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Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by hyperglycemia resulting from the destruction of insulin-producing β-cells that is traditionally deemed irreversible, but partial remission (PR) with temporary reversal of hyperglycemia is sometimes observed. Here we use single-cell RNA sequencing to delineate the immune cell landscape across patients in different T1D stages. Together with cohort validation and functional assays, we observe dynamic changes in TIGIT + CCR7 - Tregs and CD226 + CCR7 - CD8 + cytotoxic T cells during the peri-remission phase. Machine learning algorithms further identify TIGIT + CCR7 - Tregs and CD226 + CD8 + T cells as biomarkers for β-cell function decline in a predictive model, while cell communication analysis and in vitro assays suggest that TIGIT + CCR7 - Tregs may inhibit CD226 + CCR7 - CD8 + T cells via TGF-β signaling. Lastly, in both cyclophosphamide-induced and streptozotocin (STZ)-induced mouse diabetes models, CD226 inhibition postpones insulitis onset and reduces hyperglycemia severity. Our results thus identify two interrelated immune cell subsets that may serve as biomarkers for monitoring disease progression and targets for therapeutic intervention of T1D., (© 2024. The Author(s).)

Seawater direct electrolysis (SDE) using renewable energy provides a sustainable pathway to harness abundant oceanic hydrogen resources. However, the side-reaction of the chlorine electro-oxidation reaction (ClOR) severely decreased direct electrolysis efficiency of seawater and gradually corrodes the anode. In this study, a redox-mediated strategy is introduced to suppress the ClOR, and a decoupled seawater direct electrolysis (DSDE) system incorporating a separate O 2 evolution reactor is established. Ferricyanide/ferrocyanide ([Fe(CN) 6 ] 3-/4- ) serves as an electron-mediator between the cell and the reactor, thereby enabling a more dynamically favorable half-reaction to supplant the traditional oxygen evolution reaction (OER). This alteration involves a straightforward, single-electron-transfer anodic reaction without gas precipitation and effectively eliminates the generation of chlorine-containing byproducts. By operating at low voltages (~1.37 V at 10 mA cm -2 and ~1.57 V at 100 mA cm -2 ) and maintaining stability even in a Cl - -saturated seawater electrolyte, this system has the potential of undergoing decoupled seawater electrolysis with zero chlorine emissions. Further improvements in the high-performance redox-mediators and catalysts can provide enhanced cost-effectiveness and sustainability of the DSDE system., (© 2024. The Author(s).)

Visual adaptive devices have potential to simplify circuits and algorithms in machine vision systems to adapt and perceive images with varying brightness levels, which is however limited by sluggish adaptation process. Here, the avalanche tuning as feedforward inhibition in bionic two-dimensional (2D) transistor is proposed for fast and high-frequency visual adaptation behavior with microsecond-level accurate perception, the adaptation speed is over 10 4 times faster than that of human retina and reported bionic sensors. As light intensity changes, the bionic transistor spontaneously switches between avalanche and photoconductive effect, varying responsivity in both magnitude and sign (from 7.6 × 10 4 to -1 × 10 3  A/W), thereby achieving ultra-fast scotopic and photopic adaptation process of 108 and 268 μs, respectively. By further combining convolutional neural networks with avalanche-tuned bionic transistor, an adaptative machine vision is achieved with remarkable microsecond-level rapid adaptation capabilities and robust image recognition with over 98% precision in both dim and bright conditions., (© 2024. The Author(s).)

Non-volatile phase-change memory devices utilize local heating to toggle between crystalline and amorphous states with distinct electrical properties. Expanding on this kind of switching to two topologically distinct phases requires controlled non-volatile switching between two crystalline phases with distinct symmetries. Here, we report the observation of reversible and non-volatile switching between two stable and closely related crystal structures, with remarkably distinct electronic structures, in the near-room-temperature van der Waals ferromagnet Fe 5-δ GeTe 2 . We show that the switching is enabled by the ordering and disordering of Fe site vacancies that results in distinct crystalline symmetries of the two phases, which can be controlled by a thermal annealing and quenching method. The two phases are distinguished by the presence of topological nodal lines due to the preserved global inversion symmetry in the site-disordered phase, flat bands resulting from quantum destructive interference on a bipartite lattice, and broken inversion symmetry in the site-ordered phase., (© 2024. The Author(s).)

Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients., (© 2024. The Author(s).)

Surface amorphization provides electrocatalysts with more active sites and flexibility. However, there is still a lack of experimental observations and mechanistic explanations for the in situ amorphization process and its crucial role. Herein, we propose the concept that by in situ reconstructed amorphous surface, metal phosphorus trichalcogenides could intrinsically offer better catalytic performance for the alkaline hydrogen production. Trace Ru (0.81 wt.%) is doped into NiPS 3 nanosheets for alkaline hydrogen production. Using in situ electrochemical transmission electron microscopy technique, we confirmed the amorphization process occurred on the edges of NiPS 3 is critical for achieving superior activity. Comprehensive characterizations and theoretical calculations reveal Ru primarily stabilized at edges of NiPS 3 through in situ formed amorphous layer containing bridging S 2 2- species, which can effectively reduce the reaction energy barrier. This work emphasizes the critical role of in situ formed active layer and suggests its potential for optimizing catalytic activities of electrocatalysts., (© 2023. Springer Nature Limited.)

Small ubiquitin-like modifier (SUMO) typically conjugates to target proteins through isopeptide linkage to the ε-amino group of lysine residues. This posttranslational modification (PTM) plays pivotal roles in modulating protein function. Cofilins are key regulators of actin cytoskeleton dynamics and are well-known to undergo several different PTMs. Here, we show that cofilin-1 is conjugated by SUMO1 both in vitro and in vivo. Using mass spectrometry and biochemical and genetic approaches, we identify the N-terminal α-amino group as the SUMO-conjugation site of cofilin-1. Common to conventional SUMOylation is that the N-α-SUMOylation of cofilin-1 is also mediated by SUMO activating (E1), conjugating (E2), and ligating (E3) enzymes and reversed by the SUMO deconjugating enzyme, SENP1. Specific to the N-α-SUMOylation is the physical association of the E1 enzyme to the substrate, cofilin-1. Using F-actin co-sedimentation and actin depolymerization assays in vitro and fluorescence staining of actin filaments in cells, we show that the N-α-SUMOylation promotes cofilin-1 binding to F-actin and cofilin-induced actin depolymerization. This covalent conjugation by SUMO at the N-α amino group of cofilin-1, rather than at an internal lysine(s), serves as an essential PTM to tune cofilin-1 function during regulation of actin dynamics., (© 2023. Springer Nature Limited.)

Loss of the tumor suppressive activity of the protein phosphatase 2A (PP2A) is associated with cancer, but the underlying molecular mechanisms are unclear. PP2A holoenzyme comprises a heterodimeric core, a scaffolding A subunit and a catalytic C subunit, and one of over 20 distinct substrate-directing regulatory B subunits. Methylation of the C subunit regulates PP2A heterotrimerization, affecting B subunit binding and substrate specificity. Here, we report that the leucine carboxy methyltransferase (LCMT1), which methylates the L309 residue of the C subunit, acts as a suppressor of androgen receptor (AR) addicted prostate cancer (PCa). Decreased methyl-PP2A-C levels in prostate tumors is associated with biochemical recurrence and metastasis. Silencing LCMT1 increases AR activity and promotes castration-resistant prostate cancer growth. LCMT1-dependent methyl-sensitive AB56αCme heterotrimers target AR and its critical coactivator MED1 for dephosphorylation, resulting in the eviction of the AR-MED1 complex from chromatin and loss of target gene expression. Mechanistically, LCMT1 is regulated by S6K1-mediated phosphorylation-induced degradation requiring the β-TRCP, leading to acquired resistance to anti-androgens. Finally, feedforward stabilization of LCMT1 by small molecule activator of phosphatase (SMAP) results in attenuation of AR-signaling and tumor growth inhibition in anti-androgen refractory PCa. These findings highlight methyl-PP2A-C as a prognostic marker and that the loss of LCMT1 is a major determinant in AR-addicted PCa, suggesting therapeutic potential for AR degraders or PP2A modulators in prostate cancer treatment., (© 2023. Springer Nature Limited.)

Glioblastoma (GBM) is one of the most aggressive and lethal solid tumors in human. While efficacious therapeutics, such as emerging chimeric antigen receptor (CAR)-T cells and chemotherapeutics, have been developed to treat various cancers, their effectiveness in GBM treatment has been hindered largely by the blood-brain barrier and blood-brain-tumor barriers. Human neutrophils effectively cross physiological barriers and display effector immunity against pathogens but the short lifespan and resistance to genome editing of primary neutrophils have limited their broad application in immunotherapy. Here we genetically engineer human pluripotent stem cells with CRISPR/Cas9-mediated gene knock-in to express various anti-GBM CAR constructs with T-specific CD3ζ or neutrophil-specific γ-signaling domains. CAR-neutrophils with the best anti-tumor activity are produced to specifically and noninvasively deliver and release tumor microenvironment-responsive nanodrugs to target GBM without the need to induce additional inflammation at the tumor sites. This combinatory chemo-immunotherapy exhibits superior and specific anti-GBM activities, reduces off-target drug delivery and prolongs lifespan in female tumor-bearing mice. Together, this biomimetic CAR-neutrophil drug delivery system is a safe, potent and versatile platform for treating GBM and possibly other devastating diseases., (© 2023. The Author(s).)

Numerous RNAs are exported from the nucleus, abnormalities of which lead to cellular complications and diseases. How thousands of circular RNAs (circRNAs) are exported from the nucleus remains elusive. Here, we provide lines of evidence to demonstrate a link between the conserved Exportin 4 (XPO4) and nuclear export of a subset of circRNAs in metazoans. Exonic circRNAs (ecircRNAs) with higher expression levels, larger length, and lower GC content are more sensitive to XPO4 deficiency. Cellular insufficiency of XPO4 leads to nuclear circRNA accumulation, circRNA:DNA (ciR-loop) formation, linear RNA:DNA (liR-loop) buildup, and DNA damage. DDX39 known to modulate circRNA export can resolve ciR-loop, and splicing factors involved in the biogenesis of circRNAs can also affect the levels of ciR-loop. Testis and brain are two organs with high abundance of circRNAs, and insufficient XPO4 levels are detrimental, as Xpo4 heterozygous mice display male infertility and neural phenotypes. Increased levels of ciR-loop, R-loop, and DNA damage along with decreased cell numbers are observed in testis and hippocampus of Xpo4 heterozygotes. This study sheds light on the understandings of mechanism of circRNA export and reveals the significance of efficient nuclear export of circRNAs in cellular physiology., (© 2022. The Author(s).)

Pancreatic differentiation from human pluripotent stem cells (hPSCs) provides promising avenues for investigating development and treating diseases. N 6 -methyladenosine (m 6 A) is the most prevalent internal messenger RNA (mRNA) modification and plays pivotal roles in regulation of mRNA metabolism, while its functions remain elusive. Here, we profile the dynamic landscapes of m 6 A transcriptome-wide during pancreatic differentiation. Next, we generate knockout hPSC lines of the major m 6 A demethylase ALKBH5, and find that ALKBH5 plays significant regulatory roles in pancreatic organogenesis. Mechanistic studies reveal that ALKBH5 deficiency reduces the mRNA stability of key pancreatic transcription factors in an m 6 A and YTHDF2-dependent manner. We further identify that ALKBH5 cofactor α-ketoglutarate can be applied to enhance differentiation. Collectively, our findings identify ALKBH5 as an essential regulator of pancreatic differentiation and highlight that m 6 A modification-mediated mRNA metabolism presents an important layer of regulation during cell-fate specification and holds great potentials for translational applications., (© 2022. The Author(s).)

Human embryonic stem cell-derived β cells (SC-β cells) hold great promise for treatment of diabetes, yet how to achieve functional maturation and protect them against metabolic stresses such as glucotoxicity and lipotoxicity remains elusive. Our single-cell RNA-seq analysis reveals that ZnT8 loss of function (LOF) accelerates the functional maturation of SC-β cells. As a result, ZnT8 LOF improves glucose-stimulated insulin secretion (GSIS) by releasing the negative feedback of zinc inhibition on insulin secretion. Furthermore, we demonstrate that ZnT8 LOF mutations endow SC-β cells with resistance to lipotoxicity/glucotoxicity-triggered cell death by alleviating endoplasmic reticulum (ER) stress through modulation of zinc levels. Importantly, transplantation of SC-β cells with ZnT8 LOF into mice with preexisting diabetes significantly improves glycemia restoration and glucose tolerance. These findings highlight the beneficial effect of ZnT8 LOF on the functional maturation and survival of SC-β cells that are useful as a potential source for cell replacement therapies., (© 2022. The Author(s).)

X-chromosome inactivation and X-upregulation are the fundamental modes of chromosome-wide gene regulation that collectively achieve dosage compensation in mammals, but the regulatory link between the two remains elusive and the X-upregulation dynamics are unknown. Here, we use allele-resolved single-cell RNA-seq combined with chromatin accessibility profiling and finely dissect their separate effects on RNA levels during mouse development. Surprisingly, we uncover that X-upregulation elastically tunes expression dosage in a sex- and lineage-specific manner, and moreover along varying degrees of X-inactivation progression. Male blastomeres achieve X-upregulation upon zygotic genome activation while females experience two distinct waves of upregulation, upon imprinted and random X-inactivation; and ablation of Xist impedes female X-upregulation. Female cells carrying two active X chromosomes lack upregulation, yet their collective RNA output exceeds that of a single hyperactive allele. Importantly, this conflicts the conventional dosage compensation model in which naïve female cells are initially subject to biallelic X-upregulation followed by X-inactivation of one allele to correct the X dosage. Together, our study provides key insights to the chain of events of dosage compensation, explaining how transcript copy numbers can remain remarkably stable across developmental windows wherein severe dose imbalance would otherwise be experienced by the cell., (© 2022. The Author(s).)

As one of the typical bioorthogonal reactions, copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction holds great potential in organic synthesis, bioconjugation, and surface functionalization. However, the toxicity of Cu(I), inefficient catalytic activity, and the lack of cell specific targeting of the existing catalysts hampered their practical applications in living systems. Herein, we design and construct a DNA-based platform as a biocompatible, highly efficient, and precisely targeted bioorthogonal nanocatalyst. The nanocatalyst presents excellent catalytic efficiency in vitro, which is one order of magnitude higher than the commonly used catalyst CuSO 4 /sodium ascorbate. The theoretical calculation further supports the contribution of DNA structure and its interaction with substrates to the superior catalytic activity. More importantly, the system can achieve efficient prodrug activation in cancer cells through cell type-specific recognition and produce a 40-fold enhancement of transformation compared to the non-targeting nanocatalyst, resulting in enhanced antitumor efficacy and reduced adverse effects. In vivo tumor therapy demonstrates the safety and efficacy of the system in mammals., (© 2022. The Author(s).)

The separation of C 2 H 2 /CO 2 is not only industrially important for acetylene purification but also scientifically challenging owing to their high similarities in physical properties and molecular sizes. Ultramicroporous metal-organic frameworks (MOFs) can exhibit a pore confinement effect to differentiate gas molecules of similar size. Herein, we report the fine-tuning of pore sizes in sub-nanometer scale on a series of isoreticular MOFs that can realize highly efficient C 2 H 2 /CO 2 separation. The subtle structural differences lead to remarkable adsorption performances enhancement. Among four MOF analogs, by integrating appropriate pore size and specific binding sites, [Cu(dps) 2 (SiF 6 )] (SIFSIX-dps-Cu, SIFSIX = SiF 6 2- , dps = 4.4'-dipyridylsulfide, also termed as NCU-100) exhibits the highest C 2 H 2 uptake capacity and C 2 H 2 /CO 2 selectivity. At room temperature, the pore space of SIFSIX-dps-Cu significantly inhibits CO 2 molecules but takes up a large amount of C 2 H 2 (4.57 mmol g -1 ), resulting in a high IAST selectivity of 1787 for C 2 H 2 /CO 2 separation. The multiple host-guest interactions for C 2 H 2 in both inter- and intralayer cavities are further revealed by dispersion-corrected density functional theory and grand canonical Monte Carlo simulations. Dynamic breakthrough experiments show a clean C 2 H 2 /CO 2 separation with a high C 2 H 2 working capacity of 2.48 mmol g -1 ., (© 2022. The Author(s).)

Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously., (© 2021. The Author(s).)

Revealing the atomistic mechanisms for the high-temperature mechanical behavior of materials is important for optimizing their properties for service at high-temperatures and their thermomechanical processing. However, due to materials microstructure's dynamic recovery and the absence of available in situ techniques, the high-temperature deformation behavior and atomistic mechanisms of materials are difficult to evaluate. Here, we report the development of a microelectromechanical systems-based thermomechanical testing apparatus that enables mechanical testing at temperatures reaching 1556 K inside a transmission electron microscope for in situ investigation with atomic-resolution. With this unique technique, we first uncovered that tungsten fractures at 973 K in a ductile manner via a strain-induced multi-step body-centered cubic (BCC)-to-face-centered cubic (FCC) transformation and dislocation activities within the strain-induced FCC phase. Both events reduce the stress concentration at the crack tip and retard crack propagation. Our research provides an approach for timely and atomic-resolved high-temperature mechanical investigation of materials at high-temperatures.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutralizing antibodies against SARS-CoV-2 are an option for drug development for treating COVID-19. Here, we report the identification and characterization of two groups of mouse neutralizing monoclonal antibodies (MAbs) targeting the receptor-binding domain (RBD) on the SARS-CoV-2 spike (S) protein. MAbs 2H2 and 3C1, representing the two antibody groups, respectively, bind distinct epitopes and are compatible in formulating a noncompeting antibody cocktail. A humanized version of the 2H2/3C1 cocktail is found to potently neutralize authentic SARS-CoV-2 infection in vitro with half inhibitory concentration (IC50) of 12 ng/mL and effectively treat SARS-CoV-2-infected mice even when administered at as late as 24 h post-infection. We determine an ensemble of cryo-EM structures of 2H2 or 3C1 Fab in complex with the S trimer up to 3.8 Å resolution, revealing the conformational space of the antigen-antibody complexes and MAb-triggered stepwise allosteric rearrangements of the S trimer, delineating a previously uncharacterized dynamic process of coordinated binding of neutralizing antibodies to the trimeric S protein. Our findings provide important information for the development of MAb-based drugs for preventing and treating SARS-CoV-2 infections.

Electrical contact is an essential issue for all devices. Although the contacts of the emergent two-dimensional materials have been extensively investigated, it is still challenging to produce excellent contacts. The face and edge type contacts have been applied previously, however a comparative study on the site-specific contact performances is lacking. Here we report an in situ transmission electron microscopy study on the contact properties with a series of 2D materials. By manipulating the contact configurations in real time, it is confirmed that, for 2D semiconductors the vdW type face contacts exhibit superior conductivity compared with the non-vdW type contacts. The direct quantum tunneling across the vdW bonded interfaces are virtually more favorable than the Fowler-Nordheim tunneling across chemically bonded interfaces for contacts. Meanwhile, remarkable area, thickness, geometry, and defect site dependences are revealed. Our work sheds light on the significance of contact engineering for 2D materials in future applications.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

LRIG1 has been reported to be a tumor suppressor in gastrointestinal tract and epidermis. However, little is known about the expression, regulation and biological functions of LRIG1 in prostate cancer (PCa). We find that LRIG1 is overexpressed in PCa, but its expression correlates with better patient survival. Functional studies reveal strong tumor-suppressive functions of LRIG1 in both AR + and AR - xenograft models, and transgenic expression of LRIG1 inhibits tumor development in Hi-Myc and TRAMP models. LRIG1 also inhibits castration-resistant PCa and exhibits therapeutic efficacy in pre-established tumors. We further show that 1) AR directly transactivates LRIG1 through binding to several AR-binding sites in LRIG1 locus, and 2) LRIG1 dampens ERBB expression in a cell type-dependent manner and inhibits ERBB2-driven tumor growth. Collectively, our study indicates that LRIG1 represents a pleiotropic AR-regulated feedback tumor suppressor that functions to restrict oncogenic signaling from AR, Myc, ERBBs, and, likely, other oncogenic drivers.

A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was previously associated with moderate risk of brain tumors and other neoplasms. We find a positive association between this variant and soft tissue sarcoma. In sharp contrast, it is protective against breast cancer. We generated a mouse line carrying this variant and found that it accelerates spontaneous tumorigenesis and glioma development, but strikingly, delays mammary tumorigenesis. The variant creates a miR-382-5p targeting site and compromises a miR-325-3p site. Their differential expression results in p53 downregulation in the brain, but p53 upregulation in the mammary gland of polymorphic mice compared to that of wild-type littermates. Thus, this variant is at odds with Li-Fraumeni Syndrome mutants in breast cancer predisposition yet consistent in glioma predisposition. Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression.

Cd 3 As 2 is a three-dimensional Dirac semimetal with separated Dirac points in momentum space. In spite of extensive transport and spectroscopic studies on its exotic properties, the evidence of superconductivity in its surface states remains elusive. Here, we report the observation of proximity-induced surface superconductivity in Nb/Cd 3 As 2 hybrid structures. Our four-terminal transport measurement identifies a pronounced proximity-induced pairing gap (gap size comparable to Nb) on the surfaces, which exhibits a flat conductance plateau in differential conductance spectra, consistent with our theoretical simulations. The surface supercurrent from Nb/Cd 3 As 2 /Nb junctions is also achieved with a Fraunhofer/SQUID-like pattern under out-of-plane/in-plane magnetic fields, respectively. The resultant mapping shows a predominant distribution on the top and bottom surfaces as the bulk carriers are depleted, which can be regarded as a higher dimensional analog of edge supercurrent in two-dimensional quantum spin Hall insulators. Our study provides the evidence of surface superconductivity in Dirac semimetals.

Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity remains unclear. Screening ~200 castration-resistant PCa (CRPC) cores and whole-mount sections (from 89 patients) reveals 3 AR expression patterns: nuclear (nuc-AR), mixed nuclear/cytoplasmic (nuc/cyto-AR), and low/no expression (AR -/lo ). Xenograft modeling demonstrates that AR + CRPC is enzalutamide-sensitive but AR -/lo CRPC is resistant. Genome editing-derived AR + and AR-knockout LNCaP cell clones exhibit distinct biological and tumorigenic properties and contrasting responses to enzalutamide. RNA-Seq and biochemical analyses, coupled with experimental combinatorial therapy, identify BCL-2 as a critical therapeutic target and provide proof-of-concept therapeutic regimens for both AR +/hi and AR -/lo CRPC. Our study links AR expression heterogeneity to distinct castration/enzalutamide responses and has important implications in understanding the cellular basis of prostate tumor responses to AR-targeting therapies and in facilitating development of novel therapeutics to target AR -/lo PCa cells/clones.

Induced neural stem cells (iNSCs) reprogrammed from somatic cells have great potentials in cell replacement therapies and in vitro modeling of neural diseases. Direct conversion of fibroblasts into iNSCs has been shown to depend on a couple of key neural progenitor transcription factors (TFs), raising the question of whether such direct reprogramming can be achieved by non-neural progenitor TFs. Here we report that the non-neural progenitor TF Ptf1a alone is sufficient to directly reprogram mouse and human fibroblasts into self-renewable iNSCs capable of differentiating into functional neurons, astrocytes and oligodendrocytes, and improving cognitive dysfunction of Alzheimer's disease mouse models when transplanted. The reprogramming activity of Ptf1a depends on its Notch-independent interaction with Rbpj which leads to subsequent activation of expression of TF genes and Notch signaling required for NSC specification, self-renewal, and homeostasis. Together, our data identify a non-canonical and safer approach to establish iNSCs for research and therapeutic purposes.

In the originally published version of this Article, the affiliation details for Yan Wang, Yingwei Gao, Qi Deng, Yangbo Wang, Tian Zhou, Yingping Wang, Huiqing Liu, Ruining Ma, Jinke Cheng and Yong Li incorrectly omitted 'Shanghai Jiao Tong University'. This has now been corrected in both the PDF and HTML versions of the Article.' Furthermore, the Supplementary Information file originally associated with this Article inadvertently omitted Supplementary Figure 9. The error has now been fixed and the corrected version Supplementary Information PDF is available to download from the HTML version of the Article.

Endocytosis of surface receptors and their polarized recycling back to the plasma membrane are central to many cellular processes, such as cell migration, cytokinesis, basolateral polarity of epithelial cells and T cell activation. Little is known about the mechanisms that control the organization of recycling endosomes and how they connect to receptor endocytosis. Here, we follow the endocytic journey of the T cell receptor (TCR), from internalization at the plasma membrane to recycling back to the immunological synapse. We show that TCR triggering leads to its rapid uptake through a clathrin-independent pathway. Immediately after internalization, TCR is incorporated into a mobile and long-lived endocytic network demarked by the membrane-organizing proteins flotillins. Although flotillins are not required for TCR internalization, they are necessary for its recycling to the immunological synapse. We further show that flotillins are essential for T cell activation, supporting TCR nanoscale organization and signaling.

Although TRPV1 channels represent a key player of noxious heat sensation, the precise mechanisms for thermal hyperalgesia remain unknown. We report here that conditional knockout of deSUMOylation enzyme, SENP1, in mouse dorsal root ganglion (DRG) neurons exacerbated thermal hyperalgesia in both carrageenan- and Complete Freund's adjuvant-induced inflammation models. TRPV1 is SUMOylated at a C-terminal Lys residue (K822), which specifically enhances the channel sensitivity to stimulation by heat, but not capsaicin, protons or voltage. TRPV1 SUMOylation is decreased by SENP1 but upregulated upon peripheral inflammation. More importantly, the reduced ability of TRPV1 knockout mice to develop inflammatory thermal hyperalgesia was rescued by viral infection of lumbar 3/4 DRG neurons of wild-type TRPV1, but not its SUMOylation-deficient mutant, K822R. These data suggest that TRPV1 SUMOylation is essential for the development of inflammatory thermal hyperalgesia, through a mechanism that involves sensitization of the channel response specifically to thermal stimulation.

Plasmon rulers can be used for resolving ultrasmall environmental, dimensional, and material changes owing to their high sensitivity associated with a light-scattering spectral shift in response to changes in the separation between plasmonic nanostructures. Here, we show, in several experimental setups, how cavity plasmons in a metal nanowire-on-mirror setup can be used to probe vertical dimensional changes with sub-picometer differential resolutions using two carefully chosen material systems. Specifically, we monitor the dielectric layer thickness changes in response to growth using atomic-layer deposition and to thermal expansion, demonstrating a sensitivity of 14-nm spectral shift per Ångström thickness change and 0.58 pm of vertical differential resolution, respectively. The findings confirm theoretical predictions and highlight the potential use of cavity plasmons in some ultrasensitive sensing applications.

Endothelial exocytosis of Weibel-Palade body (WPB) is one of the first lines of defence against vascular injury. However, the mechanisms that control WPB exocytosis in the final stages (including the docking, priming and fusion of granules) are poorly understood. Here we show that the focal adhesion protein zyxin is crucial in this process. Zyxin downregulation inhibits the secretion of von Willebrand factor (VWF), the most abundant cargo in WPBs, from human primary endothelial cells (ECs) induced by cAMP agonists. Zyxin-deficient mice exhibit impaired epinephrine-stimulated VWF release, prolonged bleeding time and thrombosis, largely due to defective endothelial secretion of VWF. Using live-cell super-resolution microscopy, we visualize previously unappreciated reorganization of pre-existing actin filaments around WPBs before fusion, dependent on zyxin and an interaction with the actin crosslinker α-actinin. Our findings identify zyxin as a physiological regulator of endothelial exocytosis through reorganizing local actin network in the final stage of exocytosis.

MicroRNAs play important roles in regulating tumour development, progression and metastasis. Here we show that one of the miR-200 family members, miR-141, is under-expressed in several prostate cancer (PCa) stem/progenitor cell populations in both xenograft and primary patient tumours. Enforced expression of miR-141 in CD44 + and bulk PCa cells inhibits cancer stem cell properties including holoclone and sphere formation, as well as invasion, and suppresses tumour regeneration and metastasis. Moreover, miR-141 expression enforces a strong epithelial phenotype with a partial loss of mesenchymal phenotype. Whole-genome RNA sequencing uncovers novel miR-141-regulated molecular targets in PCa cells including the Rho GTPase family members (for example, CDC42, CDC42EP3, RAC1 and ARPC5) and stem cell molecules CD44 and EZH2, all of which are validated as direct and functionally relevant targets of miR-141. Our results suggest that miR-141 employs multiple mechanisms to obstruct tumour growth and metastasis.

Laser capture microscopy (LCM) coupled with global transcriptome profiling could enable precise analyses of cell populations without the need for tissue dissociation, but has so far required relatively large numbers of cells. Here we report a robust and highly efficient strategy for LCM coupled with full-length mRNA-sequencing (LCM-seq) developed for single-cell transcriptomics. Fixed cells are subjected to direct lysis without RNA extraction, which both simplifies the experimental procedures as well as lowers technical noise. We apply LCM-seq on neurons isolated from mouse tissues, human post-mortem tissues, and illustrate its utility down to single captured cells. Importantly, we demonstrate that LCM-seq can provide biological insight on highly similar neuronal populations, including motor neurons isolated from different levels of the mouse spinal cord, as well as human midbrain dopamine neurons of the substantia nigra compacta and the ventral tegmental area.

Grain boundaries in monolayer transition metal dichalcogenides have unique atomic defect structures and band dispersion relations that depend on the inter-domain misorientation angle. Here, we explore misorientation angle-dependent electrical transport at grain boundaries in monolayer MoS2 by correlating the atomic defect structures of measured devices analysed with transmission electron microscopy and first-principles calculations. Transmission electron microscopy indicates that grain boundaries are primarily composed of 5-7 dislocation cores with periodicity and additional complex defects formed at high angles, obeying the classical low-angle theory for angles <22°. The inter-domain mobility is minimized for angles <9° and increases nonlinearly by two orders of magnitude before saturating at ∼ 16 cm(2) V(-1) s(-1) around misorientation angle ≈ 20°. This trend is explained via grain-boundary electrostatic barriers estimated from density functional calculations and experimental tunnelling barrier heights, which are ≈ 0.5 eV at low angles and ≈ 0.15 eV at high angles (≥ 20°).

The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.

The great application potential for two-dimensional (2D) membranes (MoS2, WSe2, graphene and so on) aroused much effort to understand their fundamental mechanical properties. The out-of-plane bending rigidity is the key factor that controls the membrane morphology under external fields. Herein we provide an easy method to reconstruct the 3D structures of the folded edges of these 2D membranes on the atomic scale, using high-resolution (S)TEM images. After quantitative comparison with continuum mechanics shell model, it is verified that the bending behaviour of the studied 2D materials can be well explained by the linear elastic shell model. And the bending rigidities can thus be derived by fitting with our experimental results. Recall almost only theoretical approaches can access the bending properties of these 2D membranes before, now a new experimental method to measure the bending rigidity of such flexible and atomic thick 2D membranes is proposed.

Thermosensitive genic male-sterile (TGMS) lines, which are male-sterile at restrictive (high) temperatures but male-fertile at permissive (low) temperatures, have been widely used in breeding two-line hybrid rice (Oryza sativa L.). Here we find that mutation of thermosensitive genic male sterile 5 (tms5) in rice causes the TGMS trait through a loss of RNase Z(S1) function. We show that RNase Z(S1) processes the mRNAs of three ubiquitin fusion ribosomal protein L40 (UbL40) genes into multiple fragments in vitro and in vivo. In tms5 mutants, high temperature results in increased levels of UbL40 mRNAs. Overaccumulation of UbL40 mRNAs causes defective pollen production and male sterility. Our results uncover a novel mechanism of RNase Z(S1)-mediated UbL40 mRNA regulation and shows that loss of this regulation produces TGMS in rice, a finding with potential applications in hybrid crop breeding.

The search for new superconducting materials has been spurred on by the discovery of iron-based superconductors whose structure and composition is qualitatively different from the cuprates. The study of one such material, KxFe2-ySe2 with a critical temperature of 32 K, is made more difficult by the fact that it separates into two phases-a dominant antiferromagnetic insulating phase K2Fe4Se5, and a minority superconducting phase whose precise structure is as yet unclear. Here we perform electrical and magnetization measurements, scanning electron microscopy and microanalysis, X-ray diffraction and scanning tunnelling microscopy on KxFe2-ySe2 crystals prepared under different quenching processes to better understand the relationship between its microstructure and its superconducting phase. We identify a three-dimensional network of superconducting filaments within this material and present evidence to suggest that the superconducting phase consists of a single Fe vacancy for every eight Fe-sites arranged in a √8 x √10 parallelogram structure.

Grain number, panicle seed setting rate, panicle number and grain weight are the most important components of rice grain yield. To date, several genes related to grain weight, grain number and panicle number have been described in rice. However, no genes regulating the panicle seed setting rate have been functionally characterized. Here we show that the domestication-related POLLEN TUBE BLOCKED 1 (PTB1), a RING-type E3 ubiquitin ligase, positively regulates the rice panicle seed setting rate by promoting pollen tube growth. The natural variation in expression of PTB1 which is affected by the promoter haplotype and the environmental temperature, correlates with the rice panicle seed setting rate. Our results support the hypothesis that PTB1 is an important maternal sporophytic factor of pollen tube growth and a key modulator of the rice panicle seed setting rate. This finding has implications for the improvement of rice yield.

Rhizoctonia solani is a major fungal pathogen of rice (Oryza sativa L.) that causes great yield losses in all rice-growing regions of the world. Here we report the draft genome sequence of the rice sheath blight disease pathogen, R. solani AG1 IA, assembled using next-generation Illumina Genome Analyser sequencing technologies. The genome encodes a large and diverse set of secreted proteins, enzymes of primary and secondary metabolism, carbohydrate-active enzymes, and transporters, which probably reflect an exclusive necrotrophic lifestyle. We find few repetitive elements, a closer relationship to Agaricomycotina among Basidiomycetes, and expand protein domains and families. Among the 25 candidate pathogen effectors identified according to their functionality and evolution, we validate 3 that trigger crop defence responses; hence we reveal the exclusive expression patterns of the pathogenic determinants during host infection.

The origin of superconductivity in the iron pnictides remains unclear. One suggestion is that superconductivity in these materials has a magnetic origin, which would imply a sign-reversal s(±) pairing symmetry. Another suggests it is the result of orbital fluctuations, which would imply a sign-equal s(++) pairing symmetry. There is no consensus yet which of these two distinct and contrasting pairing symmetries is the right one in iron pnictide superconductors. Here we explore the nature of the pairing symmetry in the superconducting state of Na(Fe0.97-xCo0.03Cux)As by probing the effect of scattering of Cooper pairs by non-magnetic Cu impurities. Using scanning tunnelling spectroscopy, we identify the in-gap quasiparticle states induced by the Cu impurities, showing signatures of Cooper pair breaking by these non-magnetic impurities-a process that is only consistent with s(±) pairing. This experiment provides strong evidence for the s(±) pairing.