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<jats:sec> <jats:title>INTRODUCTION</jats:title> <jats:p>Parkinson’s disease (PD) is the second most common neurodegenerative disorder and leads to slowness of movement, tremor, rigidity, and, in the later stages of PD, cognitive impairment. Pathologically, PD is characterized by the accumulation of α-synuclein in Lewy bodies and neurites. There is degeneration of neurons throughout the nervous system, with the degeneration of dopamine neurons in the substantia nigra pars compacta leading to the major symptoms of PD.</jats:p> </jats:sec> <jats:sec> <jats:title>RATIONALE</jats:title> <jats:p>In the brains of PD patients, pathologic α-synuclein seems to spread from cell to cell via self-amplification, propagation, and transmission in a stereotypical and topographical pattern among neighboring cells and/or anatomically connected brain regions. The spread or transmission of pathologic α-synuclein is emerging as a potentially important driver of PD pathogenesis. The underlying mechanisms and molecular entities responsible for the transmission of pathologic α-synuclein from cell to cell are not known, but the entry of pathologic α-synuclein into neurons is thought to occur, in part, through an active clathrin-dependent endocytic process.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p>Using recombinant α-synuclein preformed fibrils (PFF) as a model system with which to study the transmission of misfolded α-synuclein from neuron to neuron, we screened a library encoding transmembrane proteins for α-synuclein-biotin PFF–binding candidates via detection with streptavidin-AP (alkaline phosphatase) staining. Three positive clones were identified that bind α-synuclein PFF and include lymphocyte-activation gene 3 (LAG3), neurexin 1β, and amyloid β precursor-like protein 1 (APLP1). Of these three transmembrane proteins, LAG3 demonstrated the highest ratio of selectivity for α-synuclein PFF over the α-synuclein monomer. α-Synuclein PFF bind to LAG3 in a saturable manner (dissociation constant = 77 nM), whereas the α-synuclein monomer does not bind to LAG3. Co-immunoprecipitation also suggests that pathological α-synuclein PFF specifically bind to LAG3. Tau PFF, β-amyloid oligomer, and β-amyloid PFF do not bind to LAG3, indicating that LAG3 is specific for α-synuclein PFF. The internalization of α-synuclein PFF involves LAG3 because deletion of LAG3 reduces the endocytosis of α-synuclein PFF. LAG3 colocalizes with the endosomal guanosine triphosphatases Rab5 and Rab7 and coendocytoses with pathologic α-synuclein. Neuron-to-neuron transmission of pathologic α-synuclein and the accompanying pathology and neurotoxicity is substantially attenuated by deletion of LAG3 or by antibodies to LAG3. The lack of LAG3 also substantially delayed α-synuclein PFF–induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo.</jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSION</jats:title> <jats:p>We discovered that pathologic α-synuclein transmission and toxicity is initiated by binding to LAG3 and that neuron-to-neuron transmission of pathological α-synuclein involves the endocytosis of exogenous α-synuclein PFF by the engagement of LAG3 on neurons. Depletion of LAG3 or antibodies to LAG3 substantially reduces the pathology set in motion by the transmission of pathologic α-synuclein. The identification of LAG3 as an α-synuclein PFF–binding protein provides a new target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies.</jats:p> <jats:fig fig-type="figure" orientation="portrait" position="float"> <jats:caption> <jats:title>LAG3 deletion or antibodies to LAG3 delay α-synuclein PFF transmission.</jats:title> <jats:p>Compared with wild-type neurons, binding and endocytosis of α-synuclein PFF is dramatically reduced with antibodies to LAG3 or when LAG3 is deleted, resulting in delayed pathologic α-synuclein transmission and toxicity. Illustration credit: I-Hsun Wu</jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="353_aah3374_fa.jpeg" /> </jats:fig> </jats:sec>

<jats:sec> <jats:title>BACKGROUND</jats:title> <jats:p>Three-dimensional (3D) printing, known more formally as additive manufacturing, has become the focus of media and public attention in recent years as the decades-old technology has at last approached the performance necessary for direct production of end-use devices. The most popular forms of standard 3D printing include vat photopolymerization, powder bed fusion, material extrusion, sheet lamination, directed energy deposition, material jetting, and binder jetting, each creating parts layer by layer and offering different options in terms of cost, feature detail, and materials. Whereas traditional manufacturing technologies, such as casting, forging, machining, and injection molding, are well suited for mass production of identical commodity items, 3D printing allows for the creation of complex geometric shapes that can be mass-customized, because no die or mold is required and design concepts are translated into products through direct digital manufacturing. Furthermore, the additively layered approach enables the merging of multiple components into a single piece, which removes the requirement for subsequent assembly operations. Recently, the patents for the original 3D printing processes have begun to expire, which is resulting in a burgeoning number of low-cost desktop systems that provide increased accessibility to society at large. Industry has recognized the manufacturing advantages of these technologies and is investing in production systems to make complex components for jet engines, customized bodies for cars, and even pharmaceuticals. Although standard 3D printing technologies have advanced so that it is now possible to print in a wide range of materials including metals, ceramics, and polymers, the resulting structures are generally limited to a single material, or, at best, a limited number of compatible materials.</jats:p> </jats:sec> <jats:sec> <jats:title>ADVANCES</jats:title> <jats:p>For the technology to become more widely adopted in mainstream manufacturing, 3D printing must provide end-use products by fabricating more than just simple structures with sufficient mechanical strength to retain shape. Recently, research has resulted in the capability to use new materials with commercial 3D printers, and customized printers have been enhanced with complementary traditional manufacturing processes, an approach known as multiprocess or hybrid 3D printing. Collectively, these advancements are leading to fabrications that are not only geometrically complex, but functionally complex as well. By introducing the robotic placement of components, micromachining for intricate detail, embedding of wires, and dispensing of functional inks, complex structures can be constructed with additional electronic, electromagnetic, optical, thermodynamic, chemical, and electromechanical content.</jats:p> </jats:sec> <jats:sec> <jats:title>OUTLOOK</jats:title> <jats:p>Multiprocess 3D printing is a nascent area of research in which basic 3D printing is augmented to fabricate structures with multifunctionality. Progress will lead to local manufacturing with customized 3D spatial control of material, geometry, and placement of subcomponents. This next generation of printers will allow for the fabrication of arbitrarily shaped end-use devices, leading to direct and distributed manufacturing of products ranging from human organs to satellites. The ramifications are substantial, given that 3D printing will enable the fabrication of customer-specific products locally and on demand, improving personalization and reducing shipping costs and delays. Examples could include replacement components for grain-milling equipment in a remote village in the developing world, biomedical devices created specifically for a patient in a hospital before surgery, and satellite components printed in orbit, thus avoiding the delays and costs associated with launch operations. The automotive, aerospace, defense, pharmaceutical, biomedical, and consumer industries, among others, will benefit from the new design and manufacturing freedom made possible by multiprocess 3D printing.</jats:p> <jats:fig fig-type="figure" orientation="portrait" position="float"> <jats:caption> <jats:title>A long-exposure photo of the Multi3D Manufacturing system for multiprocess 3D printing.</jats:title> <jats:p>Two production 3D printers are shown collaboratively printing, with a six-axis robot for conveyance and postprocess assembly. A central gantry in the background incorporatates other complementary manufacturing processes (machining, component placement, wire and foil embedding, and direct write) to provide geometrically complex structures combining polymers, metals, and active components.</jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="353_aaf2093_fa.jpeg" /> </jats:fig> </jats:sec>

<jats:sec> <jats:title>INTRODUCTION</jats:title> <jats:p>Cancer arises from clonal expansion of a single cell. Yet, most human cancers are characterized by extensive intratumor heterogeneity and comprise various subpopulations of cells with distinct phenotypes and biological properties. Intratumor heterogeneity poses major challenges in understanding cancers, managing patients, and designing effective treatment strategies. Functional heterogeneity within individual tumors is partly due to the presence of genetically distinct subclonal cell populations. Furthermore, interactions between cancer cells and the tumor microenvironment can alter the phenotype of cancer cells via nongenetic mechanisms. The combination of cell-intrinsic and cell-extrinsic changes occurring during tumor growth generates functionally distinct subsets of cells that differentially contribute to tumor maintenance.</jats:p> </jats:sec> <jats:sec> <jats:title>RATIONALE</jats:title> <jats:p>In many cancers, phenotypic and functional heterogeneity can be mapped to distinct differentiation states, suggesting that cellular hierarchies established during tumor growth may affect the long-term proliferative potential of cancer cells. To shed light on the mechanisms responsible for the generation of these hierarchies, we searched for epigenetic mechanisms that determine which cancer cells can preserve unlimited proliferative potential, and thus the ability to drive long-term tumor growth, and which cells lose this ability through a differentiation process.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p> We found that, in several cancer types, individual tumors exhibit high heterogeneity of the major chromatin protein linker histone H1.0, showing strongly reduced H1.0 levels in cells characterized by long-term self-renewal ability and tumorigenic potential and higher levels in nontumorigenic cells. Combined analysis of pan-cancer patient data sets and experimental alteration of the <jats:italic>H1F0</jats:italic> locus in tumor cells revealed that heterogeneous H1.0 expression patterns are partly due to differential methylation of an enhancer region that dynamically modulates H1.0 expression within tumors. Using a controlled system to model functional intratumor heterogeneity, we showed that maintenance of cell tumorigenic potential required silencing of H1.0 to avoid loss of unlimited proliferative capacity through differentiation. Mechanistically, absence of H1.0 led to destabilization of nucleosome-DNA interactions in AT-rich genomic regions and coordinated derepression of large sets of neighboring genes, resulting in activation of transcriptional programs that support cancer cell self-renewal. Gene expression changes induced by H1.0 loss were reversible, and epigenetic states restricting cell proliferative potential were reestablished upon H1.0 reexpression. In multiple cancer types, in agreement with the observed inhibition of cancer cell self-renewal by H1.0, patients expressing overall strongly reduced levels of H1.0 showed a significantly worse outcome than patients expressing higher H1.0 levels. </jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSION</jats:title> <jats:p>Intratumor heterogeneity has emerged as a general feature of cancer, but the molecular features underlying functionally diverse cellular phenotypes have been elusive. Our results uncover epigenetic determinants of tumor-maintaining cells and identify an integral component of chromatin as an important regulator of cell differentiation states within tumors. We propose that only cells insensitive to extracellular differentiation cues, capable of permanently silencing H1.0, can act as self-renewing tumor-maintaining cells and that such a mechanism supports maintenance of several types of cancer. Our results suggest that intervention aimed at restoring high levels of H1.0 in all cancer cells may enhance the differentiation process that naturally occurs during tumor growth and may be beneficial for therapeutic purposes.</jats:p> <jats:fig fig-type="figure" orientation="portrait" position="float"> <jats:caption> <jats:title>Epigenetic heterogeneity within tumors.</jats:title> <jats:p> In many cancer types, self-renewing and differentiated epigenetic states coexist in individual tumors. ( <jats:bold>Left</jats:bold> ) Image of a breast cancer section showing heterogeneous levels of the linker histone H1.0 (red). ( <jats:bold>Right</jats:bold> ) Schematic depiction of the chromatin status of cancer cells in which H1.0 is down-regulated (blue) or expressed at high levels (red). </jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="353_aaf1644_Fa" /> </jats:fig> </jats:sec>

<jats:p>Last week, Priscilla Chan and Mark Zuckerberg announced their new philanthropic initiative with the goal of “curing, preventing, and managing all diseases by the end of the century.” This may raise some eyebrows, but this effort—part of the $45 billion Chan Zuckerberg Initiative—joins forces with other philanthropists to push the envelope and support audacious ideas, with long-term commitments, to solve some of our greatest challenges.</jats:p>

<jats:p>A roundup of weekly science policy and related news.</jats:p>

<jats:p>NASA's aging radio antennas have faced years of budget cuts, threatening far-off spacecraft.</jats:p>

<jats:p>Barry Barish assembled the gravitational wave detectors but hasn't shared the glory.</jats:p>

<jats:p>Scientists urge Trudeau government to adopt stronger rules for project reviews.</jats:p>

<jats:p>New foundation will fund peer-reviewed grants, but scientists fear that it won't bail them out of crisis.</jats:p>