bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasminogen repairs abnormal pain perception through improving sensory function recovery and regeneration of peripheral small nerve fiber in db/db mice
Authors: Li Weiquan , Wang Ting , Chen Fen , Guo Chunying , Liao Yanghui , Quan Congcong , Zheng Fei , Li Jinan 
Published: October 2019

AbstractPainful diabetic peripheral neuropathy (PDPN) is a devastating complication of diabetes and severely threatens the health of humankind. The plasminogen activator system and plasminogen (Plg) have multiple functional roles in tissue regeneration and extracellular matrix remodeling, which suggests that Plg may have a potentially pivotal role in anti-PDPN. In the present study, we explore whether an increased level of circulating Plg has positive effect on repairing abnormal pain perception in diabetic mice model. Our data demonstrated that additional Plg not only helps healing pain allodynia or hyperalgesia on the mice at the age of 8 weeks old in early PDPN, but more important, also has positive effects of regaining normal pain perception from hypoalgesia on the mice at ages of 14-15 or 24-25 weeks in advanced PDPN. Furthermore, our data also reveal a possible mechanism for Plg’s contribution to rebuilding normal pain perception among db/db mice by promoting axonal myelination and regeneration of small nerve fiber in peripheral nervous system. Therefore, our data suggest that Plg show promise to become a drug candidate for treating diabetic peripheral neuropathic pain.
Evaluation of bacterial proliferation with a microfluidic-based device: Antibiochip
Authors: Gallo Valentina , Ruiba Alessia , Zanin Massimo , Begnamino Paolo , Ledda Sabina , Pesce Tiziana , Melioli Giovanni , Pizzi Marco 
Published: October 2019

AbstractThe measurement of the proliferation (and the relevant inhibition of proliferation) of microbes is used in different settings, from industry to laboratory medicine. Thus, in this study, the capacity of the Antibiochip (ELTEK spa), a microfluidic-based device, to measure the amount ofE. coliin certain culture conditions, was evaluated. An Antibiochip is composed of V-shaped microchannels, and the amount of microparticles (such as microbes) is measured by the surface of the pellet after centrifugation. In the present study, different geometries, volumes and times were analyzed. When the best conditions were identified, serial dilutions of microbial cultures were tested to validate the linearity of the results. Then, with the use of wildE. colistrains isolated from medical samples, the relationship between bacterial susceptibility to antibiotics (gentamicin, amikacin and ceftriaxone) measured by standard methods and that measured by the Antibiochip was evaluated. In this report, the good quality performances of the methods, their linearity and the capacity to identify susceptible microbial strains after 60 minutes of incubation are shown. These results represent a novel approach for ultrarapid antibiograms in clinics.
Pupil diameter differentiates expertise in dental radiography visual search
Authors: Castner Nora , Appel Tobias , Eder Thérése , Richter Juliane , Scheiter Katharina , Keutel Constanze , Hüttig Fabian , Duchowski Andrew , Kasneci Enkelejda 
Published: October 2019

AbstractExpert behavior is characterized by rapid information processing abilities, dependent on more structured schemata in long-term memory designated for their domain-specific tasks. From this understanding, expertise can effectively reduce cognitive load on a domain-specific task. However, certain tasks could still evoke different gradations of load even for an expert, e.g., when having to detect subtle anomalies in dental radiographs. Our aim was to measure pupil diameter response to anomalies of varying levels of difficulty in expert and student dentists’ visual examination of panoramic radiographs. We found that students’ pupil diameter dilated significantly from baseline compared to experts, but anomaly difficulty had no effect on pupillary response. In contrast, experts’ pupil diameter responded to varying levels of anomaly difficulty, where more difficult anomalies evoked greater pupil dilation from baseline. Experts thus showed proportional pupillary response indicative of increasing cognitive load with increasingly difficult anomalies, whereas students showed pupillary response indicative of higher cognitive load for all anomalies when compared to experts.
Grass Carp Reovirus (GCRV) Giving Its All to Suppress IFN Production by Countering MAVS-TBK1 Activation
Authors: Lu Long-Feng , Li Zhuo-Cong , Zhang Can , Zhou Xiao-Yu , Zhou Yu , Jiang Jing-Yu , Chen Dan-Dan , Li Shun , Zhang Yong-An 
Published: October 2019

AbstractAs a crucial signaling pathway for interferon (IFN) production, the RIG-I-like receptor (RLR) axis is usually the host target of viruses to enhance viral infection. To date, though immune evasion methods to contrapose IFN production have been characterized for a series of terrestrial viruses, the strategies employed by fish viruses remain unclear. Here, we report that all grass carp reovirus (GCRV) proteins encoded by segments S1 to S11 interact with fish RLR factors, specifically for mitochondrial antiviral signaling protein-TANK-binding kinase 1 (MAVS-TBK1) signaling transduction, leading to decreased IFN expression. First, the GCRV viral proteins blunted the MAVS-induced expression of IFN but had little effect on TBK1-induced IFN expression. Subsequently, interestingly, co-immunoprecipitation experiments demonstrated that all GCRV viral proteins interacted with several RLR cascades, especially with TBK1. To further illustrate the mechanisms of these interactions between GCRV viral proteins and host RLRs, two of the viral proteins, NS79 (S4) and VP3 (S3), were selected as representative proteins for the study. The obtained data demonstrated that NS79 did not affect the stability of the host RLR protein, but was phosphorylated by gcTBK1, leading to the reduction of host substrate gcIRF3/7 phosphorylation. On the other hand, VP3 degraded gcMAVS and the degradation was significantly reversed by 3-MA. The biological effects of both NS79 and VP3 were consistently found to be related to the suppression of IFN expression and the promotion of viral evasion. Our findings shed light on the special evasion mechanism utilized by fish virus through IFN regulation, which might differ between fish and mammals.Author summaryThe RLR signaling pathway is crucial for IFN induction when host cells are infected with virus and RLR factors are targeted by virus. To date, the evasion mechanisms of fish viruses remain mysterious. In this study, we reveal that all 11 GCRV proteins interact with fish RLR factors and suppress the activation of MAVS-TBK1 signaling transduction, leading to the reduction of IFN expression. Two viral proteins were employed as examples to investigate the different evasion mechanisms of GCRV. These findings reveal the novel countermeasures used by fish virus to avoid the host IFN response.
Predicting Alzheimer’s disease progression trajectory and clinical subtypes using machine learning
Authors: Satone Vipul K. , Kaur Rachneet , Dadu Anant , Leonard Hampton , Iwaki Hirotaka , Makarious Mary , Sargent Lana ,   for the Alzheimer’s Disease Neuroimaging Initiative, Daneshmand Ali , Scholz Sonja W. , Singleton Andrew B. , Nalls Mike A. , Campbell Roy H. , Faghri Faraz 
Published: October 2019

AbstractBackgroundAlzheimer’s disease (AD) is a common, age-related, neurodegenerative disease that impairs a person’s ability to perform day-to-day activities. Diagnosing AD is challenging, especially in the early stages. Many patients still go undiagnosed, partly due to the complex heterogeneity in disease progression. This highlights a need for early prediction of the disease course to assist its treatment and tailor therapy options to the disease progression rate. Recent developments in machine learning techniques provide the potential to not only predict disease progression and trajectory of AD but also to classify the disease into different etiological subtypes.Methods and findingsThe work shown here clusters participants in distinct and multifaceted progression subgroups of AD and discusses an approach to predict the progression rate from baseline diagnosis. We observed that the myriad of clinically reported symptoms summarized in the proposed AD progression space corresponds directly with memory and cognitive measures, which are routinely used to monitor disease onset and progression. Our analysis demonstrated accurate prediction of disease progression after four years from the first 12 months of post-diagnosis clinical data (Area Under the Curve of 0.96 (95% confidence interval (CI), 0.92-1.0), 0.81 (95% CI, 0.74-0.88) and 0.98 (95% CI, 0.96-1.0) for slow, moderate and fast progression rate patients respectively). Further, we explored the long short-term memory (LSTM) neural networks to predict the trajectory of an individual patient’s progression.ConclusionThe machine learning techniques presented in this study may assist providers in identifying different progression rates and trajectories in the early stages of the disease, hence allowing for more efficient and personalized healthcare deliveries. With additional information about the progression rate of AD at hand, providers may further individualize the treatment plans. The predictive tests discussed in this study not only allow for early AD diagnosis but also facilitate the characterization of distinct AD subtypes relating to trajectories of disease progression. These findings are a crucial step forward for early disease detection. These models can be used to design improved clinical trials for AD research.
Beneficial bacteria activate type-I interferon production via the cytosolic sensors STING and MAVS
Authors: Gutierrez-Merino Jorge , Isla Beatriz , Combes Theo , Martinez-Estrada Fernando , de Motes Carlos Maluquer 
Published: October 2019

AbstractType-I interferon (IFN-I) cytokines are produced by innate immune cells in response to microbial infections, cancer and autoimmune diseases. These cytokines trigger protective responses in neighbouring cells through the activation of IFN-I stimulated genes. One of the most predominant pathways associated with IFN-I production is mediated by the cytosolic sensors STING and MAVS, intracellular adaptors that become activated in the presence of microbial nucleic acids in the cytoplasm, leading to IFN-I production via TANK-binding kinase (TBK)-1 and IFN regulatory factors. However, the role of these sensors in responses induced by beneficial microbes has been relatively unexplored. Here we have screened 12 representative strains of lactic acid bacteria (LAB), a group of beneficial microbes found in fermented food and probiotic formulations worldwide, for their ability to trigger IFN-I responses. Two isolates (Lactobacillus plantarumandPediococcus pentosaceus) induced an IFN-I production that was significantly higher that the rest, both in macrophage cell lines and human primary macrophages. This response correlated with stronger interaction with macrophages and was susceptible to phagocytosis inhibitors, suggesting bacterial internalisation. Accordingly, macrophages deficient for STING and, to a lesser extent, MAVS failed to respond to the two LAB, showing reduced TBK-1 phosphorylation and IFN-I activation. Furthermore, LAB-induced IFN-I was biologically active and resulted in expression of interferon stimulated genes, which was also STING- and MAVS-dependent. Our findings demonstrate a major role for STING in the production of IFN-I by beneficial bacteria and the existence of bacteria-specific immune signatures, which can be exploited to modulate protective responses in the host.
Sphingomyelinase disables Piezo1 channel inactivation to enable sustained response to mechanical force
Authors: Shi Jian , Hyman Adam J , De Vecchis Dario , Chong Jiehan , Lichtenstein Laeticia , Futers T. Simon , Rouahi Myriam , Salvayre Anne Negre , Auge Nathalie , Kalli Antreas C , Beech David J 
Published: October 2019

ABSTRACTPiezo1 channels are determinants of vascular responses to fluid flow. They importantly provide sustained response to flow, but this property contrasts with the rapid inactivation that has become a hallmark of the channels in heterologous overexpression studies. Here we reveal a mechanism by which blood vessels disable inactivation to enable sustained physiological response. Creation of a molecular model of Piezo1 channel in defined lipid membranes suggested potential modulation by sphingomyelin and its product ceramide. Biological relevance was indicated by the observation that exogenous sphingomyelinase enhanced Piezo1-mediated Ca2+ entry in cultured endothelial cells. We therefore hypothesised that endogenous sphingomyelinase suppresses channel inactivation. Remarkably, in endothelium freshly-isolated from murine artery, neutral sphingomyelinase inhibitors or genetic disruption of sphingomyelin phosphodiesterase 3 (SMPD3) caused flow- and pressure-activated Piezo1 channels to become inactivating. SMPD3 retained its ability to disable inactivation in cell-free membrane patches, providing evidence for a membrane localised effect. The data suggest that inherent inactivation of Piezo1 channels is disabled by enzymatic control of lipid environment to enable physiological response to mechanical force.
Historical recombination variability contributes to deciphering the genetic basis of phenotypic traits
Authors: Ruiz-Arenas Carlos , Cáceres Alejandro , López Marcos , Pelegrí-Sisó Dolors , González Josefa , González Juan R. 
Published: October 2019

AbstractRecombination is a main source of genetic variability. However, the potential role of the variation generated by recombination in phenotypic traits, including diseases, remains unexplored as there is currently no method to infer chromosomal subpopulations based on recombination patterns differences. We developedrecombClust, a method that uses SNP-phased data to detect differences in historic recombination in a chromosome population. We validated our method by performing simulations and by using real data to accurately predict the alleles of well known recombination modifiers, including common inversions inDrosophila melanogasterand human, and the chromosomes under selective pressure at the lactase locus in humans. We then appliedrecombClustto the complex human 1q21.1 region, where nonallelic homologous recombination produces deleterious phenotypes. We discovered and validated the presence of two different recombination histories in these regions that significantly associated with the differential expression ofANKRD35in whole blood and that were in high linkage with variants previously associated with hypertension. By detecting differences in historic recombination, our method opens a way to assess the influence of recombination variation in phenotypic traits.
RESTORE: Robust intEnSiTy nORmalization mEthod for Multiplexed Imaging
Authors: Chang Young Hwan , Chin Koei , Thibault Guillaume , Eng Jennifer , Burlingame Erik , Gray Joe W. 
Published: October 2019

AbstractRecent advances in multiplexed imaging technologies promise to improve the understanding of the functional states of individual cells and the interactions between the cells in tissues. This often requires compilation of results from multiple samples. However, quantitative integration of information between samples is complicated by variations in staining intensity and background fluorescence that obscure biological variations. Failure to remove these unwanted artefacts will complicate downstream analysis and diminish the value of multiplexed imaging for clinical applications. Here, to compensate for unwanted variations, we automatically identify negative control cells for each marker within the same tissue and use their expression levels to infer background signal level. The intensity profile is normalized by the inferred level of the negative control cells to remove between-sample variation. Using a tissue microarray data and a pair of longitudinal biopsies sample, we demonstrated that the proposed approach can remove unwanted variations effectively and shows robust performance.
Transgene-mediated skeletal phenotypic variation in zebrafish
Authors: Kimmel Charles B. , Wind Alexander L. , Oliva Whitney , Ahlquist Samuel D. , Walker Charline , Dowd John , Blanco-Sánchez Bernardo , Titus Tom A. , Batzel Peter , Postlethwait John H. , Nichols James T. 
Published: October 2019

AbstractWhen considering relationships between genotype and phenotype we frequently ignore the fact that the genome of a typical animal, notably including that of a fish and a human, harbors a huge amount of foreign DNA. Some of it, including the DNA of “autonomous” transposable elements, can spontaneously mobilize to occupy new chromosomal sites and take on new functions, presenting a challenge to the host organism and also possibly introducing new fuel for evolutionary change. Transposable elements are useful for introducing transgenes, integrating them into host genomes with high efficiency. Transgenesis has become very widespread in biological research, and in our society at large. This year the governments of both Canada and the United States have approved the first use of ‘genetically engineered’ animals in food production, Atlantic salmon,Salmo salar. With the recent advent of amazing gene-editing technology, there is no doubt that the transgene industry will grow explosively in the coming years. The biology of transgenes needs to be included in our understanding of the genome. It is in this spirit that we have investigated an unexpected and novel phenotypic effect of the chromosomally integrated transgenefli1a-F-hsp70l:Gal4VP16. We examine larvalfras1mutant zebrafish (Danio rerio). Gal4VP16 is a potent transcriptional activator, and already well known for toxicity and mediating unusual transcriptional effects. In the presence of the transgene, phenotypes in the neural crest-derived craniofacial skeleton, notably fusions and shape changes associated with loss of functionfras1mutations, are made more severe, as we quantify by scoring phenotypic penetrance, the fraction of mutants expressing the trait. A very interesting feature is that the enhancements are highly specific forfras1mutant phenotypes – occurring in the apparent absence of more wide-spread changes. Except for the features due to thefras1mutation, the transgene-bearing larvae appear generally healthy and to be developing normally. The transgene behaves as a genetic partial dominant: A single copy is sufficient for the enhancements, yet, for some traits, two copies may exert a stronger effect. We made new strains bearing independent insertions of thefli1a-F-hsp70l:Gal4VP16transgene in new locations in the genome, and observed increased severities of the same phenotypes as observed for the original insertion. This finding suggests that sequences within the transgene, e.g. Gal4VP16, are responsible for the enhancements, rather than effect on neighboring host sequences (such as an insertional mutation). The specificity, and biological action underlying the traits, are subjects of considerable interest for further investigation, as we discuss. Our findings show that work with transgenes needs to be undertaken with caution and attention to detail.
The metalloproteinase Papp-aa functions as a molecular switch linking IGF signaling to adaptive epithelial growth
Authors: Liu Chengdong , Li Shuang , Noer Pernille Rimmer , Kjaer-Sorensen Kasper , Ke Caihuan , Oxvig Claus , Duan Cunming 
Published: October 2019

AbstractHuman patients carrying inactivating mutations in the pregnancy-associated plasma protein-a2 (PAPP-A2) gene display short status and lower bone mineral density. The underlying mechanisms are not well understood. Using a zebrafish model, here we report a [Ca2+]-dependent mechanism by which Papp-aa regulates bone calcification via promoting Ca2+-transporting epithelial cell (ionocyte) reactivation. Ionocyte, normally quiescent, re-enter the cell cycle in response to low [Ca2+] stress. Deletion of Papp-aa abolished ionocyte reactivation and resulted in a complete lack of calcified bone. Re-expression of Papp-aa, but not its active site mutant, rescued ionocyte reactivation. Inhibition of Papp-aa activity pharmacologically or by overexpressing STC1 or STC2 impaired ionocyte reactivation. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-mediated Akt-Tor signaling activity in ionocytes and expression of a constitutively active Akt rescued ionocyte reactivation. Biochemically, Papp-aa cleaved Igfbp5a, a high-affinity IGF binding protein specifically expressed in ionocytes. Under normal [Ca2+] conditions, the Papp-aa-mediated Igfbp5a proteolysis was suppressed and IGFs sequestered in the IGF/Igfbp5a complex. Forced release of IGFs from the complex was sufficient to activate the IGF-Akt-Tor signaling and promote ionocyte reactivation. These findings suggest that Papp-aa functions as a [Ca2+]-regulated molecular switch linking IGF signaling to adaptive epithelial growth and bone calcification.
Singing training predicts increased insula connectivity with speech and respiratory sensorimotor areas at rest
Authors: Zamorano A.M. , Zatorre R.J. , Vuust P. , Friberg A. , Birbaumer N. , Kleber B. 
Published: October 2019

AbstractThe insula contributes to the detection of salient events during goal-directed behavior and participates in the coordination of motor, multisensory, and cognitive systems. Recent task-fMRI studies with trained singers suggest that singing experience can enhance the access to these resources. However, the long-term effects of vocal training on insula based networks are still unknown. In this study, we employed resting-state fMRI to assess experience-dependent differences in insula co-activation patterns between conservatory-trained singers and non-singers. Results indicate enhanced bilateral insula connectivity in singers relative to non-singers with constituents of the speech sensorimotor network in both hemispheres. Specifically, with the cerebellum (lobule VI, crus 2), primary somatosensory cortex, the parietal lobes, and the thalamus. Furthermore, singing training predicted enhanced bilateral co-activation of primary sensorimotor areas representing the larynx (with left dorsal anterior insula, dAI) and the diaphragm (with bilateral dAI)—crucial regions for cortico-motor control of complex vocalizations, as well as the thalamus (with bilateral posterior insula/left dAI) and the left putamen (with left dAI). Together, these data support a crucial role of the insula in respiratory and laryngeal control and suggest that singing experience enhances the integration of somatosensory information within the speech motor system, perhaps by strengthening salient associations of bodily signals associated with conscious and non-conscious aspects of expressive language production within a musical framework.