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PTEN-induced kinase 1 (PINK1) is a short-lived protein required for the removal of damaged mitochondria through Parkin translocation and mitophagy. Because the short half-life of PINK1 limits its ability to be trafficked into neurites, local translation is required for this mitophagy pathway to be active far from the soma. The Pink1 transcript is associated and cotransported with neuronal mitochondria. In concert with translation, the mitochondrial outer membrane proteins synaptojanin 2 binding protein (SYNJ2BP) and synaptojanin 2 (SYNJ2) are required for tethering Pink1 mRNA to mitochondria via an RNA-binding domain in SYNJ2. This neuron-specific adaptation for the local translation of PINK1 provides distal mitochondria with a continuous supply of PINK1 for the activation of mitophagy., Competing Interests: Declaration of interests Z.H. is a co-founder of Rugen Therapeutics and Myro Therapeutics. All other authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Prior research has indicated that the people one loves the most, such as their romantic partners, ironically, are also the people toward whom they often direct destructive behaviors in times of conflict, and such destructive responses become one of the most challenging relationship problems. Identifying the conditions that promote destructive (vs. constructive) conflict-resolution strategies is a crucial gap requiring study to help individuals build healthier and happier relationships. Across three studies (total N = 728), we examined whether (a) power is related to direct destructive (vs. constructive) responses during romantic conflicts; (b) this effect was moderated by the seriousness of the conflict and the relationship's inclusiveness. In Study 1, participants involved in romantic relationships completed scales assessing interpersonal power, the conflict's seriousness, their relationship's inclusiveness, and conflict-resolution responses. In Studies 2-3, the participants were randomly assigned to complete an essay in which the conflict's seriousness and power were experimentally manipulated. Findings from hierarchical regression analyses consistently showed that power led to destructive (and lower constructive) responses. However, this only occurred when the participants faced severe conflicts and their partner was not central to their self-concept. An internal meta-analysis of the studies confirmed the reliability and significance of these relationships; |r's| =.13-37. Together, these results support the proposition that power asymmetries can threaten relationships by driving destructive responses during romantic conflicts, and untangle the conditions under which this happens. The conflict's seriousness and the inclusiveness of the relationship may be considered to provide skills that help individuals navigate their relationships' life challenges.

Background: The different conflict resolution strategies that couples use are crucial in preserving or ending their relationships. Despite the importance of these strategies, no instrument for measuring them has been adequately adapted to Spanish culture. The goal of this study is to adapt the Accommodation among Romantic Couples Scale to Spanish culture, filling this gap by providing a rigorous instrument to evaluate the construct., Method: A total of 489 participants from the general population responded to the instrument after adaptation. The scale's psychometric properties were then evaluated from a classical perspective., Results: The indexes of fit from confirmatory factor analysis indicated good fit to the four-factor structure proposed by the authors of the original scale: voice, loyalty, exit, and neglect. The reliability of these dimensions was similar to that obtained in the original version. Evidence of validity relative to other variables indicated good convergent and discriminant validity., Conclusions: The Spanish version of the Accommodation among Romantic Couples Scale is a reliable instrument with sufficient valid evidence to provide accurate measurement of conflict resolution strategies in couple relationships.

mRNA transport restricts translation to specific subcellular locations, which is the basis for many cellular functions. However, the precise process of mRNA sorting to synapses in neurons remains elusive. Here we use Rgs4 mRNA to investigate 3'-UTR-dependent transport by MS2 live-cell imaging. The majority of observed RNA granules display 3'-UTR independent bidirectional transport in dendrites. Importantly, the Rgs4 3'-UTR causes an anterograde transport bias, which requires the Staufen2 protein. Moreover, the 3'-UTR mediates dynamic, sustained mRNA recruitment to synapses. Visualization at high temporal resolution enables us to show mRNA patrolling dendrites, allowing transient interaction with multiple synapses, in agreement with the sushi-belt model. Modulation of neuronal activity by either chemical silencing or local glutamate uncaging regulates both the 3'-UTR-dependent transport bias and synaptic recruitment. This dynamic and reversible mRNA recruitment to active synapses would allow translation and synaptic remodeling in a spatially and temporally adaptive manner.

In polarized cells, such as neurons, the synthesis of an mRNA does not ensure its proper cellular expression. Most mature transcripts require the association with RNA-binding proteins, resulting in the formation of RNA granules, which are then transported within the cytoplasm along the cytoskeleton and delivered to their proper subcellular locations, where they can be locally translated. Here we review current microscopy methods that have been developed to visualize RNA granule formation, transport and translation at the single cell level with a special emphasis on the MS2 and SunTag systems. They include the labeling of mRNAs and RNA-binding proteins in living cells or even the detection of newly synthesized proteins in situ., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Neuronal function is highly sensitive to changes in oxygen levels, but how hypoxia affects dendritic spine formation and synaptogenesis is unknown. Here we report that hypoxia, chemical inhibition of the oxygen-sensing prolyl hydroxylase domain proteins (PHDs), and silencing of Phd2 induce immature filopodium-like dendritic protrusions, promote spine regression, reduce synaptic density, and decrease the frequency of spontaneous action potentials independently of HIF signaling. We identified the actin cross-linker filamin A (FLNA) as a target of PHD2 mediating these effects. In normoxia, PHD2 hydroxylates the proline residues P2309 and P2316 in FLNA, leading to von Hippel-Lindau (VHL)-mediated ubiquitination and proteasomal degradation. In hypoxia, PHD2 inactivation rapidly upregulates FLNA protein levels because of blockage of its proteasomal degradation. FLNA upregulation induces more immature spines, whereas Flna silencing rescues the immature spine phenotype induced by PHD2 inhibition., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The oxygen-sensing prolyl hydroxylase domain proteins (PHDs) regulate cellular metabolism, but their role in neuronal metabolism during stroke is unknown. Here we report that PHD1 deficiency provides neuroprotection in a murine model of permanent brain ischemia. This was not due to an increased collateral vessel network. Instead, PHD1(-/-) neurons were protected against oxygen-nutrient deprivation by reprogramming glucose metabolism. Indeed, PHD1(-/-) neurons enhanced glucose flux through the oxidative pentose phosphate pathway by diverting glucose away from glycolysis. As a result, PHD1(-/-) neurons increased their redox buffering capacity to scavenge oxygen radicals in ischemia. Intracerebroventricular injection of PHD1-antisense oligonucleotides reduced the cerebral infarct size and neurological deficits following stroke. These data identify PHD1 as a regulator of neuronal metabolism and a potential therapeutic target in ischemic stroke., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Sexual objectification of women is a subtle manifestation of gender violence. The aim of this study was to adapt the 15-item Interpersonal Sexual Objectification Scale (ISOS) to Spanish to obtain a valid instrument to evaluate this construct., Method: After its adaptation, the questionnaire was administered to 771 women from the general population. Subsequently, the psychometric properties of the questionnaire were evaluated from both the classical perspective and item response theory., Results: The data obtained were very similar to those of the original version. The ISOS showed good internal consistency and a two-factor structure: body evaluation and unwanted explicit sexual advances. In addition, the ISOS showed correlations with benevolent sexism, state-anxiety and self-esteem., Conclusions: The Spanish version of the ISOS is a reliable and valid measure of sexual objectification of women in the interpersonal context.

Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment., (Copyright © 2013 Elsevier Inc. All rights reserved.)

NMDA type glutamate receptors (NMDARs) are best known for their role in synaptogenesis and synaptic plasticity. Much less is known about their developmental role before neurons form synapses. We report here that VEGF, which promotes migration of granule cells (GCs) during postnatal cerebellar development, enhances NMDAR-mediated currents and Ca(2+) influx in immature GCs before synapse formation. The VEGF receptor Flk1 forms a complex with the NMDAR subunits NR1 and NR2B. In response to VEGF, the number of Flk1/NR2B coclusters on the cell surface increases. Stimulation of Flk1 by VEGF activates Src-family kinases, which increases tyrosine phosphorylation of NR2B. Inhibition of Src-family kinases abolishes the VEGF-dependent NR2B phosphorylation and amplification of NMDAR-mediated currents and Ca(2+) influx in GCs. These findings identify VEGF as a modulator of NMDARs before synapse formation and highlight a link between an activity-independent neurovascular guidance cue (VEGF) and an activity-regulated neurotransmitter receptor (NMDAR).

The existence of domestic violence is closely linked to several ideological factors that include sexism and other beliefs about society in general, namely the belief in a just world. In this study, which involved 485 people of both sexes aged between 18 and 70 years, we analyzed the influence of these ideological variables of the perceivers and characteristics of the situation on judgments of a gender aggression--blaming the victim and exonerating the perpetrator. Results showed differences in the reactions of observers depending on the cause that triggered the aggression. Participants blamed the victim and exonerated the aggressor more when no cause of the aggression was mentioned than when a cause was mentioned (the woman wanted to separate, to see an old male friend, or simply to take a trip with her female friends). We also found clear effects of hostile sexism and just world beliefs on the dependent variables. Results showed that the influence of just world beliefs depended on the fact of mention or not a cause for the aggression.

The role of pericytes in the control of blood-brain barrier (BBB) integrity has remained enigmatic. In this issue, Bell et al. and two concurrent studies highlight that pericyte loss causes BBB breakdown and hypoperfusion. Remarkably, these vascular changes precede neurodegeneration and cognitive defects in old age., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Although the nervous and vascular systems are functionally different, they show a high degree of anatomic parallelism and cross-talk. They also share similar mechanisms and molecular cues that regulate their development and maintenance. Malfunctioning of this cross-talk can cause or influence several vascular and neuronal disorders. In this review, we first provide a brief overview of the molecular and cellular mechanisms that govern the neurovascular link. Second, we focus on two neurodegenerative diseases, Alzheimer's disease and amyotrophic lateral sclerosis, to illustrate how a defective neurovascular link might contribute to their pathogenesis. Finally, we briefly discuss some therapeutic implications of the neurovascular link for designing strategies to treat these diseases.

Pigment epithelium-derived factor (PEDF) combines neurotrophic, neuroprotective, anti-angiogenic, anti-tumor and neural stem cell self-renewal properties in a single molecule, making this protein a valuable potential therapeutic agent. We herein analyzed the expression of human recombinant full-length PEDF, and its N- and C-terminal regions (amino acids 1-243 and 195-418, respectively) in three mammalian cell lines (HEK-293T, COS-1, and 26HCMsv), and in the yeast Pichia pastoris. The highest production of recombinant PEDF was achieved in P. pastoris which secreted approximately 30 microg of full-length rPEDF, and 47 microg of C-terminal/ml of culture medium. Full-length rPEDF was purified by one-step Ni-chelating high-performance liquid chromatography, recovering almost 70% of secreted rPEDF with a purity of 98.6%. The C-terminal region of PEDF was isolated by low-pressure liquid chromatography, recovering around 4% of the recombinant molecule with a purity of 98%. The N-terminal region of PEDF was not secreted by any expression system assayed. The two isolated recombinant PEDF polypeptides inhibited in vitro endothelial cell migration, and full-length rPEDF also increased cerebellar granule cell survival, thus demonstrating their biological activity. These polypeptides can be used to investigate the therapeutic role of PEDF in cancer, neurodegenerative and ocular diseases, and stem cell-based therapies.

Endothelial cell function and angiogenesis are modulated by aging. However, the underlying molecular mechanisms are largely unknown. Here we show that in telomerase-deficient mice Terc(-/-), short telomeres result in a sharp decrease in angiogenesis in both Matrigel implants and murine melanoma grafts. In the latter model, decreased microvessel counts in late generation Terc(-/-) mice led to diminished tumor cell proliferation and increased tumor cell apoptosis, resulting in a lower tumor growth rate. Our results indicate that telomere length is a key molecular determinant of angiogenic potential in vivo and that telomere length modifiers and telomerase inhibitors could be useful antiangiogenic agents.