CD137L,a driver of harmful inflammation in the nervous system

CD137 (TNFRSF9,4-1BB) is a member of the tumor necrosis factor (TNF) receptor family and a potent costimulatory molecule.High levels of CD137 are expressed on T cells upon activation.CD137 signaling in T cells,either by cognate interaction with antigen-presenting cells (APC)or by agonistic anti-CD137 antibodies,strongly enhances proliferation,interferon-y secretion,and cytolytic activity of T cells.Thus,CD137 signaling is a main driver of cellular,type 1 helper T cells (Th1)and type 1 cytolytic T cells (Tc1) polarised immune responses.

Combination of NMR spectroscopy and X-ray crystallography offers unique advantages for elucidation of the structural basis of protein complex assembly

NMR spectroscopy and X-ray crystallography are two premium methods for determining the atomic structures of macro-biomolecular complexes.Each method has unique strengths and weaknesses.While the two techniques are highly complementary,they have generally been used separately to address the structure and functions of biomolecular complexes.In this review,we emphasize that the combination of NMR spectroscopy and X-ray crystallography offers unique power for elucidating the structures of complicated protein assemblies.We demonstrate,using several recent examples from our own laboratory,that the exquisite sensitivity of NMR spectroscopy in detecting the conformational properties of individual atoms in proteins and their complexes,without any prior knowledge of conformation,is highly valuable for obtaining the high quality crystals necessary for structure determination by X-ray crystallography.Thus NMR spectroscopy,in addition to answering many unique structural biology questions that can be addressed specifically by that technique,can be exceedingly powerful in modern structural biology when combined with other techniques including X-ray crystallography and cryo-electron microscopy.

Nat Biotechnol:将人星形胶质细胞重编程为多巴胺能神经元,有助治疗帕金森病

帕金森病是一种主要影响运动系统的神经退行性疾病。它的特征在于大脑中的多巴胺能神经元（dopaminergic neuron）渐进性丧失。尽管当前的疗法旨在补充多巴胺水平，但是没有一种疗法能够恢复这些丢失的细胞。如今。在一项新的研究中，来自瑞典、奥地利、西班牙和美国的研究人员开发出一种方法：将神经胶质细胞（glialcell）转化为活性的多巴胺能神经元，并且所产生的多巴胺能神经元能够部分恢复帕金森病模式小鼠的运动功能。这项概念验证研究可能为开发出一种治疗这种疾病的新方法铺平道路。

Extensions of PDZ domains as important structural and functional elements

‘Divide and conquer’has been the guiding strategy for the study of protein structure and function.Proteins are divided into domains with each domain having a canonical structural definition depending on its type.In this review,we push forward with the interesting observation that many domains have regions outside of their canonical definition that affect their structure and function;we call these regions‘extensions’.We focus on the highly abundant PDZ(PSD-95,DLG1 and ZO-1)domain.Using bioinformatics,we find that many PDZ domains have potential extensions and we developed an openly-accessible website to display our results(http://bcz102.ust.hk/pdzex/).We propose,using well-studied PDZ domains as illustrative examples,that the roles of PDZ extensions can be classified into at least four categories:1)protein dynamics-based modulation of target binding affinity,2)provision of binding sites for macro-molecular assembly,3)structural integration of multi-domain modules,and 4)expansion of the target ligand-binding pocket.Our review highlights the potential structural and functional importance of domain extensions,highlighting the significance of looking beyond the canonical boundaries of protein domains in general.

Defining activation states of microglia in human brain tissue: an unresolved issue for Alzheimer's disease

The development of concepts concerning the role of microglia in different brain diseases has relied on studies of animal models or human brain tissue,which primarily use antibodies and immunohistochemistry techniques to make observations.Since initial studies defined increased expression of the major histocompatibility complexⅡprotein human leukocyte antigen-DR as a means of identifying reactive,and therefore by implication,damage-causing microglia in Alzheimer's disease(AD)or Parkinson's disease(PD),understanding and describing their activation states has evolved to an unexpected complexity.It is still difficult to ascertain the specific functions of individual microglia,particularly those associated with pathological structures,using a narrow range of antigenic markers.As many approaches to developing treatments for AD or PD are focused on anti-inflammatory strategies,a more refined understanding of microglial function is needed.In recent years,gene expression studies of human and rodent microglia have attempted to add clarity to the issue by sub-classification of messenger RNA expression of cell-sorted microglia to identify disease-associated profiles from homeostatic functions.Ultimately all newly identified markers will need to be studied in situ in human brain tissue.This review will consider the gaps in knowledge between using traditional immunohistochemistry approaches with small groups of markers that can be defined with antibodies,and the findings from cell-sorted and single-cell RNA sequencing transcription profiles.There have been three approaches to studying microglia in tissue samples:using antigenic markers identified from studies of peripheral macrophages,studying proteins associated with altered genetic risk factors for disease,and studying microglial proteins identified from mRNA expression analyses from cell-sorting and gene profiling.The technical aspects of studying microglia in human brain samples,inherent issues of working with antibodies,and findings of a range of different functional microglial markers will be reviewed.In particular,we will consider markers of microglia with expression profiles that do not definitively fall into the pro-inflammatory or anti-inflammatory classification.These additional markers include triggering receptor expressed on myeloid cells-2,CD33 and progranulin,identified from genetic findings,colony stimulating factor-1 receptor,purinergic receptor P2RY12,CD68 and Toll-like receptors.Further directions will be considered for addressing crucial issues.

High-resolution two-photon transcranial imaging of brain using direct wavefront sensing

Imaging of the brain in its native state at high spatial resolution poses major challenges to visualization techniques.Two-photon microscopy integrated with the thinned-skull or optical clearing skull technique provides a minimally invasive tool for in vivo imaging of the cortex of mice without activating immune response and inducing brain injury.However,the imaging contrast and spatial resolution are severely compromised by the optical heterogeneity of the skull,limiting the imaging depth to the superficial layer.In this work,an optimized configuration of an adaptive optics two-photon microscope system and an improved wavefront sensing algorithm are proposed for accurate correction for the aberrations induced by the skull window and brain tissue.Using this system,we achieved subcellular resolution transcranial imaging of layer 5 pyramidal neurons up to 700μm below pia in living mice.In addition,we investigated microglia–plaque interaction in living brain of Alzheimer’s disease and demonstrated high-precision laser dendrotomy and single-spine ablation.

Nlrc3-like is required for microglia maintenance in zebrafish

Microglia are tissue-resident macrophages residing in the central nervous system (CNS) and play critical roles in removing cellular debris and infectious agents as well as regulating neurogenesis and neuronal activities. Yet, the molecular basis underlying the establishment of microglia pool and the maintenance of their homeostasis in the CNS remain largely undefined. Here we report the identification and characterization of a mutant zebrafish, which harbors a point mutation in the nucleotide-binding oligomerization domain (NOD) like receptor gene nlrc3-like, resulting in the loss of microglia in a temperature sensitive manner. Temperature shift assay reveals that the late onset of nlrc3-like deficiency leads to excessive microglia cell death. Further analysis shows that the excessive microglia death in nlrc3-like deficient mutants is attributed, at least in part, to aberrant activation of canonical inflammasome pathway. Our study indicates that proper regulation of inflammasome cascade is critical for the maintenance of microglia homeostasis.

Tissue-resident macrophages: from zebrafish to mouse

Tissue-resident macrophages(TRMs),generally found in tissues under normal physiological conditions,play crucial roles not only in immunity but also in tissue development and homeostasis.Because of their diverse functions,dysregulation of their development and function has been implicated in many human disorders.In the past decade,a great deal of extensive studies have been conducted in various model organisms with cutting-edge technologies to explore the origin and function of TRMs.In this review,we summarize the recent findings on TRMs in mouse and zebrafish and compare the similarity/differences between these two species.

The p(l)ot thickens:cannabinoid receptors on astroglial mitochondria coordinate animal behaviors by regulating lactate availability for neurons

The coordinated interplay between neurons and astroglia,the latter producing essential metabolic precursors for neurons,is critical for the precision of neurotransmission in the execution of specific behaviors.Most recently,Jimenez-Blasco et al.1 identified CB1 cannabinoid receptors in astroglial mitochondria as gatekeepers of lactate production by regulating the stability of mitochondrial complex I through the hypoxia-inducible factor-1 pathway and thus,metabolically tuning neurons that control social behaviors.