Protein structuromics: A new method for protein structure-function crosstalk in glioma.

Glioma is a type of tumor that starts in the glial cells of the brain or spine. Since the 1800s, when the disease was first named, its survival rates have always been unsatisfactory. Despite great advances in molecular biology and traditional treatment methods, many questions regarding cancer occurrence and the underlying mechanism remain to be answered. In this study, we assessed the protein structural features of 20 oncogenes and 20 anti-oncogenes via protein structure and dynamic analysis methods and 3D structural and systematic analyses of the structure-function relationships of proteins. All of these results directly indicate that unfavorable group proteins show more complex structures than favorable group proteins. As the tumor cell microenvironment changes, the balance of oncogene-related and anti-oncogene-related proteins is disrupted, and most of the structures of the two groups of proteins will be disrupted. However, more unfavorable group proteins will maintain and refold to achieve their correct shape faster and perform their functions more quickly than favorable group proteins, and the former thus support cancer development. We hope that these analyses will help promote mechanistic research and the development of new treatments for glioma.

Engaged decision-makers align spontaneous movements to stereotyped task demands.

Neural activity during sensory-guided decision-making is strongly modulated by animal movements. Although the impact of movements on neural activity is now well-documented, the relationship between these movements and behavioral performance remains unclear. To understand this relationship, we first tested whether the magnitude of animal movements (assessed with posture analysis of 28 individual body parts) was correlated with performance on a perceptual decision-making task. No strong relationship was present, suggesting that task performance is not affected by the magnitude of movements. We then tested if performance instead depends on movement timing and trajectory. We partitioned the movements into two groups: task-aligned movements that were well predicted by task events (such as the onset of the sensory stimulus or choice) and task independent movement (TIM) that occurred independently of task events. TIM had a reliable, inverse correlation with performance in head-restrained mice and freely moving rats. This argues that certain movements, defined by their timing and trajectories relative to task events, might indicate periods of engagement or disengagement in the task. To confirm this, we compared TIM to the latent behavioral states recovered by a hidden Markov model with Bernoulli generalized linear model observations (GLM-HMM) and found these, again, to be inversely correlated. Finally, we examined the impact of these behavioral states on neural activity measured with widefield calcium imaging. The engaged state was associated with widespread increased activity, particularly during the delay period. However, a linear encoding model could account for more overall variance in neural activity in the disengaged state. Our analyses demonstrate that this is likely because uninstructed movements had a greater impact on neural activity during disengagement. Taken together, these findings suggest that TIM is informative about the internal state of engagement, and that movements and state together have a major impact on neural activity.

Structure-function crosstalk in liver cancer research: Protein structuromics.

Liver cancer can be primary (starting in the liver) or secondary (cancer that has spread from elsewhere to the liver, known as liver metastasis). Liver metastasis is more common than primary liver cancer. Despite great advances in molecular biology methods and treatments, liver cancer is still associated with a poor survival rate and a high death rate, and there is no cure. Many questions remain regarding the mechanisms of liver cancer occurrence and development as well as tumor reoccurrence after treatment. In this study, we assessed the protein structural features of 20 oncogenes and 20 anti-oncogenes via protein structure and dynamic analysis methods and 3D structural and systematic analyses of the structure-function relationships of proteins. Our aim was to provide new insights that may inform research on the development and treatment of liver cancer.

Pyramidal cell types drive functionally distinct cortical activity patterns during decision-making.

Understanding how cortical circuits generate complex behavior requires investigating the cell types that comprise them. Functional differences across pyramidal neuron (PyN) types have been observed within cortical areas, but it is not known whether these local differences extend throughout the cortex, nor whether additional differences emerge when larger-scale dynamics are considered. We used genetic and retrograde labeling to target pyramidal tract, intratelencephalic and corticostriatal projection neurons and measured their cortex-wide activity. Each PyN type drove unique neural dynamics, both at the local and cortex-wide scales. Cortical activity and optogenetic inactivation during an auditory decision task revealed distinct functional roles. All PyNs in parietal cortex were recruited during perception of the auditory stimulus, but, surprisingly, pyramidal tract neurons had the largest causal role. In frontal cortex, all PyNs were required for accurate choices but showed distinct choice tuning. Our results reveal that rich, cell-type-specific cortical dynamics shape perceptual decisions.

Cbln1 regulates axon growth and guidance in multiple neural regions.

The accurate construction of neural circuits requires the precise control of axon growth and guidance, which is regulated by multiple growth and guidance cues during early nervous system development. It is generally thought that the growth and guidance cues that control the major steps of axon development have been defined. Here, we describe cerebellin-1 (Cbln1) as a novel cue that controls diverse aspects of axon growth and guidance throughout the central nervous system (CNS) by experiments using mouse and chick embryos. Cbln1 has previously been shown to function in late neural development to influence synapse organization. Here, we find that Cbln1 has an essential role in early neural development. Cbln1 is expressed on the axons and growth cones of developing commissural neurons and functions in an autocrine manner to promote axon growth. Cbln1 is also expressed in intermediate target tissues and functions as an attractive guidance cue. We find that these functions of Cbln1 are mediated by neurexin-2 (Nrxn2), which functions as the Cbln1 receptor for axon growth and guidance. In addition to the developing spinal cord, we further show that Cbln1 functions in diverse parts of the CNS with major roles in cerebellar parallel fiber growth and retinal ganglion cell axon guidance. Despite the prevailing role of Cbln1 as a synaptic organizer, our study discovers a new and unexpected function for Cbln1 as a general axon growth and guidance cue throughout the nervous system.

Evidence accumulation occurs locally in the parietal cortex.

Decision making often entails evidence accumulation, a process that is represented by neural activities in a network of multiple brain areas. Yet, it has not been identified where exactly the accumulation originates. We reason that a candidate brain area should both represent evidence accumulation and information that is used to compute evidence. Therefore, we designed a two-stage probabilistic reasoning task in which the evidence for accumulation had to be first determined from sensory signals orthogonal to decisions. With a linear encoding model, we decomposed the responses of posterior parietal neurons to each stimulus into an early and a late component that represented two dissociable stages of decision making. The former reflected the transformation from sensory inputs to accumulable evidence, and the latter reflected the accumulation of evidence and the formation of decisions. The presence of both computational stages indicates that evidence accumulation signal in the parietal cortex is computed locally.

Genome-Wide Identification and Characterization of JAZ Protein Family in Two Petunia Progenitors.

Jasmonate ZIM-domain (JAZ) family proteins are the key repressors in the jasmonate signaling pathway and play crucial roles in plant development, defenses, and responses to stresses. However, our knowledge about the JAZ protein family in petunia is limited. This research respectively identified 12 and 16 JAZ proteins in two Petunia progenitors, Petunia axillaris and Petunia inflata. Phylogenetic analysis showed that the 28 proteins could be divided into four groups (Groups A-D) and further classified into six subgroups (A1, A2, B1, B3, C, and D1); members in the same subgroup shared some similarities in motif composition and sequence structure. The Ka/Ks ratios of seven paralogous pairs were less than one, suggesting the petunia JAZ family might have principally undergone purifying selection. Quantitative real-time PCR (qRT-PCR) analysis revealed that PaJAZ genes presented differential expression patterns during the development of flower bud and anther in petunia, and the expression of PaJAZ5, 9, 12 genes was generally up-regulated after MeJA treatment. Subcellular localization assays demonstrated that proteins PaJAZ5, 9, 12 were localized in nucleus. Yeast two hybrid (Y2H) elucidated most PaJAZ proteins (PaJAZ1-7, 9, 12) might interact with transcription factor MYC2. This study provides insights for further investigation of functional analysis in petunia JAZ family proteins.

An anther-specific gene PhGRP is regulated by PhMYC2 and causes male sterility when overexpressed in petunia anthers.

KEY MESSAGE: An anther-specific GRP gene, regulated by PhMYC2 , causes a significant reduction of male fertility when overexpressed in petunia, and its promoter is efficient in genetic engineering of male-sterile lines. Glycine-rich proteins (GRPs) play important roles in plant anther development; however, the underlying mechanisms and related regulatory networks are poorly understood. In this study, a novel glycine-rich family gene designated as PhGRP was isolated from Petunia hybrida 'Fantasy Red'. The qRT-PCR analysis showed that it expressed specifically in anthers, and its expression peaked earlier than those well-known tapetum-specific genes, such as TA29, and several genes with the classic cis-regulatory element 'anther-box' in petunia during its anther development. The male fertility was significantly reduced in PhGRP overexpression lines, due to the abnormal formation of pollen wall. The PhGRP promoter (pPhGRP) could drive the GUS genes expressing specifically in the anthers of the transgenic Arabidopsis plants, indicating that the anther-specific characteristic of this promoter was conserved. In addition, when pPhGRP was used to drive the expression of BARNASE, complete male-sterile petunia lines were created without changes in vegetative organs and floral parts other than anthers. Finally, when pPhGRP was used as the bait to screen a yeast-one-hybrid (Y1H) library, a transcription factor (PhMYC2) belonging to the bHLH family was successfully selected, and the binding between pPhGRP and PhMYC2 was validated both by Y1H and dual-luciferase reporter assay. Overall, these results suggest that PhGRP, which is a male fertility-related gene that expresses specifically in anthers, is regulated by PhMYC2 and whose promoter can be used as an effective tool in the creation of male-sterile lines.