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Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain of HOTAIR binds poiycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes. 10.1126/science.1192002

Tackling transmission: An important feature of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is whether or not the vaccine prevents transmission to others. In this study, Wu et al. vaccinated mice, hamsters, and cynomolgus monkeys with a SARS-CoV-2 spike protein subunit vaccine, StriFK, plus a nitrogen bisphosphonate–modified zinc-aluminum hybrid adjuvant called FH002C. The vaccine elicited antibody and cell-mediated immunity in all three models. StriFK-FH002C vaccination prevented hamsters from transmitting virus to unvaccinated, cohoused hamsters. This was associated with lower viral load in the upper respiratory tract of vaccinated hamsters after challenge. Thus, StriFK-FH002C represents an effective vaccine candidate for SARS-CoV-2. Multiple safe and effective vaccines that elicit immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary to respond to the ongoing coronavirus disease 2019 (COVID-19) pandemic. Here, we developed a protein subunit vaccine composed of spike ectodomain protein (StriFK) plus a nitrogen bisphosphonate–modified zinc-aluminum hybrid adjuvant (FH002C). StriFK-FH002C generated substantially higher neutralizing antibody titers in mice, hamsters, and cynomolgus monkeys than those observed in plasma isolated from COVID-19 convalescent individuals. StriFK-FH002C also induced both TH1- and TH2-polarized helper T cell responses in mice. In hamsters, StriFK-FH002C immunization protected animals against SARS-CoV-2 challenge, as shown by the absence of virus-induced weight loss, fewer symptoms of disease, and reduced lung pathology. Vaccination of hamsters with StriFK-FH002C also reduced within-cage virus transmission to unvaccinated, cohoused hamsters. In summary, StriFK-FH002C represents an effective, protein subunit–based SARS-CoV-2 vaccine candidate. [ABSTRACT FROM AUTHOR]

The article reports on the use of an acoustic field to help connect individual Gallium-based liquid metals (GaLM) microdroplets embedded in polymer. Topics discussed include factors that hinder the implementation of GaLMs by the electronics industry and ways to improve interactions between GaLMs and polymer matrices.

The article discusses a research study to demonstrate that differential absorption and eigenvalue repulsion can create some scattering singularities with much lower damping rates than the mean to allow reflectionless excitation in combination with a desired routing functionality. It is evident that reflectionless excitation of scattering systems is a fundamental wave scattering problem across all areas of wave engineering.

Pattern recognition receptor-mediated innate immunity is critical for host defense against viruses. A growing number of coding and noncoding genes are found to encode microproteins. However, the landscape and functions of microproteins in responsive to virus infection remain uncharacterized. Here, we systematically identified microproteins that are responsive to vesicular stomatitis virus infection. A conserved and endoplasmic reticulum-localized membrane microprotein, MAVI1 (microprotein in antiviral immunity 1), was found to interact with mitochondrion-localized MAVS protein and inhibit MAVS aggregation and type I interferon signaling activation. The importance of MAVI1 was highlighted that viral infection was attenuated and survival rate was increased in Mavi1- knockout mice. A peptide inhibitor targeting the interaction between MAVI1 and MAVS activated the type I interferon signaling to defend viral infection. Our findings uncovered that microproteins play critical roles in regulating antiviral innate immune responses, and targeting microproteins might represent a therapeutic avenue for treating viral infection.

Myelodysplastic syndrome (MDS) is a clonal malignancy arising in hematopoietic stem cells (HSCs). The mechanisms of MDS initiation in HSCs are still poorly understood. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is frequently activated in acute myeloid leukemia, but in MDS, PI3K/AKT is often down-regulated. To determine whether PI3K down-regulation can perturb HSC function, we generated a triple knockout (TKO) mouse model with Pik3ca , Pik3cb , and Pik3cd deletion in hematopoietic cells. Unexpectedly, PI3K deficiency caused cytopenias, decreased survival, and multilineage dysplasia with chromosomal abnormalities, consistent with MDS initiation. TKO HSCs exhibit impaired autophagy, and pharmacologic autophagy induction improved HSC differentiation. Using intracellular LC3 and P62 flow cytometry and transmission electron microscopy, we also observed abnormal autophagic degradation in patient MDS HSCs. Therefore, we have uncovered an important protective role for PI3K in maintaining autophagic flux in HSCs to preserve the balance between self-renewal and differentiation and to prevent MDS initiation.

Materials with programmable conductivity and stiffness offer new design opportunities for next-generation engineered systems in soft robotics and electronic devices. However, existing approaches fail to harness variable electrical and mechanical properties synergistically and lack the ability to self-respond to environmental changes. We report an electro-mechano responsive Field's metal hybrid elastomer exhibiting variable and tunable conductivity, strain sensitivity, and stiffness. By synergistically harnessing these properties, we demonstrate two applications with over an order of magnitude performance improvement compared to state-of-the-art, including a self-triggered multiaxis compliance compensator for robotic manipulators, and a resettable, highly compact, and fast current-limiting fuse with an adjustable fusing current. We envisage that the extraordinary electromechanical properties of our hybrid elastomer will bring substantial advancements in resilient robotic systems, intelligent instruments, and flexible electronics.

A stretchable conductive circuit is formed using a liquid metal-polymer composite.

Drosophila melanogaster Dscam1 encodes 38,016 isoforms via mutually exclusive splicing; however, the regulatory mechanism behind this is not fully understood. Here, we found a set of hidden RNA secondary structures that balance the stochastic choice of Dscam1 splice variants (designated balancer RNA secondary structures). In vivo mutational analyses revealed the dual function of these balancer interactions in driving the stochastic choice of splice variants, through enhancement of the inclusion of distal exon 6s by cooperating with docking site-selector pairing to form a stronger multidomain pre-mRNA structure and through simultaneous repression of the inclusion of proximal exon 6s by antagonizing their docking site-selector pairings. Thus, we provide an elegant molecular model based on competition and cooperation between two sets of docking site-selector and balancer pairings, which counteracts the "first-come, first-served" principle. Our findings provide conceptual and mechanistic insight into the dynamics and functions of long-range RNA secondary structures.

Mosquito midgut epithelium traversal is essential for malaria parasite transmission. Phospholipid flippases are eukaryotic type 4 P-type adenosine triphosphatases (P4-ATPases), which, in association with CDC50, translocate phospholipids across the membrane lipid bilayers. In this study, we investigated the function of a putative P4-ATPase, ATP7, from the rodent malaria parasite Plasmodium yoelii Disruption of ATP7 blocks the parasite infection of mosquitoes. ATP7 is localized on the ookinete plasma membrane. While ATP7-depleted ookinetes are capable of invading the midgut, they are eliminated within the epithelial cells by a process independent from the mosquito complement-like immunity. ATP7 colocalizes and interacts with the flippase cofactor CDC50C. Depletion of CDC50C phenocopies ATP7 deficiency. ATP7-depleted ookinetes fail to uptake phosphatidylcholine across the plasma membrane. Ookinete microinjection into the mosquito hemocoel reverses the ATP7 deficiency phenotype. Our study identifies Plasmodium flippase as a mechanism of parasite survival in the midgut epithelium that is required for mosquito transmission., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

CpG islands (CGIs) are key regulatory DNA elements at most promoters, but how they influence the chromatin status and transcription remains elusive. Here, we identify and characterize SAMD1 (SAM domain-containing protein 1) as an unmethylated CGI-binding protein. SAMD1 has an atypical winged-helix domain that directly recognizes unmethylated CpG-containing DNA via simultaneous interactions with both the major and the minor groove. The SAM domain interacts with L3MBTL3, but it can also homopolymerize into a closed pentameric ring. At a genome-wide level, SAMD1 localizes to H3K4me3-decorated CGIs, where it acts as a repressor. SAMD1 tethers L3MBTL3 to chromatin and interacts with the KDM1A histone demethylase complex to modulate H3K4me2 and H3K4me3 levels at CGIs, thereby providing a mechanism for SAMD1-mediated transcriptional repression. The absence of SAMD1 impairs ES cell differentiation processes, leading to misregulation of key biological pathways. Together, our work establishes SAMD1 as a newly identified chromatin regulator acting at unmethylated CGIs., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Alternative complex III (ACIII) is a multisubunit quinol:electron acceptor oxidoreductase that couples quinol oxidation with transmembrane proton translocation in both the respiratory and photosynthetic electron transport chains of bacteria. The coupling mechanism, however, is poorly understood. Here, we report the cryo-EM structures of air-oxidized and dithionite-reduced ACIII from the photosynthetic bacterium Roseiflexus castenholzii at 3.3- and 3.5-Å resolution, respectively. We identified a menaquinol binding pocket and an electron transfer wire comprising six hemes and four iron-sulfur clusters that is capable of transferring electrons to periplasmic acceptors. We detected a proton translocation passage in which three strictly conserved, mid-passage residues are likely essential for coupling the redox-driven proton translocation across the membrane. These results allow us to propose a previously unrecognized coupling mechanism that links the respiratory and photosynthetic functions of ACIII. This study provides a structural basis for further investigation of the energy transformation mechanisms in bacterial photosynthesis and respiration., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Histone H3 point mutations have been identified in incurable pediatric brain cancers, but the mechanisms through which these mutations drive tumorigenesis are incompletely understood. Here, we provide evidence that RACK7 (ZMYND8) recognizes the histone H3.3 patient mutation (H3.3G34R) in vitro and in vivo. We show that RACK7 binding to H3.3G34R suppresses transcription of CIITA , which is the master regulator of MHC (major histocompatibility complex) class II molecules and genes involved in vesicular transport of MHC class II molecules to the cell surface, resulting in suppression of MHC class II molecule expression and transport. CRISPR-based knock-in correction of the H3.3G34R mutation in human pediatric glioblastoma (pGBM) cells significantly reduces overall RACK7 chromatin binding and derepresses the same set of genes as does knocking out RACK7 in the H3.3G34R pGBM cells. By demonstrating that H3.3G34R and RACK7 work together, our findings suggest a potential molecular mechanism by which H3.3G34R promotes cancer., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

The selective formation of nanomaterials in cancer cells and tumors holds great promise for cancer diagnostics and therapy. Until now, most strategies rely on a single trigger to control the formation of nanomaterials in situ . The combination of two or more triggers may provide for more sophisticated means of manipulation. In this study, we rationally designed a molecule ( Comp. 1 ) capable of responding to two enzymes, alkaline phosphatase (ALP), and reductase. Since the A549 lung cancer cell line showed elevated levels of extracellular ALP and intracellular reductase, we demonstrated that Comp. 1 responded in a stepwise fashion to those two enzymes and displayed a tandem molecular self-assembly behavior. The selective formation of nanofibers in the mitochondria of the lung cancer cells led to the disruption of the mitochondrial membrane, resulting in an increased level of reactive oxygen species (ROS) and the release of cytochrome C (Cyt C). ROS can react with proteins, resulting in endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). This severe ER stress led to disruption of the ER, formation of vacuoles, and ultimately, apoptosis of the A549 cells. Therefore, Comp. 1 could selectively inhibit lung cancer cells in vitro and A549 xenograft tumors in vivo . Our study provides a novel strategy for the selective formation of nanomaterials in lung cancer cells, which is powerful and promising for the diagnosis and treatment of lung cancer., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 Debin Zheng et al.)

Perfect matching of an assembled physical sequence to a specified designed sequence is crucial to verify design principles in genome synthesis. We designed and de novo synthesized 536,024-base pair chromosome synV in the "Build-A-Genome China" course. We corrected an initial isolate of synV to perfectly match the designed sequence using integrative cotransformation and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated editing in 22 steps; synV strains exhibit high fitness under a variety of culture conditions, compared with that of wild-type V strains. A ring synV derivative was constructed, which is fully functional in Saccharomyces cerevisiae under all conditions tested and exhibits lower spore viability during meiosis. Ring synV chromosome can extends Sc2.0 design principles and provides a model with which to study genomic rearrangement, ring chromosome evolution, and human ring chromosome disorders., (Copyright © 2017, American Association for the Advancement of Science.)

Although apoptosis triggered by ultraviolet B (UVB)-mediated activation of the c-Jun N-terminal kinase (JNK) pathway is mediated by both intrinsic and extrinsic pathways, the mechanism of initiation of JNK activation remains obscure. Here, we report the characterization of the JNK-interacting protein 3 (JIP-3) scaffolding protein as an interacting partner of Rho-associated kinase 1 (ROCK1), as determined by tandem affinity protein purification. Upon UVB-induced stress in keratinocytes, ROCK1 was activated, bound to JIP-3, and activated the JNK pathway. Moreover, phosphorylation of JIP-3 by ROCK1 was crucial for the recruitment of JNK. Inhibition of the activity of ROCK1 in keratinocytes resulted in decreased activation of the JNK pathway and thus a reduction in apoptosis. ROCK1(+/-) mice exhibited decreased UVB-mediated activation of JNK and apoptosis relative to wild-type mice. Our findings present a new molecular mechanism by which ROCK1 functions as a UVB sensor that regulates apoptosis, an important event in the prevention of skin cancer.