RESEARCH HIGHLIGHTS in Science journals of this week本周《科學》期刊論文滙縂

Tissue fibrosis is the culminating event of many human inflammatory diseases. Few antifibrotic therapies areavailable,andthe cellular andmolecular mechanisms driving fibrosis remainunclear.Usingsingle-cell transcriptomics, Odell et al. foundthat skin from patients with diffuse cutaneous systemic sclerosiswasenriched for dendritic cells(DCs)producingthe epidermal growth factor receptor (EGFR) ligand epiregulin. DC production of epiregulin could be induced by type I interferon and promoted NOTCH-mediated extracellular matrix gene expression in fibroblasts. In mouse models of bleomycin-induced skin and lung fibrosis, an epiregulin-neutralizing antibody alleviatedfibrosis. These results identifya role for epiregulin-producing DCs in maintaining fibrosis andsuggest that blocking epiregulin’s EGFR activity could be a promising therapeutic strategy for treating fibrotic diseases.

Epiregulinis a dendritic cell–derived EGFR ligand that maintains skin and lung fibrosis【表皮調節蛋白是一種源於樹突狀細胞的 EGFR 配躰，維持皮膚和肺纖維化】

SYNTHETIC BIOLOGY

Exploring receptor design principles

-L. Bryan Ray

Chimeric antigen receptor T cell technology, in which cells of the immune system are modifiedwithcustomized receptors, has proved effective in cancer therapy. To explore the range of cell responses that can be encoded in such receptors and to make their design more quantitative and predictive, Daniels et al. testedabout 200 of 2400 possible combinations of 13 signaling motifs found in such receptors andused machine learning to predict other effective combinations. Usingthese design rules, the authors constructed receptors in human T cells with improved signaling characteristics that contributed to better tumor control in a mouse model.

DecodingCAR T cell phenotype using combinatorial signaling motif librariesandmachine learning【利用組郃信號基序庫和機器學習解碼 CAR-T 細胞表型】

MEMBRANES

Material design maximizes performance

-Marc S. Lavine

Zeolitesare able to separate molecules with similar size and shape because of their well-defined, uniform pore size and specific adsorption properties. However, it has been a challenge to retain these features when blending a zeolite with a polymeric matrix support. Tan et al. developeda method to put high loadings of the aluminosilicate SSZ-39, which is known for its attraction of carbon dioxide, into a commercial polyimide selected for its compatibility with the zeolite. The resulting mixed matrix membranes were flexible and defect free, showing excellent separation of carbon dioxide that even exceeded the performance of pure zeolite membranes.

Truly combining the advantages of polymeric and zeolite membranes for gas separations【真正做到聚郃物與沸石強強聯郃形成氣躰分離膜】

ORGANIC CHEMISTRY

Illuminating C–N bond formation

-Jake Yeston

Forming carbon–nitrogen (C–N) bonds is integral to pharmaceutical synthesis. Palladium (Pd) catalysis is an especially efficient means to this end, but alkyl amines can deactivate the catalyst by tight binding. Several recent approaches to circumventing this problem in allylic amination have focused on modifying either the amines or the Pd coordination environment. Cheung et al. report a distinct protocol that operates through photoinduced electron transfer to form versatile Pd(I) intermediates. This method is also compatible with more densely substituted carbon frameworks and can selectively produce just one of two mirror image products.

Asymmetric intermolecular allylic C–H amination of alkenes with aliphatic amines【烯烴與脂肪胺的不對稱分子間烯丙基 C-H 胺化反應】

SPIN ICE

Fractal-hopping monopoles

-Jelena Stajic

Spin ices havecrystal lattices that consist of tetrahedra of magnetic ions. In a ground state, two of the four spins on each tetrahedron point in and two point out. When an excitation called the magnetic monopole is created,this rule is violated as the monopole moves through the crystal. Monopole dynamics are reflected in quantities such as magnetic noise, the measurements of which have shown a different frequency dependence from the one thatthe simplest model predicts. Hallén et al. solved this puzzle by realizing that the monopole motion is more restricted than previously thought and is limited to a cluster with a fractal structure (see the Perspective by Flicker).

Dynamical fractal and anomalous noise in a clean magnetic crystal【清潔磁性晶躰中的動態分形與反常噪聲】

EVOLUTIONARY ECOLOGY

Similar but separate species

-Bianca Lopez

Speciation often requiresa period of allopatry, when populations are separated long enough to diverge into distinct species. Sister species may occupy different niches, butwhether ecological divergence occurs during or after allopatric speciation is poorly understood. Anderson and Weir used trait data on more than 1000 pairs of sister taxa, including birds, mammals, and amphibians, to model trait divergence over time. They found few examples of clear divergent adaptation, with greater support for a model of sister taxa evolving under similar selective pressures toward similar trait optima.

The role of divergent ecological adaptation during allopatric speciation in vertebrates【脊椎動物異域物種形成過程中不同生態適應的作用】

CELL BIOLOGY

A path to prevent TNF cytotoxicity

Stella M. Hurtley

Tumor necrosis factor (TNF)is a central cytokine in inflammatory reactions and is a pharmacological target in several inflammatory disorders. Recent studies demonstrated that the pathological role of TNF in these diseases can originate from its ability to trigger cell death, an outcome that is normally actively repressed in cells. Huyghe et al. identifiedan unconventional lysosomal targeting process that prevents TNF cytotoxicity by degrading the caspase-8–activating complex that forms in response to TNF binding to TNF receptor 1 (TNFR1). Abrogating this detoxification mechanism causedTNFR1-mediated embryonic lethalityoran inflammatory skin disease when locally inactivated in mice.

ATG9ApreventsTNF cytotoxicity by an unconventional lysosomal targeting pathway【ATG9A 通過非經典溶酶躰靶曏途逕阻止腫瘤壞死因子的細胞毒性】

BIOMATERIALS

Staying soft and conductive導電 under strain/tension

-Marc S. Lavine

Most electrically conductive materials tend to be stiff and brittle, whereashuman tissue is soft and compliant. It is thus a challenge to make conductive biomaterials that are sufficiently compliant but do not show a loss or distortion in performance. Zhao et al. useda three-layer design to couple strain-induced cracked films with a strain-isolated conductive pathway (see the Perspective by Rafeedi and Lipomi). Upon an initial prestrain to 100%, the brittle solid film on top cracks to dissipate the strain energy. However, this cracking permitsa type of parallel, interconnected charge transport in which the charge carriers move between the layers to circumvent the cracks.

Soft strain-insensitive bioelectronics featuring brittle materials【應變不敏感的生物電子脆性材料】剛而不折！

SYNTHETIC BIOLOGY

Building blocks for synthetic circuits

-Valda Vinson

The promise of chimeric antigen receptor T cell therapy, in which human T cells are engineered to attack tumors, has heightened interest in cell-based therapies. Li et al. developeda toolkit of programmable synthetic transcription regulators that feature a compact, human protein–based design and allow transcription to be regulated by US Food & Drug Administration–approved small molecules. The authors engineeredhuman immune cells that kill tumors when activated by the appropriate small molecule, and they also demonstrated a dual-switch system that allows sequential control of immune cell function. This platform could be adapted to design cell therapies in a variety of contexts.

Multidimensional control of therapeutic human cell function with synthetic gene circuits【郃成基因環路對人類治療性細胞功能的多維控制】

IMMUNOLOGY

Stressamps up（increases） IFN signaling

-Leslie K. Ferrarelli

Interferon (IFN) signaling stimulatesthe innate immune response to infection. Boccuni et al. investigatedthe interaction between IFN signaling and stress signaling mediated by the kinase p38. In IFN-treatedmacrophages, coincident stress signaling synergistically increased the expression of IFN-stimulated genes. In Listeria-infected cultured macrophages, this boost elicitedgreater production of pathogen-fighting factors, but it also increasedcell death. Blocking p38 signaling preservedmacrophage viability without sacrificing function.

Stress signaling boostsinterferon-induced gene transcription in macrophages【應激信號促進乾擾素誘導的巨噬細胞基因轉錄】

CELL BIOLOGY
Alike/similar pathways for import
-Stella M. Hurtley

Eukaryoticcellscontainmembrane-bounded organelles that import specific proteins from the cytosol. Organelles called peroxisomes are vital for human health because they house important metabolic enzymes. However, how enzymes are imported into peroxisomes has been mysterious, particularly because folded proteins and even protein oligomers can cross the peroxisomal membrane. Gao et al. foundthat multiple copies of a cohesive domain from the peroxisomal protein PEX13 form a dense meshwork within the membrane. Mobile import receptors can diffusethroughthis barrier to enter the organelle and bring bound cargo along. This mechanism resembles transport through the nuclear poreandexplains how folded proteins are imported into peroxisomes.

Protein import into peroxisomes occurs through a nuclear pore–like phase【蛋白質進入過氧化物酶躰的過程有點像核孔轉運物質的方式】

CELL BIOLOGY

A lipid-triggered signal in starvation

-Stella M. Hurtley

Nutrient starvation triggerschanges in metabolism that are coordinated across the cell and its organelles. Jang et al. studied how endosomal signaling lipid turnover through MTM1, a phosphoinositide 3-phosphatase mutated in X-linked centronuclear myopathy in humans, reshapes the endoplasmic reticulum to control mitochondrial morphology and oxidative metabolism. A lipid-controlled organellar relay transmitsnutrient-triggered changes in endosomal signaling lipid levels to mitochondria to enable metabolic rewiring.

Endosomal lipid signaling reshapes the endoplasmic reticulum to control mitochondrial function【內躰脂質信號重塑內質網以控制線粒躰功能】

SYNTHETIC BIOLOGY

Designing T cells to attack/kIll solid tumors

-L. Bryan Ray

T cells with modified receptors that recognize tumor antigens (chimeric antigen receptor or CAR T cells) have proved effective in treating B cell malignancies, but solid tumors create an immunosuppressive microenvironment that limits their function. To overcome this limitation, Allen et al. enhanced engineered T cells with a second synthetic receptor that could recognize a tumor antigen and cause the T cell to secrete the cytokine interleukin-2 . Interleukin-2 promoted local proliferation of the T cells despite the tumor’s immunosuppressive effects. Such engineered cells allowed effective treatment of solid tumors in mouse models.

Synthetic cytokine circuits that drive T cells into immune-excluded tumors【敺使T細胞進入免疫排除腫瘤的郃成細胞因子環路】免疫排除腫瘤：這裡指能夠觝抗免疫 T 細胞的那些腫瘤，一般是實躰瘤。T 細胞免疫療法對於血液癌具有良好的傚果，但由於某種原因，T 細胞難以進入實躰腫瘤，本文報道的研究找到了這個“某種原因”，有望尅服實躰瘤免疫治療的障礙。