Drosophila Spastin Regulates Synaptic Microtubule Networks and Is Required for Normal Motor Function

Nina Tang Sherwood is with California Institute of Technology, Qi Sun is with California Institute of Technology, Mingshan Xue is with UT Austin, Bing Zhang is with UT Austin, Kai Zinn is with California Institute of Technology.The most common form of human autosomal dominant hereditary spastic paraplegia (AD-HSP) is caused by mutations in the SPG4 (spastin) gene, which encodes an AAA ATPase closely related in sequence to the microtubule-severing protein Katanin. Patients with AD-HSP exhibit degeneration of the distal regions of the longest axons in the spinal cord. Loss-of-function mutations in the Drosophila spastin gene produce larval neuromuscular junction (NMJ) phenotypes. NMJ synaptic boutons in spastin mutants are more numerous and more clustered than in wild-type, and transmitter release is impaired. spastin-null adult flies have severe movement defects. They do not fly or jump, they climb poorly, and they have short lifespans. spastin hypomorphs have weaker behavioral phenotypes. Overexpression of Spastin erases the muscle microtubule network. This gain-of-function phenotype is consistent with the hypothesis that Spastin has microtubule-severing activity, and implies that spastin loss-of-function mutants should have an increased number of microtubules. Surprisingly, however, we observed the opposite phenotype: in spastin-null mutants, there are fewer microtubule bundles within the NMJ, especially in its distal boutons. The Drosophila NMJ is a glutamatergic synapse that resembles excitatory synapses in the mammalian spinal cord, so the reduction of organized presynaptic microtubules that we observe in spastin mutants may be relevant to an understanding of human Spastin's role in maintenance of axon terminals in the spinal cord.Biological Sciences, School o

Functional divergence of the rapidly evolving miR-513 subfamily in primates

BACKGROUND: The miR-513 subfamily belongs to an X-linked primate-specific miR506-514 cluster. Across primate species, there have been several duplication events and different species each possess a variety of miR-513 copies, indicating it underwent rapid evolution. Evidence suggests that this subfamily is preferentially expressed in the testis, but otherwise, to date, the evolutionary history and functional significance of this miRNA subfamily has remained largely unexplored. RESULTS: We analyzed the evolutionary pattern of gene duplications and their functional consequence for the miR-513 subfamily in primates. Sequence comparisons showed that the duplicated copies of miR-513 were derived from transposable element (MER91C). Moreover, duplication events of the miR-513 subfamily seem to have occurred independently in Platyrrhini (New World monkeys) and Catarrhini (Old World monkeys, apes and humans) after they diverged. Different copies of the miR-513 subfamily (miR-513a/b/c) have different seed sequences, due to after-duplication sequence divergences, which eventually led to functional divergences. The results of functional assays indicated that miR-513b could inhibit the expression of its target gene, the down-regulator of transcription 1 (DR1) at both the mRNA and protein levels. In the developing testis of rhesus macaques, we observed a temporal coupling of expression levels between miR-513b and DR1, suggesting that miR-513b could affect male sexual maturation by negatively regulating the development-stage related functioning of DR1. CONCLUSIONS: The miR-513 subfamily underwent multiple independent gene duplications among five different lineages of primates. The after-duplication sequence divergences among the different copies of miR-513 led to functional divergence of these copies in primates

Learning Symbolic Model-Agnostic Loss Functions via Meta-Learning

In this paper, we develop upon the emerging topic of loss function learning, which aims to learn loss functions that significantly improve the performance of the models trained under them. Specifically, we propose a new meta-learning framework for learning model-agnostic loss functions via a hybrid neuro-symbolic search approach. The framework first uses evolution-based methods to search the space of primitive mathematical operations to find a set of symbolic loss functions. Second, the set of learned loss functions are subsequently parameterized and optimized via an end-to-end gradient-based training procedure. The versatility of the proposed framework is empirically validated on a diverse set of supervised learning tasks. Results show that the meta-learned loss functions discovered by the newly proposed method outperform both the cross-entropy loss and state-of-the-art loss function learning methods on a diverse range of neural network architectures and datasets

Study of qqqqˉQqqq\bar{q}Q pentaquark system in the Chiral Quark Model

With the discovery of some hidden-charm pentaquark resonances by the LHCb Collaboration, investigations of pentaquark states containing heavy quarks have aroused the interest of theorists. We study herein $qqq\bar{q}Q$ ($q = u$ or $d$, $Q=c$ or $b$) pentaquark system, in the framework of the chiral quark model. In consequence, some charmed and bottomed pentaquarks are considered to exist by five-body dynamical calculations. In the charm sector, $\Sigma_c\pi(IJ^P=0\frac{1}{2}^-)$ and $\Sigma_c^*\pi(IJ^P=0\frac{3}{2}^-)$ are possible candidates of $\Lambda_c(2595)$ and $\Lambda_c(2625)$, respectively. Besides, two high-spin states, $\Sigma_c^*\rho(IJ^P=0\frac{5}{2}^-)$ and $\Delta D^*(IJ^P=1\frac{5}{2}^-)$, are also found in the energy region of $3.2 \sim 3.3$ GeV. In the bottom sector, $\Sigma_b\pi(IJ^P=0\frac{1}{2}^-)$, $\Sigma_b^*\pi(IJ^P=0\frac{3}{2}^-)$ could be candidates of $\Lambda_b(5912)$ and $\Lambda_b(5920)$, respectively. And $\Sigma_b^*\rho(IJ^P=0\frac{5}{2}^-)$ and $\Delta B^*(IJ^P=1\frac{5}{2}^-)$ are found in the energy region of $6.5 \sim 6.6$ GeV. $\Sigma_c^{(*)}\pi$ and $\Sigma_b^{(*)}\pi$ are expected as compact states, while $\Sigma_c^*\rho$, $\Sigma_b^*\rho$, $\Delta D^*$ and $\Delta B^*$ are expected as molecular states.Comment: 11 pages, 1 figur

Glycogen Synthase Kinase 3β Regulates IRF3 Transcription Factor-Mediated Antiviral Response via Activation of the Kinase TBK1

SummaryViral infection activates transcription factors IRF3 and NF-κB, which collaborate to induce type I interferons (IFNs). Here, we identified glycogen synthase kinase 3β (GSK3β) as an important regulator for virus-triggered IRF3 and NF-κB activation, IFN-β induction, and cellular antiviral response. Overexpression of GSK3β potentiated virus-induced activation of IRF3 and transcription of the IFNB1 gene, whereas reduced expression or deletion of GSK3β impaired virus-induced IRF3 and NF-κB activation, transcription of the IFNB1 gene, as well as cellular antiviral response. GSK3β physically associated with the kinase TBK1 in a viral infection-dependent manner. GSK3β promoted TBK1 self-association and autophosphorylation at Ser172, which is critical for virus-induced IRF3 activation and IFN-β induction. The effect of GSK3β on virus-induced signaling is independent of its kinase activity. Our findings suggest that GSK3β plays important roles in virus-triggered IRF3 activation by promoting TBK1 activation and provide new insights to the molecular mechanisms of cellular antiviral response