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Supplemental Figure 1 shows Pancreatic stellate cells (PSCs) promoted tumor cell invasion through close cell-cell interactions.

Pancreatic cancer has an abysmal 5-year survival rate of 8%, making it a deadly disease with a need for novel therapies. Here we describe a multitargeting heparin-based mimetic, necuparanib, and its antitumor activity in both in vitro and in vivo models of pancreatic cancer. Necuparanib reduced tumor cell proliferation and invasion in a three-dimensional (3D) culture model; in vivo, it extended survival and reduced metastasis. Furthermore, proteomic analysis demonstrated that necuparanib altered the expression levels of multiple proteins involved in cancer-driving pathways including organ development, angiogenesis, proliferation, genomic stability, cellular energetics, and invasion and metastasis. One protein family known to be involved in invasion and metastasis and altered by necuparanib treatment was the matrix metalloprotease (MMP) family. Necuparanib reduced metalloproteinase 1 (MMP1) and increased tissue inhibitor of metalloproteinase 3 (TIMP3) protein levels and was found to increase RNA expression of TIMP3. MMP enzymatic activity was also found to be reduced in the 3D model. Finally, we confirmed necuparanib's in vivo activity by analyzing plasma samples of patients enrolled in a phase I/II study in patients with metastatic pancreatic cancer; treatment with necuparanib plus standard of care significantly increased TIMP3 plasma protein levels. Together, these results demonstrate necuparanib acts as a broad multitargeting therapeutic with in vitro and in vivo anti-invasive and antimetastatic activity.

Supplementary Table 2 lists GO Categories significantly altered by necuparanib treatment, assigned to cancer-driving pathways

Supplementary Table 1 lists proteins significantly altered by necuparanib treatment

Supplemental Figure 3 shows MMP1 and MMP7 protein levels were unchanged in the plasma of patients.

Supplemental Figure 2 shows GM6001 reduced spheroid growth and invasion in the 3D co-culture model.

True or false? “A woodpecker is the only bird that can fly backwards”. When such a claim appears with a related, but non-probative photo (e.g., a photo of a woodpecker perched on a tree) people are more likely to think the claim is true – a truthiness effect. This truthiness effect holds across a range of judgments, including judgments about general knowledge facts, predictions about future events, and judgments about our own episodic memories. Throughout, adding a photograph to a claim rapidly increases people’s belief in that claim. We review the literature on truthiness, documenting the ways in which photos and other kinds of non-probative information can rapidly change people’s beliefs, memories, and estimations of their own general knowledge. We also examine the mechanisms contributing to truthiness and explore the implications for misinformation and fake news.

In everyday language, abstract concepts are described in terms of concrete physical experiences (e.g., good things are “up”; the past is “behind” us). Stimuli congruent with such conceptual metaphors are processed faster than stimuli that are not. Since ease of processing enhances aesthetic pleasure, stimuli should be perceived as more pleasing when their presentation matches (rather than mismatches) the metaphorical mapping. In six experiments, speakers of English (Experiment 1-3a) and Farsi (Experiment 3b and 4) viewed valence- and time-related photos in arrangements congruent and incongruent with their metaphorical mapping. Consistent with the valence-verticality metaphor in both languages, English and Farsi speakers preferred visual arrangements that placed the happy photo above the sad photo. In contrast, participants' preferences for time-related photos were moderated by the direction of writing. English speakers, who write from left to right, preferred arrangements that placed past-themed photos to the left of modern-themed photos; this was not observed for Farsi speakers, who write from right to left as well as left to right. In sum, identical stimuli enjoy an aesthetic advantage when their spatial arrangement matches the spatial ordering implied by applicable conceptual metaphors.

Pancreatic cancer has an abysmal 5-year survival rate of 8%, making it a deadly disease with a need for novel therapies. Here we describe a multitargeting heparin-based mimetic, necuparanib, and its antitumor activity in both in vitro and in vivo models of pancreatic cancer. Necuparanib reduced tumor cell proliferation and invasion in a three-dimensional (3D) culture model; in vivo, it extended survival and reduced metastasis. Furthermore, proteomic analysis demonstrated that necuparanib altered the expression levels of multiple proteins involved in cancer-driving pathways including organ development, angiogenesis, proliferation, genomic stability, cellular energetics, and invasion and metastasis. One protein family known to be involved in invasion and metastasis and altered by necuparanib treatment was the matrix metalloprotease (MMP) family. Necuparanib reduced metalloproteinase 1 (MMP1) and increased tissue inhibitor of metalloproteinase 3 (TIMP3) protein levels and was found to increase RNA expression of TIMP3. MMP enzymatic activity was also found to be reduced in the 3D model. Finally, we confirmed necuparanib's in vivo activity by analyzing plasma samples of patients enrolled in a phase I/II study in patients with metastatic pancreatic cancer; treatment with necuparanib plus standard of care significantly increased TIMP3 plasma protein levels. Together, these results demonstrate necuparanib acts as a broad multitargeting therapeutic with in vitro and in vivo anti-invasive and antimetastatic activity.

International audience; Conflict is risky, but mechanisms that allow animals to assess dominance status without aggression can reduce such costs. Two different mechanisms of competitor assessment are expected to evolve in different contexts: badges of status are expected in larger, anonymous groups, whereas individual recognition is feasible in small, stable groups. However, both mechanisms may be important when social interactions occur both within and across stable social groups. We manipulated plumage in golden‐crowned sparrows (Zonotrichia atricapilla) and found that two known badges of status – gold and black head plumage patch sizes – independently affect dominance among strangers but manipulations had no effect on dominance among familiar flockmates. Moreover, familiar flockmates showed less aggression and increased foraging relative to strangers. Our study provides clear experimental evidence that social recognition affects badge function, and suggests that variation in social contexts maintains coexistence and context‐dependent use of these two dominance resolution mechanisms.

This report describes the identification and characterization of the murine orphan GPCR, Gpr101. Both human and murine genes were localized to chromosome X. Similar to its human ortholog, murine Gpr101 mRNA was detected predominantly in the brain within discrete nuclei. A knowledge-restricted hidden Markov model-based algorithm, capable of accurately predicting G-protein coupling selectivity, indicated that both human and murine GPR101 were likely coupled to Gs. This prediction was supported by the elevation of cyclic AMP levels and the activation of a cyclic AMP response element-luciferase reporter gene in HEK293 cells over-expressing human GPR101. Consistent with this, over-expression of human GPR101 in a yeast-based system yielded an elevated, agonist-independent reporter gene response in the presence of a yeast chimeric Gαs protein. These results indicate that GPR101 participates in a potentially wide range of activities in the CNS via modulation of cAMP levels.

Neuropathic pain resulting from nerve lesions or dysfunction represents one of the most challenging neurological diseases to treat. A better understanding of the molecular mechanisms responsible for causing these maladaptive responses can help develop novel therapeutic strategies and biomarkers for neuropathic pain. We performed a miRNA expression profiling study of dorsal root ganglion (DRG) tissue from rats four weeks post spinal nerve ligation (SNL), a model of neuropathic pain. TaqMan low density arrays identified 63 miRNAs whose level of expression was significantly altered following SNL surgery. Of these, 59 were downregulated and the ipsilateral L4 DRG, not the injured L5 DRG, showed the most significant downregulation suggesting that miRNA changes in the uninjured afferents may underlie the development and maintenance of neuropathic pain. TargetScan was used to predict mRNA targets for these miRNAs and it was found that the transcripts with multiple predicted target sites belong to neurologically important pathways. By employing different bioinformatic approaches we identified neurite remodeling as a significantly regulated biological pathway, and some of these predictions were confirmed by siRNA knockdown for genes that regulate neurite growth in differentiated Neuro2A cells. In vitro validation for predicted target sites in the 3′-UTR of voltage-gated sodium channel Scn11a, alpha 2/delta1 subunit of voltage-dependent Ca-channel, and purinergic receptor P2rx ligand-gated ion channel 4 using luciferase reporter assays showed that identified miRNAs modulated gene expression significantly. Our results suggest the potential for miRNAs to play a direct role in neuropathic pain.

In rodents, the orphan G protein-coupled receptor, Gpr88, is highly expressed in brain regions implicated in the pathophysiology of and is modulated by treatments for schizophrenia. We compared striatal function of Gpr88 knockout mice (Gpr88KOs) to wild-type mice using molecular, neurochemical and behavioral tests. Gpr88KOs lacked expression of Gpr88 in striatum, nucleus accumbens and layer IV of cortex. Gpr88KOs had normal striatal dopamine D2 receptor density and affinity and DARPP-32 expression but Gpr88KOs had higher basal striatal phosphorylated DARPP-32 Thr-34. In vivo microdialysis detected lower basal dopamine in Gpr88KOs while amphetamine-induced dopamine release was normal. Behaviorally, Gpr88KOs demonstrated disrupted prepulse inhibition of startle (PPI) and increased sensitivity to apomorphine-induced climbing and stereotypy (AICS) and amphetamine-stimulated locomotor activity. Antipsychotic administration to Gpr88KOs normalized the PPI deficit and blocked AICS. The modulatory role of Gpr88 in striatal dopamine function suggests it may be a new target for treatments for psychiatric disorders.

GPR26 and GPR78 are orphan GPCRs (oGPCRs) that share 51% amino acid sequence identity and are widely expressed in selected tissues of the human brain as well as the developing and adult mouse brain. Investigation of the functional activity of GPR26 and GPR78 via expression in HEK293 cells showed that both proteins are constitutively active and coupled to elevated cAMP production. Accordingly, in yeast, GPR26 demonstrated apparent agonist-independent coupling to a chimeric Gpa1 protein in which the 5 C-terminal amino acids were from Galphas. A comparison of the proteins revealed an atypical glutamine residue in GPR78 in place of the conserved arginine residue (R3.50) in the so-called DRY box. Site-directed mutants R3.50 in GPR26 were constructed and retained their constitutive activity suggesting that these 2 receptors activate G proteins in a manner that is distinct from other group 1 GPCRs.

Objective— Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating reactive oxygen species (ROS) production primarily through the VEGF receptor-2 (VEGFR2). One of the initial responses in established vessels to stimulate angiogenesis is loss of vascular endothelial (VE)-cadherin–based cell–cell adhesions; however, little is known about the underlying mechanisms. IQGAP1 is a novel VEGFR2 binding protein, and it interacts directly with actin, cadherin, and β-catenin, thereby regulating cell motility and morphogenesis. Methods and Results— Confocal microscopy analysis shows that IQGAP1 colocalizes with VE-cadherin at cell–cell contacts in unstimulated human endothelial cells (ECs). VEGF stimulation reduces staining of IQGAP1 and VE-cadherin at the adherens junction without affecting interaction of these proteins. Knockdown of IQGAP1 using siRNA inhibits localization of VE-cadherin at cell–cell contacts, VEGF-stimulated recruitment of VEGFR2 to the VE-cadherin/β-catenin complex, ROS-dependent tyrosine phosphorylation of VE-cadherin, which is required for loss of cell–cell contacts and capillary tube formation. IQGAP1 expression is increased in a mouse hindlimb ischemia model of angiogenesis. Conclusions— IQGAP1 is required for establishment of cell–cell contacts in quiescent ECs. To induce angiogenesis, it may function to link VEGFR2 to the VE-cadherin containing adherens junctions, thereby promoting VEGF-stimulated, ROS-dependent tyrosine phosphorylation of VE-cadherin and loss of cell–cell contacts.

The article of record as published may be found at https://doi.org/10.1145/882033.882034 Computer-aided prototyping shows promise that one system under development frees designers from implementation details by executing specifications via reusable components. Ada is first choice for constructing such reusable object-oriented components because Ada95 is the only international standard programming language that supports object-oriented real-time distributed systems. But Ada has diversified object forms that are so intricate that people feel it difficult to find an equivalence of a class between Java (C++) and Ada95. In computer-aided prototyping, automatic prototype generating is facing one of key problems on how to map a well-defined prototyping specification to an executable prototype with different OOPLs. This paper addresses several key problems in automatic prototype generating with reusable object foundation based on an optimized object model. These problems include transformation of a PSDL specification to the executable system composed from componential object entities, compositional pattern enforcing interactions among components, generalized role wrappers from which physical components can be derived and an optimized object model used to unify different object forms in popular OOPLs.