Structure, function, and recombinant production of EGFL7.

The secreted factor Epidermal growth factor-like protein 7 (EGFL7) is involved in angiogenesis, vasculogenesis, as well as neurogenesis. Importantly, EGFL7 is also implicated in various pathological conditions, including tumor angiogenesis in human cancers. Thus, understanding the mechanisms through which EGFL7 regulates and promotes blood vessel formation is of clear practical importance. One principle means by which EGFL7's function is investigated is via the expression and purification of the recombinant protein. This mini-review describes three methods used to produce recombinant EGFL7 protein. First, a brief overview of EGFL7's genetics, structure, and function is provided. This is followed by an examination of the advantages and disadvantages of three common expression systems used in the production of recombinant EGFL7; (i) Escherichia coli (E. coli), (ii) human embryonic kidney (HEK) 293 cells or other mammalian cells, and (iii) a baculovirus-based Sf9 insect cell expression system. Based on the available evidence, we conclude that the baculovirus-based Sf9 insect cell expression currently has the advantages of producing active recombinant EGFL7 in the native conformation with the presence of acceptable posttranslational modifications, while providing sufficient yield and stability for experimental purposes.

Gender differences in empathy, compassion, and prosocial donations, but not theory of mind in a naturalistic social task.

Despite broad interest, experimental evidence for gender differences in social abilities remains inconclusive. Two important factors may have limited previous results: (i) a lack of clear distinctions between empathy (sharing another's feelings), compassion (a feeling of concern toward others), and Theory of Mind (ToM; inferring others' mental states), and (ii) the absence of robust, naturalistic social tasks. Overcoming these limitations, in Study 1 (N = 295) we integrate three independent, previously published datasets, each using a dynamic and situated, video-based paradigm which disentangles ToM, empathy, and compassion, to examine gender differences in social abilities. We observed greater empathy and compassion in women compared to men, but found no evidence that either gender performed better in ToM. In Study 2 (n = 226) we extend this paradigm to allow participants to engage in prosocial donations. Along with replicating the findings of Study 1, we also observed greater prosocial donations in women compared to men. Additionally, we discuss an exploratory, novel finding, namely that ToM performance is positively associated with prosocial donations in women, but not men. Overall, these results emphasize the importance of establishing experimental designs that incorporate dynamic, complex stimuli to better capture the social realities that men and women experience in their daily lives.

The origin of brain malignancies at the blood-brain barrier.

Despite improvements in extracranial therapy, survival rate for patients suffering from brain metastases remains very poor. This is coupled with the incidence of brain metastases continuing to rise. In this review, we focus on core contributions of the blood-brain barrier to the origin of brain metastases. We first provide an overview of the structure and function of the blood-brain barrier under physiological conditions. Next, we discuss the emerging idea of a pre-metastatic niche, namely that secreted factors and extracellular vesicles from a primary tumor site are able to travel through the circulation and prime the neurovasculature for metastatic invasion. We then consider the neurotropic mechanisms that circulating tumor cells possess or develop that facilitate disruption of the blood-brain barrier and survival in the brain's parenchyma. Finally, we compare and contrast brain metastases at the blood-brain barrier to the primary brain tumor, glioma, examining the process of vessel co-option that favors the survival and outgrowth of brain malignancies.

Feedback circuits are numerous in embryonic gene regulatory networks and offer a stabilizing influence on evolution of those networks.

The developmental gene regulatory networks (dGRNs) of two sea urchin species, Lytechinus variegatus (Lv) and Strongylocentrotus purpuratus (Sp), have remained remarkably similar despite about 50 million years since a common ancestor. Hundreds of parallel experimental perturbations of transcription factors with similar outcomes support this conclusion. A recent scRNA-seq analysis suggested that the earliest expression of several genes within the dGRNs differs between Lv and Sp. Here, we present a careful reanalysis of the dGRNs in these two species, paying close attention to timing of first expression. We find that initial expression of genes critical for cell fate specification occurs during several compressed time periods in both species. Previously unrecognized feedback circuits are inferred from the temporally corrected dGRNs. Although many of these feedbacks differ in location within the respective GRNs, the overall number is similar between species. We identify several prominent differences in timing of first expression for key developmental regulatory genes; comparison with a third species indicates that these heterochronies likely originated in an unbiased manner with respect to embryonic cell lineage and evolutionary branch. Together, these results suggest that interactions can evolve even within highly conserved dGRNs and that feedback circuits may buffer the effects of heterochronies in the expression of key regulatory genes.

EGFL7 loss correlates with increased VEGF-D expression, upregulating hippocampal adult neurogenesis and improving spatial learning and memory.

Neural stem cells reside in the subgranular zone, a specialized neurogenic niche of the hippocampus. Throughout adulthood, these cells give rise to neurons in the dentate gyrus, playing an important role in learning and memory. Given that these core cognitive processes are disrupted in numerous disease states, understanding the underlying mechanisms of neural stem cell proliferation in the subgranular zone is of direct practical interest. Here, we report that mature neurons, neural stem cells and neural precursor cells each secrete the neurovascular protein epidermal growth factor-like protein 7 (EGFL7) to shape this hippocampal niche. We further demonstrate that EGFL7 knock-out in a Nestin-CreERT2-based mouse model produces a pronounced upregulation of neurogenesis within the subgranular zone. RNA sequencing identified that the increased expression of the cytokine VEGF-D correlates significantly with the ablation of EGFL7. We substantiate this finding with intraventricular infusion of VEGF-D upregulating neurogenesis in vivo and further show that VEGF-D knock-out produces a downregulation of neurogenesis. Finally, behavioral studies in EGFL7 knock-out mice demonstrate greater maintenance of spatial memory and improved memory consolidation in the hippocampus by modulation of pattern separation. Taken together, our findings demonstrate that both EGFL7 and VEGF-D affect neurogenesis in the adult hippocampus, with the ablation of EGFL7 upregulating neurogenesis, increasing spatial learning and memory, and correlating with increased VEGF-D expression.

Soundtrack to the social world: Emotional music enhances empathy, compassion, and prosocial decisions but not theory of mind.

Music is a human universal and has the ability to evoke powerful, genuine emotions. But does music influence our capacity to understand and feel with others? A growing body of evidence indicates that empathy (sharing another's feelings) and compassion (a feeling of concern toward others) are behaviorally and neutrally distinct, both from each other and from the social-cognitive process theory of mind (ToM; i.e., inferring others' mental states). Yet little is known as to whether and how these dissociable routes to feeling with and understanding others can be independently modulated. The goal of the current study was to investigate if emotional music has the potential to enhance social affect and/or social cognition. Using a naturalistic, video-based paradigm which disentangles empathy, compassion, and ToM, we demonstrate selective enhancement of social affect through music during the videos. Specifically, we found enhanced empathy and compassion when emotional, but not when neutral music was present during videos displaying emotionally negative narrations. No such enhancement was present for ToM performance. Similarly, prosocial decision making increased after emotionally negative videos with emotional music. These findings demonstrate how emotional music can enhance empathic responding, compassion and prosocial decisions as well as contribute to the growing evidence for separable processes within the social mind. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

USH2A is a Meissner's corpuscle protein necessary for normal vibration sensing in mice and humans.

Fingertip mechanoreceptors comprise sensory neuron endings together with specialized skin cells that form the end-organ. Exquisitely sensitive, vibration-sensing neurons are associated with Meissner's corpuscles in the skin. In the present study, we found that USH2A, a transmembrane protein with a very large extracellular domain, was found in terminal Schwann cells within Meissner's corpuscles. Pathogenic USH2A mutations cause Usher's syndrome, associated with hearing loss and visual impairment. We show that patients with biallelic pathogenic USH2A mutations also have clear and specific impairments in vibrotactile touch perception, as do mutant mice lacking USH2A. Forepaw rapidly adapting mechanoreceptors innervating Meissner's corpuscles, recorded from Ush2a-/- mice, showed large reductions in vibration sensitivity. However, the USH2A protein was not found in sensory neurons. Thus, loss of USH2A in corpuscular end-organs reduced mechanoreceptor sensitivity as well as vibration perception. Thus, a tether-like protein is required to facilitate detection of small-amplitude vibrations essential for the perception of fine-grained tactile surfaces.

Individual differences in envy experienced through perspective-taking involves functional connectivity of the superior frontal gyrus.

Envy is the painful or resentful awareness of another's advantage combined with a desire to possess that same advantage. Recent neuroscientific research has begun to shed light on the brain regions that process the experience of envy, including regions of the prefrontal cortex involved in emotional processing and social cognition. It is still unclear, however, which regions of the brain are functionally connected during the experience of envy. We recorded functional neuroimaging data while inducing simulated envy in participants, experienced through a perspective-taking hypothetical scenario task. In this task, participants took the perspective of a protagonist portrayed in a written description and compared themselves to either i) a self-similar/superior individual, ii) a self-dissimilar/superior individual, or iii) a self-dissimilar/average individual. During each comparison, participants also reported how much envy they experienced while taking the protagonists perspective. We demonstrate an inverse relationship in the connectivity of the left superior frontal gyrus to both the right supramarginal gyrus and the precuneus with respect to self-reported envy ratings across participants. In other words, we show that the greater the functional connectivity that the left superior frontal gyrus shares with the right supramarginal gyrus and precuneus, the less reported envy a participant experiences. Overall, our results are in line with previous research implicating the superior frontal gyrus in the reappraisal of negative emotions and extend these findings by showing this region is also involved in modulating the simulated experience of the social comparative, negative emotion of envy.