Nuclear Import of Smad: A Dissertation

Signal transduction by transforming growth factor β (TGF-β) cytokines is mediated by an evolutionarily conserved mechanism that depends on the Smad proteins to transduce an extracellular stimulus into the nucleus. In the unstimulated state, Smads spontaneously shuttle across the nuclear envelope and distribute throughout the cell. Upon TGF-β or bone morphogenetic protein (BMP) stimulation, the receptor-activated Smads are phosphorylated, assemble into complexes with Smad4, and become mostly localized in the nucleus. Such signal-induced nuclear translocation of activated Smads is essential for TGF-β–dependent gene regulation that is critical for embryonic development and homeostasis. The molecular machinery responsible for this process, especially how the activated Smads are imported as complexes, is not entirely clear. Thus, I became interested in investigating the molecular requirements for nuclear targeting of Smads upon stimulation. Recently, whole-genome RNAi screening offers a complementary cell-based approach to functionally identify molecules that mediate nuclear accumulation of Smads in response to TGF-β. In the first part of this dissertation, I performed a genome-wide RNAi screen that uncovered the importin moleskin (Msk) required in nuclear import of Dpp-activated MAD. Both genetic and biochemical studies further confirmed this finding. I also investigated Smad interactions with the Msk mammalian orthologues, Importin7 and 8 and validated that Smads are bona fide cargos of Imp7/8. Besides the importin Msk, the screen also uncovered a subset of nucleoporins as required factors in signal-induced nuclear accumulation of MAD. Thus in the second part of this thesis, I focused on how the NPC mediates this Msk-dependent nuclear import of activated MAD. Most of these nucleoporins, including Sec13, Nup75, Nup93 and Nup205, were thought to be structural nucleoporins without known cargo-specific functions. We, however, demonstrated that this subset of nucleoporins was specifically used in the Msk-dependent nuclear import of activated MAD but not the constitutive import of cargos containing a classic nuclear localization signal (cNLS). I also uncovered novel pathway-specific functions of Sec13 and Nup93. Regulation of TGF-β signaling can be achieved not only by modulating Smad nuclear translocation but also by modifying Smad phosphorylation status. Previously we identified a kinase, Misshapen (Msn), that caused the linker phosphorylation of MAD, resulting in negative regulation of Dpp signaling (Drosophila BMP). In the third part of this thesis, I investigated the biological relevance of Msn kinase to Dpp signaling in Drosophila wings. Both over-expression and RNAi studies suggest that Msn is a negative regulator of the Dpp/MAD pathway in vivo. As a whole, my findings delineated two critical requirements for MAD nuclear import: the importin Msk and a unique subset of nucleoporins. For the first time, structural Nups are implicated in the direct involvement of cargo import, providing a unique trans-NPC mechanism

Mechanism and Regulation of Nucleocytoplasmic Trafficking of Smad

Smad proteins are the intracellular mediators of transforming growth factor β (TGF-β) signaling. Smads function as transcription factors and their activities require carboxyl-terminal phosphorylation by TGF-β receptor kinases which are embedded in the cell membrane. Therefore, the translocation of activated Smads from the cytoplasm into the nucleus is a rate-limiting step in TGF-β signal transduction into the nucleus. On the other hand, the export of Smads out of the nucleus turns off TGF-β effect. Such spatial control of Smad ensures a tight regulation of TGF-β target genes. Several cross-talk pathways have been shown to affect TGF-β signaling by impairing nuclear translocation of Smad, exemplifying the biological importance of the nuclear transport process. Many laboratories have investigated the underlying molecular mechanism of Smad nucleocytoplasmic translocation, combining genetics, biochemistry and sophisticated live cell imaging approaches. The last few years have witnessed the elucidation of several key players in Smad nuclear transport, most importantly the karyopherins that carry Smads across the nuclear envelope and nuclear pore proteins that facilitate the trans-nuclear envelope movement. The foundation is now set to further elucidate how the nuclear transport process is regulated and exploit such knowledge to manipulate TGF-β signaling. In this review we will discuss the current understanding of the molecular machinery responsible for nuclear import and export of Smads

How far is brain-inspired artificial intelligence away from brain?

Fueled by the development of neuroscience and artificial intelligence (AI), recent advances in the brain-inspired AI have manifested a tipping-point in the collaboration of the two fields. AI began with the inspiration of neuroscience, but has evolved to achieve a remarkable performance with little dependence upon neuroscience. However, in a recent collaboration, research into neurobiological explainability of AI models found that these highly accurate models may resemble the neurobiological representation of the same computational processes in the brain, although these models have been developed in the absence of such neuroscientific references. In this perspective, we review the cooperation and separation between neuroscience and AI, and emphasize on the current advance, that is, a new cooperation, the neurobiological explainability of AI. Under the intertwined development of the two fields, we propose a practical framework to evaluate the brain-likeness of AI models, paving the way for their further improvements

Improving Relationships by Elevating Positive Illusion and the Underlying Psychological and Neural Mechanisms

Romantic relationships are difficult to maintain novel and exciting for long periods of time, and individuals in love are known to engage in a variety of efforts to protect and maintain their romantic relationship. How to protect and maintain these relationships more effectively has, however, plagued people, psychologists, and therapists. Intimate partners typically perceive their relationship and their partners in a positive light or bias, a phenomenon called positive illusion. Interestingly, higher levels of positive illusion between partners have been associated with a decreased risk for relationship dissolution, as well as higher satisfaction, and less conflict or doubt in relationships. These findings indicate that elevating positive illusion amongst romantic partners may be of benefit and improve romantic relationships. In the present article, we discuss solving the paradox of positive illusion. As positive illusion may have relationship-enhancing attributes, we discuss the psychological and neural mechanisms that may underlie positive illusion. By elucidating the mechanisms underlying positive illusion, we shine a spotlight on potential future directions for research that aims to improve positive illusion and thus enhance the satisfaction and longevity of romantic relationships

Using Transcranial Alternating Current Stimulation (tACS) to Improve Romantic Relationships Can Be a Promising Approach

The romantic relationship refers to the specific relationship in which partners are dependent upon each other to obtain satisfactory outcomes and facilitate the pursuit of their most important needs and goals. Satisfying romantic relationships is a strong predictor of better psychological well-being, better physical health, and longer life expectancy. However, romantic relationships are not all smooth-sailing and lovers are often confronted with a variety of unavoidable issues that constantly challenge the stability of their romantic relationships. Dissatisfying romantic relationships are harmful and even destructive. Dyads of lovers engage in a variety of efforts to protect and maintain their romantic relationships based on qualitative research methods including theories- and psychological consultation-based approaches. Unfortunately, those existing approaches do not seem to effectively improve romantic relationships. Thus, it is necessary to seek an efficient approach regulating dyads of lovers in romantic relationships simultaneously. Transcranial alternating current stimulation (tACS) with advantages over existing approaches satisfies this purpose. We discuss the practicability of tACS in detail, as well as why and how tACS can be utilized to improve romantic relationships. In summary, this review firstly introduced the concept of romantic relationship and the necessity of enhancing it. Then, it discussed methods to improve romantic relationships including some existing approaches. This review next discussed the practicability of using tACS to improve romantic relationships. Finally, it shone a spotlight on potential future directions for researches aiming to improve romantic relationships

Neuroimaging Studies Reveal the Subtle Difference Among Social Network Size Measurements and Shed Light on New Directions

Social network size is a key feature when we explore the constructions of human social networks. Despite the disparate understanding of individuals’ social networks, researchers have reached a consensus that human’s social networks are hierarchically organized with different layers, which represent emotional bonds and interaction frequency. Social brain hypothesis emphasizes the significance of complex and demanding social interaction environments and assumes that the cognitive constraints may have an impact on the social network size. This paper reviews neuroimaging studies on social networks that explored the connection between individuals’ social network size and neural mechanisms and finds that Social Network Index (SNI) and Social Network Questionnaires (SNQs) are the mostly-adopted measurements of one’s social network size. The two assessments have subtle difference in essence as they measure the different sublayers of one’s social network. The former measures the relatively outer sub-layer of one’s stable social relationship, similar to the sympathy group, while the latter assesses the innermost layer—the core of one’s social network, often referred to as support clique. This subtle difference is also corroborated by neuroimaging studies, as SNI-measured social network size is largely correlated with the amygdala, while SNQ-assessed social network size is closely related to both the amygdala and the orbitofrontal cortex. The two brain regions respond to disparate degrees of social closeness, respectively. Finally, it proposes a careful choice among the measurements for specific purposes and some new approaches to assess individuals’ social network size

Msk is required for nuclear import of TGF-{beta}/BMP-activated Smads

Nuclear translocation of Smad proteins is a critical step in signal transduction of transforming growth factor beta (TGF-beta) and bone morphogenetic proteins (BMPs). Using nuclear accumulation of the Drosophila Smad Mothers against Decapentaplegic (Mad) as the readout, we carried out a whole-genome RNAi screening in Drosophila cells. The screen identified moleskin (msk) as important for the nuclear import of phosphorylated Mad. Genetic evidence in the developing eye imaginal discs also demonstrates the critical functions of msk in regulating phospho-Mad. Moreover, knockdown of importin 7 and 8 (Imp7 and 8), the mammalian orthologues of Msk, markedly impaired nuclear accumulation of Smad1 in response to BMP2 and of Smad2/3 in response to TGF-beta. Biochemical studies further suggest that Smads are novel nuclear import substrates of Imp7 and 8. We have thus identified new evolutionarily conserved proteins that are important in the signal transduction of TGF-beta and BMP into the nucleus

The Effect of the Irreversible Inequality on Pro-social Behaviors of People With Disabilities

Inequalities have always been central to psychology, sociology and related fields such as social policy, gender studies, critical race studies, and human geography. Although inequality affects pro-social behaviors, there are still some controversies over this issue among people with disabilities. The current study aimed to investigate pro-social behaviors of people with disabilities and the effect of the irreversible inequality on pro-social behaviors. A dictator game was used to explore the difference of pro-social behaviors between people with disabilities and people without disabilities, when facing intra- or inter-group members. The results showed that compared to people with disabilities, people without disabilities were likely to show more pro-social behaviors. People with disabilities preferred intra-group cooperation, while people without disabilities preferred inter-group cooperation. Indeed, the intra-group cooperation was significantly greater than the expected cooperation of the intra-group members for people with disabilities. When facing the inter-group members, people without disabilities showed more than expected, that others would cooperate with them. These findings indicated that social avoidance was a common phenomenon for people with disabilities in China, but the situation would be different when they faced different groups. In addition, irreversible inequality could influence individuals’ cooperative strategies when facing individuals in a different status