bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of the expression of LAT1 as a prognostic indicator and a therapeutic target in renal cell carcinoma
Authors: Higuchi Kosuke , Sakamoto Shinichi , Ando Keisuke , Maimaiti Maihulan , Takeshita Nobushige , Okunushi Kentaro , Reien Yoshie , Imamura Yusuke , Sazuka Tomokazu , Nakamura Kazuyoshi , Matsushima Jun , Furihata Tomomi , Ikehara Yuzuru , Ichikawa Tomohiko , Anzai Naohiko
Published: November 2019

Large neutral amino acid transporter 1 (LAT1, SLC7A5) is abundantly expressed in various types of cancer, and it has been thought to assist cancer progression through its activity for uptake of neutral amino acids. However, the roles of LAT1 in renal cell carcinoma (RCC) prognosis and treatment remain uncharacterized. Therefore, we first retrospectively examined the LAT1 expression profile and its associations with clinical factors in RCC tissues (n = 92). The results of immunohistochemistry showed that most of the tissues examined (92%) had cancer-associated LAT1 expression. Furthermore, the overall survival (OS) and progression-free survival (PFS) were shorter in patients with high LAT1 expression levels than in those with low LAT1 expression levels (P = 0.018 and 0.014, respectively), and these associations were further strengthened by the results of univariate and multivariate analyses. Next, we tested the effects of JPH203, which is a selective LAT1 inhibitor, on RCC-derived Caki-1 and ACHN cells. It was found that JPH203 inhibited the growth of these cell types in a dose-dependent manner. Moreover, JPH203 clearly suppressed their migration and invasion activities. Thus, our results show that LAT1 has a great potential to become not only a prognosis biomarker but also a therapeutic target in RCC clinical settings.
An exome-wide rare variant analysis of Korean men identifies three novel genes predisposing to prostate cancer
Authors: Oh Jong Jin , Shivakumar Manu , Miller Jason , Verma Shefali , Lee Hakmin , Hong Sung Kyu , Lee Sang Eun , Lee Younghee , Lee Soo Ji , Sung Joohon , Kim Dokyoon , Byun Seok-Soo
Published: November 2019

Since prostate cancer is highly heritable, common variants associated with prostate cancer have been studied in various populations, including those in Korea. However, rare and low-frequency variants have a significant influence on the heritability of the disease. The contributions of rare variants to prostate cancer susceptibility have not yet been systematically evaluated in a Korean population. In this work, we present a large-scale exome-wide rare variant analysis of 7,258 individuals (985 cases with prostate cancer and 6,273 controls). In total, 19 rare variant loci spanning 7 genes contributed to an association with prostate cancer susceptibility. In addition to replicating previously known susceptibility genes (e.g., CDYL2, MST1R, GPER1, and PARD3B), 3 novel genes were identified (FDR q < 0.05), including the non-coding RNAs ENTPD3-AS1, LOC102724438, and protein-coding gene SPATA3. Additionally, 6 pathways were identified based on identified variants and genes, including estrogen signaling pathway, signaling by MST1, IL-15 production, MSP-RON signaling pathway, and IL-12 signaling and production in macrophages, which are known to be associated with prostate cancer. In summary, we report novel genes and rare variants that potentially play a role in prostate cancer susceptibility in the Korean population. These observations demonstrated a path towards one of the fundamental goals of precision medicine, which is to identify biomarkers for a subset of the population with a greater risk of disease than others.
Machine Learning Approach for Prescriptive Plant Breeding
Authors: Parmley Kyle A. , Higgins Race H. , Ganapathysubramanian Baskar , Sarkar Soumik , Singh Asheesh K.
Published: November 2019

We explored the capability of fusing high dimensional phenotypic trait (phenomic) data with a machine learning (ML) approach to provide plant breeders the tools to do both in-season seed yield (SY) prediction and prescriptive cultivar development for targeted agro-management practices (e.g., row spacing and seeding density). We phenotyped 32 SoyNAM parent genotypes in two independent studies each with contrasting agro-management treatments (two row spacing, three seeding densities). Phenotypic trait data (canopy temperature, chlorophyll content, hyperspectral reflectance, leaf area index, and light interception) were generated using an array of sensors at three growth stages during the growing season and seed yield (SY) determined by machine harvest. Random forest (RF) was used to train models for SY prediction using phenotypic traits (predictor variables) to identify the optimal temporal combination of variables to maximize accuracy and resource allocation. RF models were trained using data from both experiments and individually for each agro-management treatment. We report the most important traits agnostic of agro-management practices. Several predictor variables showed conditional importance dependent on the agro-management system. We assembled predictive models to enable in-season SY prediction, enabling the development of a framework to integrate phenomics information with powerful ML for prediction enabled prescriptive plant breeding.
The association between high-arched feet, plantar pressure distribution and body posture in young women
Authors: Woźniacka Renata , Oleksy Łukasz , Jankowicz-Szymańska Agnieszka , Mika Anna , Kielnar Renata , Stolarczyk Artur
Published: November 2019

The aim of this study was to examine the effect of excessive feet arching (symmetrical and asymmetrical) on plantar pressure distribution and on the alignment of pelvis, spine and shoulder girdle. Eighty-one women (20–40 years old, 61 +/− 12 kg, 165 +/− 5 cm) were divided into 3 groups based on the foot arch index (Group 1 - with normally arched feet, Group 2 with one foot properly arched and the other high-arched, Group 3 with both feet high-arched). Plantar pressure distribution between the right and left foot for the forefoot, midfoot and rearfoot, respectively and body posture were assessed. A slight increase in longitudinal arch of the foot caused changes in the distribution of feet loads both between limbs and between the forefoot and rearfoot and also influenced the whole body. Asymmetrical high-arching of the feet resulted in asymmetry of lower limb load and in the height of the shoulder girdle. We have suggested that any alteration of the foot arch may be harmful to body tissues and should not be considered as correct. Due to the fact that slight increases in longitudinal arch of the foot are very common, they should be considered as a foot defect, and appropriate corrective exercises should be used to prevent forefoot overload and alterations in body posture.
Tenofovir disoproxil fumarate induces peripheral neuropathy and alters inflammation and mitochondrial biogenesis in the brains of mice
Authors: Fields Jerel Adam , Swinton Mary K. , Carson Aliyah , Soontornniyomkij Benchawanna , Lindsay Charmaine , Han May Madi , Frizzi Katie , Sambhwani Shrey , Murphy Anne , Achim Cristian L. , Ellis Ronald J. , Calcutt Nigel A.
Published: November 2019

Mounting evidence suggests that antiretroviral therapy (ART) drugs may contribute to the prevalence of HIV-associated neurological dysfunction. The HIV envelope glycoprotein (gp120) is neurotoxic and has been linked to alterations in mitochondrial function and increased inflammatory gene expression, which are common neuropathological findings in HIV+ cases on ART with neurological disorders. Tenofovir disproxil fumarate (TDF) has been shown to affect neurogenesis in brains of mice and mitochondria in neurons. In this study, we hypothesized that TDF contributes to neurotoxicity by modulating mitochondrial biogenesis and inflammatory pathways. TDF administered to wild-type (wt) and GFAP-gp120 transgenic (tg) mice caused peripheral neuropathy, as indicated by nerve conduction slowing and thermal hyperalgesia. Conversely TDF protected gp120-tg mice from cognitive dysfunction. In the brains of wt and gp120-tg mice, TDF decreased expression of mitochondrial transcription factor A (TFAM). However, double immunolabelling revealed that TFAM was reduced in neurons and increased in astroglia in the hippocampi of TDF-treated wt and gp120-tg mice. TDF also increased expression of GFAP and decreased expression of IBA1 in the wt and gp120-tg mice. TDF increased tumor necrosis factor (TNF) α in wt mice. However, TDF reduced interleukin (IL) 1β and TNFα mRNA in gp120-tg mouse brains. Primary human astroglia were exposed to increasing doses of TDF for 24 hours and then analyzed for mitochondrial alterations and inflammatory gene expression. In astroglia, TDF caused a dose-dependent increase in oxygen consumption rate, extracellular acidification rate and spare respiratory capacity, changes consistent with increased metabolism. TDF also reduced IL-1β-mediated increases in IL-1β and TNFα mRNA. These data demonstrate that TDF causes peripheral neuropathy in mice and alterations in inflammatory signaling and mitochondrial activity in the brain.
A thrips vector of tomato spotted wilt virus responds to tomato acylsugar chemical diversity with reduced oviposition and virus inoculation
Authors: Ben-Mahmoud Sulley , Anderson Taylor , Chappell Thomas M. , Smeda John R. , Mutschler Martha A. , Kennedy George G. , De Jong Darlene M. , Ullman Diane E.
Published: November 2019

There is increasing evidence that acylsugars deter insect pests and plant virus vectors, including the western flower thrips (WFT), Frankliniella occidentalis (Pergande), vector of tomato spotted wilt virus (TSWV). Acylsugars are sugar-polyesters composed of saturated, un-saturated, and variously branched short and long chain fatty acids (FAs) esterified to a glucose (acylglucose) or sucrose (acylsucrose) moiety. We sought to understand how acylsucrose amount and composition of associated FA profiles interacted to mediate resistance to WFT oviposition and TSWV inoculation on tomato leaves. Towards this goal, we examined WFT oviposition and TSWV inoculation behavior on tomato lines bred to exude varying amounts of acylsucrose in association with diverse FA profiles. Our data show that as acylsucrose amounts increased, WFT egg-laying (oviposition) decreased and TSWV inoculation was suppressed. Western flower thrips also responded to FA profiles that included iC4, iC11, nC12 and nC10 FA. These findings support improving acylsugar-mediated resistance against WFT by breeding tomatoes exuding greater amounts of acylsucrose associated with specific FA profiles. We show that increasing acylsucrose amount output by type IV trichomes and selecting for particular FA profiles through advanced breeding profoundly affects WFT behavior in ways that benefit management of WFT as direct pests and as TSWV vectors.
The NATO project: nanoparticle-based countermeasures for microgravity-induced osteoporosis
Authors: Cristofaro F. , Pani G. , Pascucci B. , Mariani A. , Balsamo M. , Donati A. , Mascetti G. , Rea G. , Rizzo A. M. , Visai L.
Published: November 2019

Recent advances in nanotechnology applied to medicine and regenerative medicine have an enormous and unexploited potential for future space and terrestrial medical applications. The Nanoparticles and Osteoporosis (NATO) project aimed to develop innovative countermeasures for secondary osteoporosis affecting astronauts after prolonged periods in space microgravity. Calcium- and Strontium-containing hydroxyapatite nanoparticles (nCa-HAP and nSr-HAP, respectively) were previously developed and chemically characterized. This study constitutes the first investigation of the effect of the exogenous addition of nCa-HAP and nSr-HAP on bone remodeling in gravity (1 g), Random Positioning Machine (RPM) and onboard International Space Station (ISS) using human bone marrow mesenchymal stem cells (hBMMSCs). In 1 g conditions, nSr-HAP accelerated and improved the commitment of cells to differentiate towards osteoblasts, as shown by the augmented alkaline phosphatase (ALP) activity and the up-regulation of the expression of bone marker genes, supporting the increased extracellular bone matrix deposition and mineralization. The nSr-HAP treatment exerted a protective effect on the microgravity-induced reduction of ALP activity in RPM samples, and a promoting effect on the deposition of hydroxyapatite crystals in either ISS or 1 g samples. The results indicate the exogenous addition of nSr-HAP could be potentially used to deliver Sr to bone tissue and promote its regeneration, as component of bone substitute synthetic materials and additive for pharmaceutical preparation or food supplementary for systemic distribution.
On the existence of a perennial river in the Harappan heartland
Authors: Chatterjee Anirban , Ray Jyotiranjan S. , Shukla Anil D. , Pande Kanchan
Published: November 2019

The legendary river Saraswati of Indian mythology has often been hypothesized to be an ancient perennial channel of the seasonal river Ghaggar that flowed through the heartland of the Bronze Age Harappan civilization in north-western India. Despite the discovery of abundant settlements along a major paleo-channel of the Ghaggar, many believed that the Harappans depended solely on monsoonal rains, because no proof existed for the river’s uninterrupted flow during the zenith of the civilization. Here, we present unequivocal evidence for the Ghaggar’s perennial past by studying temporal changes of sediment provenance along a 300 km stretch of the river basin. This is achieved using 40Ar/39Ar ages of detrital muscovite and Sr-Nd isotopic ratios of siliciclastic sediment in fluvial sequences, dated by radiocarbon and luminescence methods. We establish that during 80-20 ka and 9-4.5 ka the river was perennial and was receiving sediments from the Higher and Lesser Himalayas. The latter phase can be attributed to the reactivation of the river by the distributaries of the Sutlej. This revived perennial condition of the Ghaggar, which can be correlated with the Saraswati, likely facilitated development of the early Harappan settlements along its banks. The timing of the eventual decline of the river, which led to the collapse of the civilization, approximately coincides with the commencement of the Meghalayan Stage.
New Fair Multiparty Quantum Key Agreement Secure against Collusive Attacks
Authors: Sun Zhiwei , Cheng Rong , Wu Chunhui , Zhang Cai
Published: November 2019

Fairness is an important standard needed to be considered in a secure quantum key agreement (QKA) protocol. However, it found that most of the quantum key agreement protocols in the travelling model are not fair, i.e., some of the dishonest participants can collaborate to predetermine the final key without being detected. Thus, how to construct a fair and secure key agreement protocol has obtained much attention. In this paper, a new fair multiparty QKA protocol that can resist the collusive attack is proposed. More specifically, we show that in a client-server scenario, it is possible for the clients to share a key and reveal nothing about what key has been agreed upon to the server. The server prepares quantum states for clients to encode messages to avoid the participants’ collusive attack. This construction improves on previous work, which requires either preparing multiple quantum resources by clients or two-way quantum communication. It is proven that the protocol does not reveal to any eavesdropper, including the server, what key has been agreed upon, and the dishonest participants can be prevented from collaborating to predetermine the final key.
Intrinsic dimension estimation for locally undersampled data
Authors: Erba Vittorio , Gherardi Marco , Rotondo Pietro
Published: November 2019

Identifying the minimal number of parameters needed to describe a dataset is a challenging problem known in the literature as intrinsic dimension estimation. All the existing intrinsic dimension estimators are not reliable whenever the dataset is locally undersampled, and this is at the core of the so called curse of dimensionality. Here we introduce a new intrinsic dimension estimator that leverages on simple properties of the tangent space of a manifold and extends the usual correlation integral estimator to alleviate the extreme undersampling problem. Based on this insight, we explore a multiscale generalization of the algorithm that is capable of (i) identifying multiple dimensionalities in a dataset, and (ii) providing accurate estimates of the intrinsic dimension of extremely curved manifolds. We test the method on manifolds generated from global transformations of high-contrast images, relevant for invariant object recognition and considered a challenge for state-of-the-art intrinsic dimension estimators.
Early detection of enamel demineralization by optical coherence tomography
Authors: Tsai Meng-Tsan , Wang Yen-Li , Yeh Ting-Wei , Lee Hsiang-Chieh , Chen Wen-Ju , Ke Jia-Ling , Lee Ya-Ju
Published: November 2019

Enamel is the outermost layer of the tooth that protects it from invasion. In general, an acidic environment accelerates tooth demineralization, leading to the formation of cavities. Scanning electron microscopy (SEM) is conventionally used as an in vitro tool for the observation of tooth morphology changes with acid attacks. Yet, SEM has intrinsic limitations for the potential application of in vivo detection in the early demineralization process. In this study, a high-resolution optical coherence tomography (OCT) system with the axial and transverse resolutions of 2.0 and 2.7 μm in teeth has been utilized for characterizing the effect of the acidic environment (simulated by phosphoric acid) on the enamel topology. The scattering coefficient and the surface roughness of enamel can be directly derived from the OCT results, enabling a quantitative evaluation of the topology changes with demineralization. The dynamic process induced by the acid application is also recorded and analyzed with OCT, depicting the evolution of the demineralization process on enamel. Notably, the estimated enamel scattering coefficient and surface roughness significantly increase with the application time of acid and the results illustrate that the values of both parameters after demineralization are significantly larger than those obtained before the demineralization, illustrating both parameters could be effective to differentiate the healthy and demineralized teeth and determine the severity. The obtained results unambiguously illustrate that demineralization of the tooth surface can be successfully detected by OCT and further used as an indicator of early-stage cavity formation.
Genome-wide CRISPR Screen to Identify Genes that Suppress Transformation in the Presence of Endogenous KrasG12D
Authors: Huang Jianguo , Chen Mark , Xu Eric S. , Luo Lixia , Ma Yan , Huang Wesley , Floyd Warren , Klann Tyler S. , Kim So Young , Gersbach Charles A. , Cardona Diana M. , Kirsch David G.
Published: November 2019

Cooperating gene mutations are typically required to transform normal cells enabling growth in soft agar or in immunodeficient mice. For example, mutations in Kras and transformation-related protein 53 (Trp53) are known to transform a variety of mesenchymal and epithelial cells in vitro and in vivo. Identifying other genes that can cooperate with oncogenic Kras and substitute for Trp53 mutation has the potential to lead to new insights into mechanisms of carcinogenesis. Here, we applied a genome-wide CRISPR/Cas9 knockout screen in KrasG12D immortalized mouse embryonic fibroblasts (MEFs) to search for genes that when mutated cooperate with oncogenic Kras to induce transformation. We also tested if mutation of the identified candidate genes could cooperate with KrasG12D to generate primary sarcomas in mice. In addition to identifying the well-known tumor suppressor cyclin dependent kinase inhibitor 2A (Cdkn2a), whose alternative reading frame product p19 activates Trp53, we also identified other putative tumor suppressors, such as F-box/WD repeat-containing protein 7 (Fbxw7) and solute carrier family 9 member 3 (Slc9a3). Remarkably, the TCGA database indicates that both FBXW7 and SLC9A3 are commonly co-mutated with KRAS in human cancers. However, we found that only mutation of Trp53 or Cdkn2a, but not Fbxw7 or Slc9a3 can cooperate with KrasG12D to generate primary sarcomas in mice. These results show that mutations in oncogenic Kras and either Fbxw7 or Slc9a3 are sufficient for transformation in vitro, but not for in vivo sarcomagenesis.
Negative frequency dependent selection on plasmid carriage and low fitness costs maintain extended spectrum β-lactamases in Escherichia coli
Authors: Dimitriu Tatiana , Medaney Frances , Amanatidou Elli , Forsyth Jessica , Ellis Richard J. , Raymond Ben
Published: November 2019

Plasmids may maintain antibiotic resistance genes in bacterial populations through conjugation, in the absence of direct selection pressure. However, the costs and benefits of conjugation for plasmid and bacterial fitness are not well understood. Using invasion and competition experiments with plasmid mutants we explicitly tested how conjugation contributes to the maintenance of a plasmid bearing a single extended-spectrum ß-lactamase (ESBL) gene (blaCTX-M-14). Surprisingly, conjugation had little impact on overall frequencies, although it imposed a substantial fitness cost. Instead, stability resulted from the plasmid conferring fitness benefits when rare. Frequency dependent fitness did not require a functional blaCTX-M-14 gene, and was independent of culture media. Fitness benefits when rare are associated with the core plasmid backbone but are able to drive up frequencies of antibiotic resistance because fitness burden of the blaCTX-M-14 gene is very low. Negative frequency dependent fitness can contribute to maintaining a stable frequency of resistance genes in the absence of selection pressure from antimicrobials. In addition, persistent, low cost resistance has broad implications for antimicrobial stewardship.
Characterization of laser-driven proton acceleration from water microdroplets
Authors: Becker Georg A. , Schwab Matthew B. , Lötzsch Robert , Tietze Stefan , Klöpfel Diethard , Rehwald Martin , Schlenvoigt Hans-Peter , Sävert Alexander , Schramm Ulrich , Zepf Matt , Kaluza Malte C.
Published: November 2019

We report on a proton acceleration experiment in which high-intensity laser pulses with a wavelength of 0.4 μm and with varying temporal intensity contrast have been used to irradiate water droplets of 20 μm diameter. Such droplets are a reliable and easy-to-implement type of target for proton acceleration experiments with the potential to be used at very high repetition rates. We have investigated the influence of the laser’s angle of incidence by moving the droplet along the laser polarization axis. This position, which is coupled with the angle of incidence, has a crucial impact on the maximum proton energy. Central irradiation leads to an inefficient coupling of the laser energy into hot electrons, resulting in a low maximum proton energy. The introduction of a controlled pre-pulse produces an enhancement of hot electron generation in this geometry and therefore higher proton energies. However, two-dimensional particle-in-cell simulations support our experimental results confirming, that even slightly higher proton energies are achieved under grazing laser incidence when no additional pre-plasma is present. Illuminating a droplet under grazing incidence generates a stream of hot electrons that flows along the droplet’s surface due to self-generated electric and magnetic fields and ultimately generates a strong electric field responsible for proton acceleration. The interaction conditions were monitored with the help of an ultra-short optical probe laser, with which the plasma expansion could be observed.
Thymic precursor cells generate acute myeloid leukemia in NUP98-PHF23/NUP98-HOXD13 double transgenic mice
Authors: Kundu Subhadip , Park Eun Sil , Chung Yang Jo , Walker Robert L. , Zhu Yuelin J. , Negi Vijay , Meltzer Paul S. , Aplan Peter D.
Published: November 2019

Transgenic mice that express either a NUP98–PHF23 (NP23) or NUP98-HOXD13 (NHD13) fusion in the hematopoietic compartment develop a wide spectrum of leukemias, including myeloid, erythroid, megakaryocytic and lymphoid, at age 9–14 months. NP23-NHD13 double transgenic mice were generated by interbreeding NP23 and NHD13 mice. Remarkably, 100% of the NP23-NHD13 double transgenic mice developed acute myeloid leukemia (AML) within three months, characterized by replacement of the thymus with leukemic myeloblasts. The marked infiltration of thymus led to the intriguing hypothesis that AML generated in NP23-NHD13 mice arose in the thymus, as opposed to the bone marrow (BM). Transplantation of CD4-CD8- double negative (DN) thymocytes (which were also negative for Mac1 and Gr1) from leukemic NHD13/NP23 mice demonstrated that DN thymocytes could transmit AML, and limiting dilution studies showed that leukemia initiating cells were increased 14-fold in the thymus compared to BM. Further thymocyte fractionation demonstrated that DN1 and DN2, but not DN3 or DN4 fractions transmitted AML, and a marked expansion (100-fold) of Lineage-Sca1 + Kit + (LSK) cells in the thymus of the NP23-NHD13 mice. Taken together, these results show that the thymus of NP23-NHD13 mice acts as a reservoir for AML initiating cells and that thymic progenitors can transmit AML.
Appetitive and aversive motivation in depression: The temporal dynamics of task-elicited asymmetries in alpha oscillations
Authors: Messerotti Benvenuti Simone , Buodo Giulia , Mennella Rocco , Dal Bò Elisa , Palomba Daniela
Published: November 2019

The capability model of alpha asymmetries posits that state emotional manipulations are a more powerful detector of depression-related motivational deficits than alpha activity at rest. The present study used a time-frequency approach to investigate the temporal dynamics of event-related changes in alpha power during passive viewing of emotional pictures in individuals with dysphoria (n = 23) and in individuals without dysphoria (n = 24). In the whole group, the processing of pleasant and unpleasant compared to neutral pictures was associated with a decrease in event-related alpha power (i.e., alpha desynchronization) at centro-parietal and parietal scalp sites in the 538–1400 ms post-stimulus. The group with dysphoria revealed a smaller alpha desynchronization than the group without dysphoria in response to pleasant, but not neutral and unpleasant, stimuli at frontal, fronto-central and centro-parietal sites. Interestingly, at central and centro-parietal scalp sites, the difference between groups in response to pleasant stimuli was lateralized to the right hemisphere, whereas no clear lateralization was observed at frontal and fronto-central scalp sites. These findings suggest that decreased cortical activity (i.e., reduced alpha desynchronization) in a network involving bilateral frontal and right-lateralized parietal regions may provide a specific measure of deficits in approach-related motivation in depression.
Functional characterization of human pluripotent stem cell-derived cortical networks differentiated on laminin-521 substrate: comparison to rat cortical cultures
Authors: Hyvärinen Tanja , Hyysalo Anu , Kapucu Fikret Emre , Aarnos Laura , Vinogradov Andrey , Eglen Stephen J. , Ylä-Outinen Laura , Narkilahti Susanna
Published: November 2019

Human pluripotent stem cell (hPSC)-derived neurons provide exciting opportunities for in vitro modeling of neurological diseases and for advancing drug development and neurotoxicological studies. However, generating electrophysiologically mature neuronal networks from hPSCs has been challenging. Here, we report the differentiation of functionally active hPSC-derived cortical networks on defined laminin-521 substrate. We apply microelectrode array (MEA) measurements to assess network events and compare the activity development of hPSC-derived networks to that of widely used rat embryonic cortical cultures. In both of these networks, activity developed through a similar sequence of stages and time frames; however, the hPSC-derived networks showed unique patterns of bursting activity. The hPSC-derived networks developed synchronous activity, which involved glutamatergic and GABAergic inputs, recapitulating the classical cortical activity also observed in rodent counterparts. Principal component analysis (PCA) based on spike rates, network synchronization and burst features revealed the segregation of hPSC-derived and rat network recordings into different clusters, reflecting the species-specific and maturation state differences between the two networks. Overall, hPSC-derived neural cultures produced with a defined protocol generate cortical type network activity, which validates their applicability as a human-specific model for pharmacological studies and modeling network dysfunctions.
Particle Mobility Analysis Using Deep Learning and the Moment Scaling Spectrum
Authors: Arts Marloes , Smal Ihor , Paul Maarten W. , Wyman Claire , Meijering Erik
Published: November 2019

Quantitative analysis of dynamic processes in living cells using time-lapse microscopy requires not only accurate tracking of every particle in the images, but also reliable extraction of biologically relevant parameters from the resulting trajectories. Whereas many methods exist to perform the tracking task, there is still a lack of robust solutions for subsequent parameter extraction and analysis. Here a novel method is presented to address this need. It uses for the first time a deep learning approach to segment single particle trajectories into consistent tracklets (trajectory segments that exhibit one type of motion) and then performs moment scaling spectrum analysis of the tracklets to estimate the number of mobility classes and their associated parameters, providing rich fundamental knowledge about the behavior of the particles under study. Experiments on in-house datasets as well as publicly available particle tracking data for a wide range of proteins with different dynamic behavior demonstrate the broad applicability of the method.
PAK1, PAK1Δ15, and PAK2: similarities, differences and mutual interactions
Authors: Grebeňová Dana , Holoubek Aleš , Röselová Pavla , Obr Adam , Brodská Barbora , Kuželová Kateřina
Published: November 2019

P21-activated kinases (PAK) are key effectors of the small GTPases Rac1 and Cdc42, as well as of Src family kinases. In particular, PAK1 has several well-documented roles, both kinase-dependent and kinase-independent, in cancer-related processes, such as cell proliferation, adhesion, and migration. However, PAK1 properties and functions have not been attributed to individual PAK1 isoforms: besides the full-length kinase (PAK1-full), a splicing variant lacking the exon 15 (PAK1Δ15) is annotated in protein databases. In addition, it is not clear if PAK1 and PAK2 are functionally overlapping. Using fluorescently tagged forms of human PAK1-full, PAK1Δ15, and PAK2, we analyzed their intracellular localization and mutual interactions. Effects of PAK inhibition (IPA-3, FRAX597) or depletion (siRNA) on cell-surface adhesion were monitored by real-time microimpedance measurement. Both PAK1Δ15 and PAK2, but not PAK1-full, were enriched in focal adhesions, indicating that the C-terminus might be important for PAK intracellular localization. Using coimmunoprecipitation, we documented direct interactions among the studied PAK group I members: PAK1 and PAK2 form homodimers, but all possible heterocomplexes were also detected. Interaction of PAK1Δ15 or PAK2 with PAK1-full was associated with extensive PAK1Δ15/PAK2 cleavage. The impedance measurements indicate, that PAK2 depletion slows down cell attachment to a surface, and that PAK1-full is involved in cell spreading. Altogether, our data suggest a complex interplay among different PAK group I members, which have non-redundant functions.
Author Correction: Cytotoxic unsaturated electrophilic compounds commonly target the ubiquitin proteasome system
Authors: Selvaraju Karthik , Mofers Arjan , Pellegrini Paola , Salomonsson Johannes , Ahlner Alexandra , Morad Vivian , Hillert Ellin-Kristina , Espinosa Belen , Arnér Elias S. J. , Jensen Lasse , Malmström Jonas , Turkina Maria V. , D’Arcy Padraig , Walters Michael A. , Sunnerhagen Maria , Linder Stig
Published: November 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Author Correction: Climate change, range shifts, and the disruption of a pollinator-plant complex
Authors: Gómez-Ruiz Emma P. , Lacher Thomas E.
Published: November 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Integrative genetic map of repetitive DNA in the sole Solea senegalensis genome shows a Rex transposon located in a proto-sex chromosome
Authors: García Emilio , Cross Ismael , Portela-Bens Silvia , Rodríguez María E. , García-Angulo Aglaya , Molina Belén , Cuadrado Angeles , Liehr Thomas , Rebordinos Laureana
Published: November 2019

Repetitive sequences play an essential role in the structural and functional evolution of the genome, particularly in the sexual chromosomes. The Senegalese sole (Solea senegalensis) is a valuable flatfish in aquaculture albeit few studies have addressed the mapping and characterization of repetitive DNA families. Here we analyzed the Simple Sequence Repeats (SSRs) and Transposable elements (TEs) content from fifty-seven BAC clones (spanning 7.9 Mb) of this species, located in chromosomes by multiple fluorescence in situ hybridization (m-BAC-FISH) technique. The SSR analysis revealed an average density of 675.1 loci per Mb and a high abundance (59.69%) of dinucleotide coverage was observed, being ‘AC’ the most abundant. An SSR-FISH analysis using eleven probes was also carried out and seven of the 11 probes yielded positive signals. ‘AC’ probes were present as large clusters in almost all chromosomes, supporting the bioinformatic analysis. Regarding TEs, DNA transposons (Class II) were the most abundant. In Class I, LINE elements were the most abundant and the hAT family was the most represented in Class II. Rex/Babar subfamily, observed in two BAC clones mapping to chromosome pair 1, showed the longest match. This chromosome pair has been recently reported as a putative sexual proto-chromosome in this species, highlighting the possible role of the Rex element in the evolution of this chromosome. In the Rex1 phylogenetic tree, the Senegalese sole Rex1 retrotransposon could be associated with one of the four major ancient lineages in fish genomes, in which it is included O. latipes.
Transcriptional Activation of Arabidopsis Zygotes Is Required for Initial Cell Divisions
Authors: Kao Ping , Nodine Michael D.
Published: November 2019

Commonly referred to as the maternal-to-zygotic transition, the shift of developmental control from maternal-to-zygotic genomes is a key event during animal and plant embryogenesis. Together with the degradation of parental gene products, the increased transcriptional activities of the zygotic genome remodels the early embryonic transcriptome during this transition. Although evidence from multiple flowering plants suggests that zygotes become transcriptionally active soon after fertilization, the timing and developmental requirements of zygotic genome activation in Arabidopsis thaliana (Arabidopsis) remained a matter of debate until recently. In this report, we optimized an expansion microscopy technique for robust immunostaining of Arabidopsis ovules and seeds. This enabled the detection of marks indicative of active transcription in zygotes before the first cell division. Moreover, we employed a live-imaging culture system together with transcriptional inhibitors to demonstrate that such active transcription is physiologically required in zygotes and early embryos. Our results indicate that zygotic genome activation occurs soon after fertilization and is required for the initial zygotic divisions in Arabidopsis.
Fabrication and characterization of AlN-based flexible piezoelectric pressure sensor integrated into an implantable artificial pancreas
Authors: Signore M. A. , Rescio G. , De Pascali C. , Iacovacci V. , Dario P. , Leone A. , Quaranta F. , Taurino A. , Siciliano P. , Francioso L.
Published: November 2019

This study reports on the fabrication and characterization of an event detection subsystem composed of a flexible piezoelectric pressure sensor and the electronic interface to be integrated into an implantable artificial pancreas (IAP) for diabetic patients. The developed sensor is made of an AlN layer, sandwiched between two Ti electrodes, sputtered on Kapton substrate, with a preferential orientation along c-axis which guarantees the best piezoelectric response. The IAP is made of an intestinal wall-interfaced refilling module, able to dock an ingestible insulin capsule. A linearly actuated needle punches the duodenum tissue and then the PDMS capsule to transfer the insulin to an implanted reservoir. The device is located at the connection of the needle with the linear actuator to reliably detect the occurred punching of the insulin-filled capsule. Finite Element Analysis (FEA) simulations were performed to evaluate the piezoelectric charge generated for increasing loads in the range of interest, applied on both the sensor full-area and footprint area of the Hamilton needle used for the capsule punching. The sensor-interface circuit was simulated to estimate the output voltage that can be obtained in real operating conditions. The characterization results confirmed a high device sensitivity during the punching, in the low forces (0–4 N) and low actuator speed (2–3 mm/s) ranges of interest, meeting the requirement of the research objective. The choice of a piezoelectric pressure sensor is particularly strategic in the medical field due to the request of self-powered implantable devices which do not need any external power source to output a signal and harvest energy from natural sources around the patient.
In vivo efficacy of combination of colistin with fosfomycin or minocycline in a mouse model of multidrug-resistant Acinetobacter baumannii pneumonia
Authors: Ku Nam Su , Lee Su-Hyung , Lim Young- soun , Choi Heun , Ahn Jin Young , Jeong Su Jin , Shin Sung Jae , Choi Jun Yong , Choi Young Hwa , Yeom Joon-Sup , Yong Dongeun , Song Young Goo , Kim June Myung
Published: November 2019

Unfortunately, the options for treating multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections are extremely limited. Recently, fosfomycin and minocycline were newly introduced as a treatment option for MDR A. baumannii infection. Therefore, we investigated the efficacy of the combination of colistin with fosfomycin and minocycline, respectively, as therapeutic options in MDR A. baumannii pneumonia. We examined a carbapenem-resistant A. baumannii isolated from clinical specimens at Severance Hospital, Seoul, Korea. The effect of colistin with fosfomycin, and colistin with minocycline on the bacterial counts in lung tissue was investigated in a mouse model of pneumonia caused by MDR A. baumannii. In vivo, colistin with fosfomycin or minocycline significantly (p < 0.05) reduced the bacterial load in the lungs compared with the controls at 24 and 48 h. In the combination groups, the bacterial loads differed significantly (p < 0.05) from that with the more active antimicrobial alone. Moreover, the combination regimens of colistin with fosfomycin and colistin with minocycline showed bactericidal and synergistic effects compared with the more active antimicrobial alone at 24 and 48 h. This study demonstrated the synergistic effects of combination regimens of colistin with fosfomycin and minocycline, respectively, as therapeutic options in pneumonia caused by MDR A. baumannii.
Photo-ID and telemetry highlight a global whale shark hotspot in Palawan, Philippines
Authors: Araujo Gonzalo , Agustines Ariana , Tracey Brian , Snow Sally , Labaja Jessica , Ponzo Alessandro
Published: November 2019

The Philippines is home to the second largest known population of whale sharks in the world. The species is listed as endangered due to continued population declines in the Indo-Pacific. Knowledge about the connectivity within Southeast Asia remains poor, and thus international management is difficult. Here, we employed pop-up archival tags, data mining and dedicated effort to understand an aggregation of whale sharks at Honda Bay, Palawan, Philippines, and its role in the species' conservation. Between Apr and Oct 2018, we conducted 159 surveys identifying 117 individual whale sharks through their unique spot patterns (96.5% male, mean 4.5 m). A further 66 individual whale sharks were identified from local operators, and data mined on social media platforms. The satellite telemetry data showed that the whale sharks moved broadly, with one individual moving to Sabah, Malaysia, before returning to the site <1 year later. Similarly, another tagged whale shark returned to the site at a similar periodicity after reaching the Malay-Filipino border. One individual whale shark first identified in East Kalimantan, Indonesia by a citizen scientist was resighted in Honda Bay ~3.5 years later. Honda Bay is a globally important site for the endangered whale shark with connectivity to two neighbouring countries, highlighting the need for international cooperation to manage the species.
Divergence in social traits in Trinidadian guppies selectively bred for high and low leadership in a cooperative context
Authors: Dimitriadou S. , Croft D. P. , Darden S. K.
Published: November 2019

In many animal species, individuals with certain morphological, physiological, or behavioural traits may have a disproportionately large role in determining group behaviour. While most empirical studies of leadership have focused on behaviour of individuals exploring new environments or foraging, little is known about leading behaviour in other ecological contexts. Here, we use a selective breeding design in the Trinidadian guppy (Poecilia reticulata) to quantify the heritability of leadership in a cooperative context, and determine the behavioural traits associated with it. Firstly we found that phenotypic selection for high and low leadership (HL and LL, respectively) over three filial generations resulted in pronounced differences in leadership tendency with a moderate degree of heritability. In our assay of other social traits, LL males were more aggressive and sampled their social environment less than HL males, but HL and LL females did not differ in either aggressiveness or sociability. Traits such as boldness and exploratory tendency did not diverge between the two lines. Leading behaviour was thus associated with social traits in males, but not females; suggesting that there may be sex-specific mechanisms driving the emergence of leadership in this context. We discuss our findings in the context of the evolution of cooperation.
A Four Month Randomized Controlled Trial on the Efficacy of Once-daily Fenofibrate Monotherapy in Persons with Spinal Cord Injury
Authors: La Fountaine Michael F. , Cirnigliaro Christopher M. , Hobson Joshua C. , Lombard Alexander T. , Specht Adam F. , Dyson-Hudson Trevor A. , Kirshblum Steven C. , Bauman William A.
Published: November 2019

An open-label, randomized clinical trial of once-daily fenofibrate monotherapy administered for 2- (Mo2) and 4- (Mo4) months using modified intervention thresholds for triglyceride (TG) was performed in persons with chronic spinal cord injury (SCI). Fenofibrate (145 mg tablet) was self-administered daily in 10 persons with SCI for 4 months with monthly blood testing to quantify the lipoprotein profile (e.g., serum TG, LDL-C, and HDL-C concentrations). Eight SCI participants were control subjects. In comparison to the control group, the treatment group at Mo2 had a 40% (±12%; p < 0.05) reduction in serum TG concentration, a 28% (±21%; p < 0.05) increase in HDL-C and 14% (±20%; p < 0.05) decline in LDL-C. In the same comparison at Mo4, the treatment group maintained a 40% (±20%; p < 0.05) reduction in serum TG concentration, had an 18% in reduction in LDL-C (±12%; p < 0.05) and a 23% (±23%; p < 0.05) increase in HDL-C. Fenofibrate monotherapy for Mo2 and Mo4 initiated in persons with SCI resulted in a robust and favorable change in the serum lipoprotein profile and ratios, suggesting reduced risk for cardiovascular disease.
Role of opioid receptors in modulation of P2X receptor-mediated cardiac sympathoexcitatory reflex response
Authors: Fu Liang-Wu , Tjen-A-Looi Stephanie C. , Barvarz Sherwin , Guo Zhi-Ling , Malik Shaista
Published: November 2019

Myocardial ischemia evokes powerful reflex responses through activation of vagal and sympathetic afferents in the heart through the release of ischemic metabolites. We have demonstrated that extracellular ATP stimulates cardiac sympathetic afferents through P2 receptor-mediated mechanism, and that opioid peptides suppress these afferents’ activity. However, the roles of both P2 receptor and endogenous opioids in cardiac sympathoexcitatory reflex (CSR) responses remain unclear. We therefore hypothesized that activation of cardiac P2 receptor evokes CSR responses by stimulating cardiac sympathetic afferents and these CSR responses are modulated by endogenous opioids. We observed that intrapericardial injection of α,β-methylene ATP (α,β-meATP, P2X receptor agonist), but not ADP (P2Y receptor agonist), caused a graded increase in mean arterial pressure in rats with sinoaortic denervation and vagotomy. This effect of α,β-meATP was abolished by blockade of cardiac neural transmission with intrapericardial procaine treatment and eliminated by intrapericardial A-317491, a selective P2X2/3and P2X3receptor antagonist. Intrapericardial α,β-meATP also evoked CSR response in vagus-intact rats. Furthermore, the P2X receptor-mediated CSR responses were enhanced by intrapericardial naloxone, a specific opioid receptor antagonist. These data suggest that stimulation of cardiac P2X2/3and P2X3, but not P2Y receptors, powerfully evokes CSR responses through activation of cardiac spinal afferents, and that endogenous opioids suppress the P2X receptor-mediated CSR responses.
Colibacter massiliensis gen. nov. sp. nov., a novel Gram-stain-positive anaerobic diplococcal bacterium, isolated from the human left colon
Authors: Anani Hussein , Abdallah Rita Abou , Khoder May , Fontanini Anthony , Mailhe Morgane , Ricaboni Davide , Raoult Didier , Fournier Pierre-Edouard
Published: November 2019

The gut microbiota is considered to play a key role in human health. As a consequence, deciphering its microbial diversity is mandatory. A polyphasic taxonogenomic strategy based on the combination of phenotypic and genomic analyses was used to characterize a new bacterium, strain Marseille-P2911. This strain was isolated from a left colon sample of a 60-year old man who underwent a colonoscopy for an etiological investigation of iron-deficiency anemia in Marseille, France. On the basis of 16S rRNA sequence comparison, the closest phylogenetic neighbor was Anaeroglobus geminatus (94.59% 16S rRNA gene sequence similarity) within the family Veillonellaceae. Cells were anaerobic, Gram-stain-positive, non-spore-forming, catalase/oxidase negative cocci grouped in pairs. The bacterium was able to grow at 37 °C after 2 days of incubation. Strain Marseille-P2911 exhibited a genome size of 1,715,864-bp with a 50.2% G + C content, and digital DNA-DNA hybridization (dDDH) and OrthoANI values with A. geminatus of only 19.1 ± 4.5% and 74.42%, respectively. The latter value being lower than the threshold for genus delineation (80.5%), we propose the creation of the new genus Colibacter gen. nov., with strain Marseille-P2911T (=DSM 103304 = CSUR P2911) being the type strain of the new species Colibacter massiliensis gen. nov., sp. nov.