bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function
Authors: Guo Daji , Peng Yinghui , Wang Laijian , Sun Xiaoyu , Wang Xiaojun , Liang Chunmei , Yang Xiaoman , Li Shengnan , Xu Junyu , Ye Wen-Cai , Jiang Bin , Shi Lei 
Published: August 2019

AbstractGenetic studies of autism spectrum disorder (ASD) have revealed multigene variations that converge on synaptic dysfunction. DOCK4, a gene at 7q31.1 that encodes the Rac1 guanine nucleotide exchange factor Dock4, has been identified as a risk gene for ASD and other neuropsychiatric disorders. However, whether and how Dock4 disruption leads to ASD features through a synaptic mechanism remain unexplored. We generated and characterized a line of Dock4 knockout (KO) mice, which intriguingly displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning. Mice with conditional deletion of Dock4 in hippocampal CA1 recapitulated social preference deficit in KO mice. Examination in CA1 pyramidal neurons revealed that excitatory synaptic transmission was drastically attenuated in KO mice, accompanied by decreased spine density and synaptic content of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)- and NMDA (N-methyl-D-aspartate)-type glutamate receptors. Moreover, Dock4 deficiency markedly reduced Rac1 activity in the hippocampus, which resulted in downregulation of global protein synthesis and diminished expression of AMPA and NMDA receptor subunits. Notably, Rac1 replenishment in the hippocampal CA1 of Dock4 KO mice restored excitatory synaptic transmission and corrected impaired social deficits in these mice, and pharmacological activation of NMDA receptors also restored social novelty preference in Dock4 KO mice. Together, our findings uncover a previously unrecognized Dock4-Rac1-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and social behavior.
Hydrogen peroxide inducible clone-5 sustains NADPH oxidase-dependent reactive oxygen species-c-jun N-terminal kinase signaling in hepatocellular carcinoma
Authors: Wu Jia-Ru , You Ren-In , Hu Chi-Tan , Cheng Chuan-Chu , Rudy Rudy , Wu Wen-Sheng 
Published: August 2019

AbstractTarget therapy aiming at critical molecules within the metastatic signal pathways is essential for prevention of hepatocellular carcinoma (HCC) progression. Hic-5 (hydrogen peroxide inducible clone-5) which belongs to the paxillin superfamily, can be stimulated by a lot of metastatic factors, such as transforming growth factor (TGF-β), hepatocyte growth factor (HGF), and reactive oxygen species (ROS). Previous studies implicated Hic-5 cross-talks with the ROS-c-jun N-terminal kinase (JNK) signal cascade in a positive feedback manner. In this report, we addressed this issue in a comprehensive manner. By RNA interference and ectopic Hic-5 expression, we demonstrated Hic-5 was essential for activation of NADPH oxidase and ROS generation leading to activation of downstream JNK and c-jun transcription factor. This was initiated by interaction of Hic-5 with the regulator and adaptor of NADPH oxidase, Rac1 and Traf4, respectively, which may further phosphorylate the nonreceptor tyrosine kinase Pyk2 at Tyr881. On the other hand, promoter activity assay coupled with deletion mapping and site directed mutagenesis strategies demonstrated the distal c-jun and AP4 putative binding regions (943–1126 bp upstream of translational start site) were required for transcriptional activation of Hic-5. Thus Hic-5 was both downstream and upstream of NADPH oxidase-ROS-JNK-c-jun cascade. This signal circuit was essential for regulating the expression of epithelial mesenchymal transition (EMT) factors, such as Snail, Zeb1, E-cadherin, and matrix metalloproteinase 9, involved in HCC cell migration and metastasis. Due to the limited expression of Hic-5 in normal tissue, it can be a promising therapeutic target for preventing HCC metastasis.
TonEBP/NFAT5 promotes obesity and insulin resistance by epigenetic suppression of white adipose tissue beiging
Authors: Lee Hwan Hee , An Seung Min , Ye Byeong Jin , Lee Jun Ho , Yoo Eun Jin , Jeong Gyu Won , Kang Hyun Je , Alfadda Assim A. , Lim Sun Woo , Park Jiyoung , Lee-Kwon Whaseon , Kim Jae Bum , Choi Soo Youn , Kwon Hyug Moo 
Published: August 2019

AbstractTonicity-responsive enhancer binding protein (TonEBP or NFAT5) is a regulator of cellular adaptation to hypertonicity, macrophage activation and T-cell development. Here we report that TonEBP is an epigenetic regulator of thermogenesis and obesity. In mouse subcutaneous adipocytes, TonEBP expression increases > 50-fold in response to high-fat diet (HFD) feeding. Mice with TonEBP haplo-deficiency or adipocyte-specific TonEBP deficiency are resistant to HFD-induced obesity and metabolic defects (hyperglycemia, hyperlipidemia, and hyperinsulinemia). They also display increased oxygen consumption, resistance to hypothermia, and beiging of subcutaneous fat tissues. TonEBP suppresses the promoter of β3-adrenoreceptor gene, a critical regulator of lipolysis and thermogenesis, in ex vivo and cultured adipocytes. This involves recruitment of DNMT1 DNA methylase and methylation of the promoter. In human subcutaneous adipocytes TonEBP expression displays a correlation with body mass index but an inverse correlation with β3-adrenoreceptor expression. Thus, TonEBP is an attractive therapeutic target for obesity, insulin resistance, and hyperlipidemia.
Synaptotagmin 17 controls neurite outgrowth and synaptic physiology via distinct cellular pathways
Authors: Ruhl David A. , Bomba-Warczak Ewa , Watson Emma T. , Bradberry Mazdak M. , Peterson Tabitha A. , Basu Trina , Frelka Alyssa , Evans Chantell S. , Briguglio Joseph S. , Basta Tamara , Stowell Michael H. B. , Savas Jeffrey N. , Roopra Avtar , Pearce Robert A. , Piper Robert C. , Chapman Edwin R. 
Published: August 2019

AbstractThe synaptotagmin (syt) proteins have been widely studied for their role in regulating fusion of intracellular vesicles with the plasma membrane. Here we report that syt-17, an unusual isoform of unknown function, plays no role in exocytosis, and instead plays multiple roles in intracellular membrane trafficking. Syt-17 is localized to the Golgi complex in hippocampal neurons, where it coordinates import of vesicles from the endoplasmic reticulum to support neurite outgrowth and facilitate axon regrowth after injury. Further, we discovered a second pool of syt-17 on early endosomes in neurites. Loss of syt-17 disrupts endocytic trafficking, resulting in the accumulation of excess postsynaptic AMPA receptors and defective synaptic plasticity. Two distinct pools of syt-17 thus control two crucial, independent membrane trafficking pathways in neurons. Function of syt-17 appears to be one mechanism by which neurons have specialized their secretory and endosomal systems to support the demands of synaptic communication over sprawling neurite arbors.
Cytokinin functions as an asymmetric and anti-gravitropic signal in lateral roots
Authors: Waidmann Sascha , Ruiz Rosquete Michel , Schöller Maria , Sarkel Elizabeth , Lindner Heike , LaRue Therese , Petřík Ivan , Dünser Kai , Martopawiro Shanice , Sasidharan Rashmi , Novak Ondrej , Wabnik Krzysztof , Dinneny José R. , Kleine-Vehn Jürgen 
Published: August 2019

AbstractDirectional organ growth allows the plant root system to strategically cover its surroundings. Intercellular auxin transport is aligned with the gravity vector in the primary root tips, facilitating downward organ bending at the lower root flank. Here we show that cytokinin signaling functions as a lateral root specific anti-gravitropic component, promoting the radial distribution of the root system. We performed a genome-wide association study and reveal that signal peptide processing of Cytokinin Oxidase 2 (CKX2) affects its enzymatic activity and, thereby, determines the degradation of cytokinins in natural Arabidopsis thaliana accessions. Cytokinin signaling interferes with growth at the upper lateral root flank and thereby prevents downward bending. Our interdisciplinary approach proposes that two phytohormonal cues at opposite organ flanks counterbalance each other’s negative impact on growth, suppressing organ growth towards gravity and allow for radial expansion of the root system.
A single shot coherent Ising machine based on a network of injection-locked multicore fiber lasers
Authors: Babaeian Masoud , Nguyen Dan T. , Demir Veysi , Akbulut Mehmetcan , Blanche Pierre-A , Kaneda Yushi , Guha Saikat , Neifeld Mark A. , Peyghambarian N. 
Published: August 2019

AbstractCombinatorial optimization problems over large and complex systems have many applications in social networks, image processing, artificial intelligence, computational biology and a variety of other areas. Finding the optimized solution for such problems in general are usually in non-deterministic polynomial time (NP)-hard complexity class. Some NP-hard problems can be easily mapped to minimizing an Ising energy function. Here, we present an analog all-optical implementation of a coherent Ising machine (CIM) based on a network of injection-locked multicore fiber (MCF) lasers. The Zeeman terms and the mutual couplings appearing in the Ising Hamiltonians are implemented using spatial light modulators (SLMs). As a proof-of-principle, we demonstrate the use of optics to solve several Ising Hamiltonians for up to thirteen nodes. Overall, the average accuracy of the CIM to find the ground state energy was ~90% for 120 trials. The fundamental bottlenecks for the scalability and programmability of the presented CIM are discussed as well.
Wine aging: a bottleneck story
Authors: Karbowiak Thomas , Crouvisier-Urion Kevin , Lagorce Aurélie , Ballester Jordi , Geoffroy André , Roullier-Gall Chloé , Chanut Julie , Gougeon Régis D. , Schmitt-Kopplin Philippe , Bellat Jean-Pierre 
Published: August 2019

AbstractThe sporadic oxidation of white wines remains an open question, making wine shelf life a subjective debate. Through a multidisciplinary synoptic approach performed as a remarkable case study on aged bottles of white wine, this work unraveled a yet unexplored route for uncontrolled oxidation. By combining sensory evaluation, chemical and metabolomics analyses of the wine, and investigating oxygen transfer through the bottleneck/stopper, this work elucidates the importance of the glass/cork interface. It shows unambiguously that the transfer of oxygen at the interface between the cork stopper and the glass bottleneck must be considered a potentially significant contributor to oxidation state during the bottle aging, leading to a notable modification of a wine’s chemical signature.
Bifurcation analysis of the dynamics of interacting subnetworks of a spiking network
Authors: Lagzi Fereshteh , Atay Fatihcan M. , Rotter Stefan 
Published: August 2019

AbstractWe analyze the collective dynamics of hierarchically structured networks of densely connected spiking neurons. These networks of sub-networks may represent interactions between cell assemblies or different nuclei in the brain. The dynamical activity pattern that results from these interactions depends on the strength of synaptic coupling between them. Importantly, the overall dynamics of a brain region in the absence of external input, so called ongoing brain activity, has been attributed to the dynamics of such interactions. In our study, two different network scenarios are considered: a system with one inhibitory and two excitatory subnetworks, and a network representation with three inhibitory subnetworks. To study the effect of synaptic strength on the global dynamics of the network, two parameters for relative couplings between these subnetworks are considered. For each case, a bifurcation analysis is performed and the results have been compared to large-scale network simulations. Our analysis shows that Generalized Lotka-Volterra (GLV) equations, well-known in predator-prey studies, yield a meaningful population-level description for the collective behavior of spiking neuronal interaction, which have a hierarchical structure. In particular, we observed a striking equivalence between the bifurcation diagrams of spiking neuronal networks and their corresponding GLV equations. This study gives new insight on the behavior of neuronal assemblies, and can potentially suggest new mechanisms for altering the dynamical patterns of spiking networks based on changing the synaptic strength between some groups of neurons.
Convolutional Neural Networks for Spectroscopic Analysis in Retinal Oximetry
Authors: DePaoli Damon T. , Tossou Prudencio , Parent Martin , Sauvageau Dominic , Côté Daniel C. 
Published: August 2019

AbstractRetinal oximetry is a non-invasive technique to investigate the hemodynamics, vasculature and health of the eye. Current techniques for retinal oximetry have been plagued by quantitatively inconsistent measurements and this has greatly limited their adoption in clinical environments. To become clinically relevant oximetry measurements must become reliable and reproducible across studies and locations. To this end, we have developed a convolutional neural network algorithm for multi-wavelength oximetry, showing a greatly improved calculation performance in comparison to previously reported techniques. The algorithm is calibration free, performs sensing of the four main hemoglobin conformations with no prior knowledge of their characteristic absorption spectra and, due to the convolution-based calculation, is invariable to spectral shifting. We show, herein, the dramatic performance improvements in using this algorithm to deduce effective oxygenation (SO2), as well as the added functionality to accurately measure fractional oxygenation ($${{\bf{SO}}}_{{\bf{2}}}^{{\boldsymbol{f}}{\boldsymbol{r}}}$$

SO

2

f
r

). Furthermore, this report compares, for the first time, the relative performance of several previously reported multi-wavelength oximetry algorithms in the face of controlled spectral variations. The improved ability of the algorithm to accurately and independently measure hemoglobin concentrations offers a high potential tool for disease diagnosis and monitoring when applied to retinal spectroscopy.
An efficacy evaluation method for non-normal outcomes in randomized controlled trials
Authors: Li Yang , Zhang Zhang , Feng Qian , Yi Danhui , Lu Fang 
Published: August 2019

AbstractRandomized controlled trials (RCT) are widely used in clinical efficacy evaluation studies. Linear regression is a general method to evaluate treatment efficacy considering the existence of confounding variables. However, when residuals are not normally distributed, parameter estimation based on ordinary least squares (OLS) is inefficient. This study introduces an exponential squared loss (ESL) model to evaluate treatment effect. The proposed method provides robust estimation for non-normal data. Simulation results show that it outperforms ordinary least squares regression with contaminated data. In the mild cognitive impairment (MCI) efficacy evaluation study with traditional Chinese medicine, our method is applied to construct a linear efficacy evaluation model for the difference in Alzheimer’s disease assessment scale-cognitive (ADAS-cog) scores between the final and baseline records (ADASFA), with the existence of confounding factors and non- normal residuals. The results coincide with existing medical literatures. This proposed method overcomes the limitation of confounding variables and non-normal residuals in RCT efficacy studies. It outperforms OLS on estimation efficiency in situations where the percentage of non-normal contamination reaches 30%. These advantages make it a good method for real-world clinical studies.
Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake
Authors: Banerjee Sreemoti , Andrew Robert J. , Duff Christopher J. , Fisher Kate , Jackson Carolyn D. , Lawrence Catherine B. , Maeda Nobuyo , Greenspan Daniel S. , Kellett Katherine A. B. , Hooper Nigel M. 
Published: August 2019

AbstractThe development of cardiovascular disease is intimately linked to elevated levels of low-density lipoprotein (LDL) cholesterol in the blood. Hepatic LDL receptor (LDLR) levels regulate the amount of plasma LDL. We identified the secreted zinc metalloproteinase, bone morphogenetic protein 1 (BMP1), as responsible for the cleavage of human LDLR within its extracellular ligand-binding repeats at Gly171↓Asp172. The resulting 120 kDa membrane-bound C-terminal fragment (CTF) of LDLR had reduced capacity to bind LDL and when expressed in LDLR null cells had compromised LDL uptake as compared to the full length receptor. Pharmacological inhibition of BMP1 or siRNA-mediated knockdown prevented the generation of the 120 kDa CTF and resulted in an increase in LDL uptake into cells. The 120 kDa CTF was detected in the livers from humans and mice expressing human LDLR. Collectively, these results identify that BMP1 regulates cellular LDL uptake and may provide a target to modulate plasma LDL cholesterol.
Maternal transmission of an Igf2r domain 11: IGF2 binding mutant allele (Igf2rI1565A) results in partial lethality, overgrowth and intestinal adenoma progression
Authors: Hughes Jennifer , Surakhy Mirvat , Can Sermet , Ducker Martin , Davies Nick , Szele Francis , Bühnemann Claudia , Carter Emma , Trikin Roman , Crump Matthew P. , Frago Susana , Hassan A. Bassim 
Published: August 2019

AbstractThe cation-independent mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R or IGF2R) traffics IGF2 and M6P ligands between pre-lysosomal and extra-cellular compartments. Specific IGF2 and M6P high-affinity binding occurs via domain-11 and domains-3-5-9, respectively. Mammalian maternal Igf2r allele expression exceeds the paternal allele due to imprinting (silencing). Igf2r null-allele maternal transmission results in placenta and heart over-growth and perinatal lethality (>90%) due to raised extra-cellular IGF2 secondary to impaired ligand clearance. It remains unknown if the phenotype is due to either ligand alone, or to both ligands. Here, we evaluate Igf2r specific loss-of-function of the domain-11 IGF2 binding site by replacing isoleucine with alanine in the CD loop (exon 34, I1565A), a mutation also detected in cancers. Igf2rI1565A/+p maternal transmission (heterozygote), resulted in placental and embryonic over-growth with reduced neonatal lethality (<60%), and long-term survival. The perinatal mortality (>80%) observed in homozygotes (Igf2rI1565A/I1565A) suggested that wild-type paternal allele expression attenuates the heterozygote phenotype. To evaluate Igf2r tumour suppressor function, we utilised intestinal adenoma models known to be Igf2 dependent. Bi-allelic Igf2r expression suppressed intestinal adenoma (ApcMin). Igf2rI1565A/+p in a conditional model (Lgr5-Cre, Apcloxp/loxp) resulted in worse survival and increased adenoma proliferation. Growth, survival and intestinal adenoma appear dependent on IGF2R-domain-11 IGF2 binding.
Pancreatic (pro)enzymes treatment suppresses BXPC-3 pancreatic Cancer Stem Cell subpopulation and impairs tumour engrafting
Authors: Hernández-Camarero Pablo , López-Ruiz Elena , Griñán-Lisón Carmen , García María Ángel , Chocarro-Wrona Carlos , Marchal Juan Antonio , Kenyon Julian , Perán Macarena 
Published: August 2019

AbstractCancer stem cells (CSCs) subpopulation within the tumour is responsible for metastasis and cancer relapse. Here we investigate in vitro and in vivo the effects of a pancreatic (pro)enzyme mixture composed of Chymotrypsinogen and Trypsinogen (PRP) on CSCs derived from a human pancreatic cell line, BxPC3. Exposure of pancreatic CSCs spheres to PRP resulted in a significant decrease of ALDEFLUOR and specific pancreatic CSC markers (CD 326, CD 44 and CxCR4) signal tested by flow cytometry, further CSCs markers expression was also analyzed by western and immunofluorescence assays. PRP also inhibits primary and secondary sphere formation. Three RT2 Profiler PCR Arrays were used to study gene expression regulation after PRP treatment and resulted in, (i) epithelial-mesenchymal transition (EMT) inhibition; (ii) CSCs related genes suppression; (iii) enhanced expression of tumour suppressor genes; (iv) downregulation of migration and metastasis genes and (v) regulation of MAP Kinase Signalling Pathway. Finally, in vivo anti-tumor xenograft studies demonstrated high anti-tumour efficacy of PRP against tumours induced by BxPC3 human pancreatic CSCs. PRP impaired engrafting of pancreatic CSC’s tumours in nude mice and displayed an antigrowth effect toward initiated xenografts. We concluded that (pro)enzymes treatment is a valuable strategy to suppress the CSC population in solid pancreatic tumours.
Effect of α-glycosidase inhibitors from endophytic fungus Alternaria destruens on survival and development of insect pest Spodoptera litura Fab. and fungal phytopathogens
Authors: Kaur Jasleen , Sharma Avinash , Sharma Manish , Kumari Manhas Rajesh , Kaur Sanehdeep , Kaur Amarjeet 
Published: August 2019

AbstractIn the present study the production of α-glycosidase inhibitors was used as a strategy to screen endophytic fungi with insecticidal and antifungal potential. Endophytic fungi were isolated from Calotropis gigantea L. (Gentianales: Apocynaceae) and evaluated for their α-glycosidase inhibitory activity. Maximum inhibitory activity was observed in an isolate AKL-3, identified to be Alternaria destruens E.G.Simmons on the basis of morphological and molecular analysis. Production of inhibitory metabolites was carried out on malt extract and partially purified using column chromatography. Insecticidal potential was examined on Spodoptera litura Fab. (Lepidoptera: Noctudiae). Partially purified α-glycosidase inhibitors induced high mortality, delayed the development period as well as affected the adult emergence and induced adult deformities. Nutritional analysis revealed the toxic and antifeedant effect of AKL-3 inhibitors on various food utilization parameters of S. litura. They also inhibited the in vivo digestive enzymes activity in S. litura. Partially purified α-glycosidase inhibitors were also studied for their antifungal potential. Inhibitors demonstrated antifungal activity against the tested phytopathogens inducing severe morphological changes in mycelium and spores. This is the first report on production of α-glycosidase inhibitors from A. destruens with insecticidal and antifungal activity. The study also highlights the importance of endophytes in providing protection against insect pests and pathogens to the host.