Yoon-Jung , Jo Youhwa , Lee Yeon-Hee , Park Kyungpyo , Park Hee-Kyung , Choi Se-Young
Published: November 2019

Zn2+ is a divalent cation that is essential for many biological activities, as it influences many ion channels and enzymatic activities. Zn2+ can evoke G-protein-coupled receptor signaling via activation of the metabotropic zinc receptor ZnR/GPR39. In spite of evidence suggesting the presence of ZnR/GPR39 in salivary gland cells, there has been no evidence of ZnR/GPR39-mediated modulation of salivary gland function. Here we characterized the role of ZnR/GPR39 in human submandibular gland cells. A 0.25% ZnCl2 solution evoked secretion of unstimulated and stimulated whole saliva in humans. We found that ZnR/GPR39 is expressed in human submandibular glands and HSG cells. Zn2+ increased cytosolic Ca2+ concentration ([Ca2+]i) in a concentration-dependent manner. Muscarinic antagonist had no effect on Zn2+-induced [Ca2+]i increase, which was completely blocked by the phospholipase C-β inhibitor. As with muscarinic agonist, Zn2+ also induced the translocation of aquaporin-5 (AQP-5) to the plasma membrane, which was drastically decreased in ZnR/GPR39-knockdown cells. These data suggest that the metabotropic Zn2+ receptor ZnR/GPR39 can modulate salivary secretion in human submandibular gland cells independent of muscarinic or histamine receptor signaling.
Physics-informed Deep Learning for Dual-Energy Computed Tomography Image Processing
Authors: Poirot Maarten G. , Bergmans Rick H. J. , Thomson Bart R. , Jolink Florine C. , Moum Sarah J. , Gonzalez Ramon G. , Lev Michael H. , Tan Can Ozan , Gupta Rajiv
Published: November 2019

Dual-energy CT (DECT) was introduced to address the inability of conventional single-energy computed tomography (SECT) to distinguish materials with similar absorbances but different elemental compositions. However, material decomposition algorithms based purely on the physics of the underlying attenuation process have several limitations, leading to low signal-to-noise ratio (SNR) in the derived material-specific images. To overcome these, we trained a convolutional neural network (CNN) to develop a framework to reconstruct non-contrast SECT images from DECT scans. We show that the traditional physics-based decomposition algorithms do not bring to bear the full information content of the image data. A CNN that leverages the underlying physics of the DECT image generation process as well as the anatomic information gleaned via training with actual images can generate higher fidelity processed DECT images.
Sema4C mediates EMT inducing chemotherapeutic resistance of miR-31-3p in cervical cancer cells
Authors: Jing Li , Bo Wang , Yourong Feng , Tian Wang , Shixuan Wang , Mingfu Wu
Published: November 2019

Sema4C, the target of many miRNAs, is involved in EMT-mediated chemotherapeutic resistance of many malignant tumors. However, the underlying upstream regulatory mechanisms of Sema4C-induced EMT and Sema4C-mediated drug resistance are still unclear. The aim of this study was to explore the potential role of miR-31-3p/Sema4C in regulating EMT in cisplatin-resistant (CR) cervical cancer cells. High expression levels of Sema4C were more frequently found in cervical cancer tissues and were associated with poor prognosis, whereas miR-31-3p was significantly downregulated in cervical cancer tissues, which was associated with shorter disease-free and overall survival. Overexpression of miR-31-3p inhibited malignant behaviors and EMT of cervical cancer cells in vitro. Furthermore, miR-31-3p was identified to directly target Sema4C, and upregulation of miR-31-3p reversed EMT-mediated biological functions, including cisplatin resistance of Sema4C in cervical cancer cells. These results suggest that Sema4C promoted EMT-mediated cisplatin resistance in cervical cancer cells and that this effect was inhibited by overexpression of miR-31-3p. Thus, silencing Sema4C or overexpression of miR-31-3p could be a novel approach to treat drug resistance to chemotherapy in cervical cancers.