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Photothermal heating and photocatalytic treatment are two solar-driven water processing approaches by harnessing NIR and UV-vis light, respectively, which can fully utilize solar energy if integrated. However, it remains a challenge to achieve high performance in both approaches when integrated in a material due to uncontrollable heat diffusion. Here, we report a demonstration of heat confinement on photothermal sites and fluid cooling on photocatalysis sites at the nanoscale, within a well-designed heat and fluid confinement nanofiber reactor. Photothermal and photocatalytic nanostructures were alternatively aligned in electrospun nanofibers for on-demand nanofluidic thermal management as well as easy folding into 3D structures with enhanced light utilization and mass transfer. Such a design showed simultaneously high photothermal evaporation rate (2.59 kg m-2 h-1, exceeding the limit rate) and efficient photocatalytic upcycling of microplastics pollutant into valued products. Enabled by controlled photothermal heating, the valued main product (i.e., methyl acetate) can be evaporated out with 100% selectivity by in situ separation. [ABSTRACT FROM AUTHOR]

Floral organs are properly developed on the basis of timed floral meristem (FM) termination in Arabidopsis. In this process, two known regulatory pathways are involved. The WUSCHEL (WUS)-CLAVATA3 (CLV3) feedback loop is vital for the spatial establishment and maintenance of the FM, while AGAMOUS (AG)-WUS transcriptional cascades temporally repress FM. At stage 6 of flower development, a C2H2-type zinc finger repressor that is a target of AG, KNUCKLES (KNU), directly represses the stem cell identity gene WUS in the organizing center for FM termination. However, how the robust FM activity is fully quenched within a limited time frame to secure carpel development is not fully understood. Here, we demonstrate that KNU directly binds to the CLV1 locus and the cis-regulatory element on CLV3 promoter and represses their expression during FM determinacy control. Furthermore, KNU physically interacts with WUS, and this interaction inhibits WUS from sustaining CLV3 in the central zone. The KNU-WUS interaction also interrupts the formation of WUS homodimers and WUS-HAIRYMERISTEM 1 heterodimers, both of which are required for FM maintenance. Overall, our findings describe a regulatory framework in which KNU plays a position-specific multifunctional role for the tightly controlled FM determinacy. [ABSTRACT FROM AUTHOR]

TMEM39A encodes an evolutionarily conserved transmembrane protein and carries single-nucleotide polymorphisms associated with increased risk of major human autoimmune diseases, including multiple sclerosis. The exact cellular function of TMEM39A remains not well understood. Here, we report that TMEM-39, the sole Caenorhabditis elegans (C. elegans) ortholog of TMEM39A, regulates lysosome distribution and accumulation. Elimination of tmem-39 leads to lysosome tubularization and reduced lysosome mobility, as well as accumulation of the lysosome-associated membrane protein LMP-1. In mammalian cells, loss of TMEM39A leads to redistribution of lysosomes from the perinuclear region to cell periphery. Mechanistically, TMEM39A interacts with the dynein intermediate light chain DYNC1I2 to maintain proper lysosome distribution. Deficiency of tmem-39 or the DYNC1I2 homolog in C. elegans impairs mTOR signaling and activates the downstream TFEB-like transcription factor HLH-30. We propose evolutionarily conserved roles of TMEM39 family proteins in regulating lysosome distribution and lysosome-associated signaling, dysfunction of which in humans may underlie aspects of autoimmune diseases. [ABSTRACT FROM AUTHOR]

IFN-stimulated genes (ISGs) are essential effectors of the IFN-dependent antiviral immune response. Dysregulation of ISG expression can cause dysfunctional antiviral responses and autoimmune disorders. Epitranscriptomic regulation, such as N6-methyladenosine (m6A) modification of mRNAs, plays key roles in diverse biological processes. Here, we found that the m6A “reader" YT521-B homology domain-containing family 3 (YTHDF3) suppresses ISG expression under basal conditions by promoting translation of the transcription corepressor forkhead box protein O3 (FOXO3). YTHDF3 cooperates with two cofactors, PABP1 and eIF4G2, to promote FOXO3 translation by binding to the translation initiation region of FOXO3 mRNA. Both the YTH and the P/Q/N-rich domains of YTHDF3 were required for FOXO3 RNA-binding capacity, however, METTL3-mediated m6A modification was not involved in the process observed. Moreover, YTHDF3-/- mice had increased ISG levels and were resistant to several viral infections. Our findings uncover the role of YTHDF3 as a negative regulator of antiviral immunity through the translational promotion of FOXO3 mRNA under homeostatic conditions, adding insight into the networks of RNAbinding protein-RNA interactions in homeostatically maintaining host antiviral immune function and preventing inflammatory response. [ABSTRACT FROM AUTHOR]

Terpenes are the major secondary metabolites produced by plants, and have diverse industrial applications as pharmaceuticals, fragrance, solvents, and biofuels. Cyanobacteria are equipped with efficient carbon fixation mechanism, and are ideal cell factories to produce various fuel and chemical products. Past efforts to produce terpenes in photosynthetic organisms have gained only limited success. Here we engineered the cyanobacterium Synechococcus elongatus PCC 7942 to efficiently produce limonene through modeling guided study. Computational modeling of limonene flux in response to photosynthetic output has revealed the downstream terpene synthase as a key metabolic flux-controlling node in the MEP (2-C-methyl-d-erythritol 4-phosphate) pathway-derived terpene biosynthesis. By enhancing the downstream limonene carbon sink, we achieved over 100-fold increase in limonene productivity, in contrast to the marginal increase achieved through stepwise metabolic engineering. The establishment of a strong limonene flux revealed potential synergy between photosynthate output and terpene biosynthesis, leading to enhanced carbon flux into the MEP pathway. Moreover, we show that enhanced limonene flux would lead to NADPH accumulation, and slow down photosynthesis electron flow. Fine-tuning ATP/NADPH toward terpene biosynthesis could be a key parameter to adapt photosynthesis to support biofuel/bioproduct production in cyanobacteria. [ABSTRACT FROM AUTHOR]

Water oxidation on magnetic catalysts has generated significant interest due to the spin-polarization effect. Recent studies have revealed that the disappearance of magnetic domain wall upon magnetization is responsible for the observed oxygen evolution reaction (OER) enhancement. However, an atomic picture of the reaction pathway remains unclear, i.e., which reaction pathway benefits most from spin-polarization, the adsorbent evolution mechanism, the intermolecular mechanism (I2M), the lattice oxygen-mediated one, or more? Here, using three model catalysts with distinguished atomic chemistries of active sites, we are able to reveal the atomic-level mechanism. We found that spin-polarized OER mainly occurs at interconnected active sites, which favors direct coupling of neighboring ligand oxygens (I2M). Furthermore, our study reveals the crucial role of lattice oxygen participation in spin-polarized OER, significantly facilitating the coupling kinetics of neighboring oxygen radicals at active sites. [ABSTRACT FROM AUTHOR]

At an early stage during Bacillus subtilis endospore development the bacterium divides asymmetrically to produce two daughter cells. The smaller cell (forespore) differentiates into the endospore, while the larger cell (mother cell) becomes a terminally differentiated cell that nurtures the developing forespore. During development the mother cell engulfs the forespore to produce a protoplast, surrounded by two bilayer membranes, which separate it from the cytoplasm of the mother cell. The activation of σ[supG], which drives late gene expression in the forespore. follows forespore engulfment and requires expression of the spolllA locus in the mother cell. One of the spolllA-encoded proteins SpolllAH is targeted specifically to the membrane surrounding the forespore, through an interaction of its C-terminal extracellular domain with the C-terminal extracellular domain of the forespore membrane protein SpollQ. We identified a homologous relationship between the C-terminal domain of SpolllAH and the YscJ/FliF protein family, members of which form multimeric rings involved in type Ill secretion systems and flagella. If Sp0IIIAH forms a similar ring structure, it may also form a channel between the mother cell and forespore membranes. To test this hypothesis we developed a compartmentalized biotinylation assay, which we used to show that the C-terminal extracellular domain of Sp0IIIAH is accessible to enzymatic modification from the forespore cytoplasm. These and other results lead us to suggest that Sp0IIIAH forms part of a channel between the forespore and mother cell that is required for the activation of σ[supG]. [ABSTRACT FROM AUTHOR]

Caspase-1 plays a key role in inflammatory pathways by processing pro-IL-Iβ into the active cytokine mature IL-1β. Given its sequence similarity with the Caenorhabditis elegans cell death gene ced-3, it has long been speculated that caspase-1 may also play a role in cell death. However, an unequivocal role for caspase-1 in cell death has been questioned, and not definitively demonstrated. Furthermore, if caspase-1 does play a role in cell death, its position in the apoptotic hierarchy has not been clearly defined. Previous studies have shown that caspase-1 knockout (KO) mice and transgenic mice expressing a dominant-negative caspase-1 construct are resistant to ischemic brain injury. We provide direct evidence that caspase-1 plays a key role in neuronal cell death and that caspase-1 is an apical activator of the cell death pathway in the premitochondrial collapse stage. Furthermore, we demonstrate that Rip2/ Cardiak/Rick is a stress-inducible upstream modulator of procaspase-1 apoptotic activation. We provide evidence that Bid cleavage appears to be an important downstream effector of caspase-l-mediated cell death. Our data demonstrate that caspase-1 is an apical mediator of neuronal cell death during in vitro hypoxia, and confirmed in vivo in ischemia, and provide insights into the sequence of events involved in this pathological cell death process. [ABSTRACT FROM AUTHOR]

Studies the origin, properties, and liver repopulating capacity of murine oval cells. Induction of the oval cell proliferation in adult mouse liver by 3,5-diethoxycarbonyl-1,4-dihydrocolidine; Development of a method for the isolation of the oval cells; Suggestion that hepatic oval cells do not originate in bone marrow but in the liver itself; Mouse strains and animal husbandry.

Minocycline is broadly protective in neurologic disease models featuring cell death and is being evaluated in clinical trials. We previously demonstrated that minocycline-mediated protection against caspase-dependent cell death related to its ability to prevent mitochondrial cytochrome c release. These results do not explain whether or how minocycline protects against caspaseindependent cell death. Furthermore, there is no information on whether Smac/Diablo or apoptosis-inducing factor might play a role in chronic neurodegeneration. In a striatal cell model of Huntington's disease and in R6/2 mice, we demonstrate the association of cell death/disease progression with the recruitment of mitochondrial caspase-independent (apoptosis-inducing factor) and caspase-dependent (Smac/Diablo and cytochrome c) triggers. We show that minocycline is a drug that directly inhibits both caspase-independent and -dependent mitochondrial cell death pathways. Furthermore, this report demonstrates recruitment of Smac/Diablo and apoptosis-inducing factor in chronic neurodegeneration. Our results further delineate the mechanism by which minocycline mediates its remarkably broad neuroprotective effects. [ABSTRACT FROM AUTHOR]

The exploitation of novel wound healing methods with real-time infection sensing and high spatiotemporal precision is highly important for human health. Pt-based metal-organic cycles/cages (MOCs) have been employed as multifunctional antibacterial agents due to their superior Pt-related therapeutic efficiency, various functional subunits and specific geometries. However, how to rationally apply these nanoscale MOCs on the macroscale with controllable therapeutic output is still challenging. Here, a centimeter-scale Pt MOC film was constructed via multistage assembly and subsequently coated on a N,N'-dimethylated dipyridinium thiazolo[5,4-d]thiazole (MPT)-stained silk fabric to form a smart wound dressing for bacterial sensing and wound healing. The MPT on silk fabric could be used to monitor wound infection in real-time through the bacteria-mediated reduction of MPT to its radical form via a color change. The MPT radical also exhibited an excellent photothermal effect under 660 nm light irradiation, which could not only be applied for photothermal therapy but also induce the disassembly of the Pt MOC film suprastructure. The highly ordered Pt MOC film suprastructure exhibited high biosafety, while it also showed improved antibacterial efficiency after thermally induced disassembly. In vitro and in vivo studies revealed that the combination of the Pt MOC film and MPT-stained silk can provide real-time information on wound infection for timely treatment through noninvasive techniques. This study paves the way for bacterial sensing and wound healing with centimeter-scale metal-organic materials. [ABSTRACT FROM AUTHOR]

L-type voltage-gated calcium (Ca2+) channels (L-VGCC) dysfunction is implicated in several neurological and psychiatric diseases. While a popular therapeutic target, it is unknown whether molecular mechanisms leading to disrupted L-VGCC across neurodegenerative disorders are conserved. Importantly, L-VGCC integrate synaptic signals to facilitate a plethora of cellular mechanisms; however, mechanisms that regulate L-VGCC channel density and subcellular compartmentalization are understudied. Herein, we report that in disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), deficits in dendritic L-VGCC activity are associated with increased expression of the RNA-binding protein (RBP) Parkinsonism-associated deglycase (DJ-1). DJ-1 binds the mRNA coding for the alpha and auxiliary Ca2+ channel subunits CaV1.2 and a2d2, and represses their mRNA translation, only in the disease states, specifically preclinical models of tuberous sclerosis complex (TSC) and Alzheimer's disease (AD). In agreement, DJ-1-mediated repression of CaV1.2/a2d2 protein synthesis in dendrites is exaggerated in mouse models of AD and TSC, resulting in deficits in dendritic L-VGCC calcium activity. Finding of DJ-1-regulated L-VGCC activity in dendrites in TSC and AD provides a unique signaling pathway that can be targeted in clinical mTORopathies. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) play vital roles in establishing a suitable tumor microenvironment. In this study, RNA sequencing data revealed that CAFs could promote cell proliferation, angiogenesis, and ECM reconstitution by binding to integrin families and activating PI3K/AKT pathways in esophageal squamous cell carcinoma (ESCC). The secretions of CAFs play an important role in regulating these biological activities. Among these secretions, we found that MFGE8 is specifically secreted by CAFs in ESCC. Additionally, the secreted MFGE8 protein is essential in CAF-regulated vascularization, tumor proliferation, drug resistance, and metastasis. By binding to Integrin aVß3/aVß5 receptors, MFGE8 promotes tumor progression by activating both the PI3K/AKT and ERK/AKT pathways. Interestingly, the biological function of MFGE8 secreted by CAFs fully demonstrated the major role of CAFs in ESCC and its mode of mechanism, showing that MFGE8 could be a driver factor of CAFs in remodeling the tumor environment. In vivo treatment targeting CAFs-secreting MFGE8 or its receptor produced significant inhibitory effects on ESCC growth and metastasis, which provides an approach for the treatment of ESCC. [ABSTRACT FROM AUTHOR]

Epithelial barrier disruption is a major cause of inflammatory bowel disease (IBD),however, the cellular and molecular regulation of intestinal epithelial homeostasis remains largely undefined. Here, we show that the C-type lectin receptor LSECtin (Clec4g) on macrophages is required for protection against dextran sulfate sodiuminduced colitis. Mechanistically, LSECtin promotes apoptotic cell clearance by macrophages and induces the production of antiinflammatory/ tissue repair factors in an engulfment-dependent manner, which in turn stimulates epithelial cell proliferation. Deletion of LSECtin results in defective engulfment by colon macrophages, leading to aberrant proresolving factor production and impaired intestinal epithelium repair. Collectively, our findings suggest that LSECtindependent corpse clearance by macrophages can direct intestinal regeneration and maintenance of the mucosal barrier after injury. [ABSTRACT FROM AUTHOR]

Defense against ultraviolet (UV) radiation exposure is essential for survival, especially in high-elevation species. Although some specific genes involved in UV response have been reported, the full view of UV defense mechanisms remains largely unexplored. Herein, we used integrated approaches to analyze UV responses in the highest-elevation frog, Nanorana parkeri. We show less damage and more efficient antioxidant activity in skin of this frog than those of its lower-elevation relatives after UV exposure. We also reveal genes related to UV defense and a corresponding temporal expression pattern in N. parkeri. Genomic and metabolomic analysis along with large-scale transcriptomic profiling revealed a time-dependent coordinated defense mechanism in N. parkeri. We also identified several microRNAs that play important regulatory roles, especially in decreasing the expression levels of cell cycle genes. Moreover, multiple defense genes (i.e., TYR for melanogenesis) exhibit positive selection with function-enhancing substitutions. Thus, both expression shifts and gene mutations contribute to UV adaptation in N. parkeri. Our work demonstrates a genetic framework for evolution of UV defense in a natural environment. [ABSTRACT FROM AUTHOR]

High-performance metabolic analysis is emerging in the diagnosis and prognosis of breast cancer (BrCa). Still, advanced tools are in demand to deliver the application potentials of metabolic analysis. Here, we used fast nanoparticle-enhanced laser desorption/ ionization mass spectrometry (NPELDI-MS) to record serum metabolic fingerprints (SMFs) of BrCa in seconds, achieving high reproducibility and low consumption of direct serum detection without treatment. Subsequently, machine learning of SMFs generated by NPELDI-MS functioned as an efficient readout to distinguish BrCa from non-BrCa with an area under the curve of 0.948. Furthermore, a metabolic prognosis scoring system was constructed using SMFs with effective prediction performance toward BrCa (P < 0.005). Finally, we identified a biomarker panel of seven metabolites that were differentially enriched in BrCa serum and their related pathways. Together, our findings provide an efficient serum metabolic tool to characterize BrCa and highlight certain metabolic signatures as potential diagnostic and prognostic factors of diseases including but not limited to BrCa. [ABSTRACT FROM AUTHOR]

Insects have evolved diverse methods of predator avoidance, many of which implicate complex adaptations of their wings (e.g., Phylliidae, Nymphalidae, Notodontidae). Among these, angiosperm leaf mimicry is one of the most dramatic, although the historical origins of such modifications are unclear owing to a dearth of paleontological records. Here, we report evidence of pinnate leaf mimesis in two lacewings (Neuroptera): Bellinympha filicifolia Y. Wang, Ren, Liu & Engel gen. et sp. nov. and Bellinympha dancei Y. Wang, Ren, Shih & Engel, sp. nov., from the Middle Jurassic, representing a 165-million-year-old specialization between insects and contemporaneous gymnosperms of the Cycadales or Bennettitales. Furthermore, such lacewings demonstrate a preangiosperm origin for leaf mimesis, revealing a lost evolutionary scenario of interactions between insects and gymnosperms. The current fossil record suggests that this enigmatic lineage became extinct during the Early Cretaceous, apparently closely correlated with the decline of Cycadales and Bennettitales at that time, and perhaps owing to the changing floral environment resulted from the rise of flowering plants. [ABSTRACT FROM AUTHOR]

The ubiquitin E3 ligase Bre1-mediated H2B monoubiquitination (H2Bub) is essential for proper DNA replication and repair in eukaryotes. Deficiency in H2Bub causes genome instability and cancer. How the Bre1-H2Bub pathway is evoked in response to DNA replication or repair remains unknown. Here, we identify that the singlestranded DNA (ssDNA) binding factor RPA acts as a key mediator that couples Bre1-mediated H2Bub to DNA replication and repair in yeast. We found that RPA interacts with Bre1 in vitro and in vivo, and this interaction is stimulated by ssDNA. This association ensures the recruitment of Bre1 to replication forks or DNA breaks but does not affect its E3 ligase activity. Disruption of the interaction abolishes the local enrichment of H2Bub, resulting in impaired DNA replication, response to replication stress, and repair by homologous recombination, accompanied by increased genome instability and DNA damage sensitivity. Notably, we found that RNF20, the human homolog of Bre1, interacts with RPA70 in a conserved mode. Thus, RPA functions as amaster regulator for the spatial-temporal control of H2Bub chromatin landscape during DNA replication and recombination, extending the versatile roles of RPA in guarding genome stability. [ABSTRACT FROM AUTHOR]

Cholesterol 25-hydroxylase (CH25H) is an interferon (IFN)-stimulated gene that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of cholesterol export. Our results highlight one of the possible antiviral mechanisms of 25HC and provide the molecular basis for its therapeutic development. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and thus repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a restraint energy distribution (RED) function, making the practical FEP-ABFE-based virtual screening of the existing drug library possible. As a result, out of 25 drugs predicted, 15 were confirmed as potent inhibitors of SARS-CoV-2 Mpro. The most potent one is dipyridamole (inhibitory constant Ki = 0.04 µM)which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki = 0.36 µM) and chloroquine (Ki = 0.56 µM) were also found to potently inhibit SARS-CoV-2 Mpro. We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts. [ABSTRACT FROM AUTHOR]

Morphological profiling is a method to classify target pathways of antibacterials based on how bacteria respond to treatment through changes to cellular shape and spatial organization. Here we utilized the cell-to-cell variation in morphological features of Mycobacterium tuberculosis bacilli to develop a rapid profiling platform called Morphological Evaluation and Understanding of Stress (MorphEUS). MorphEUS classified 94% of tested drugs correctly into broad categories according to modes of action previously identified in the literature. In the other 6%, MorphEUS pointed to key off-target activities. We observed cell wall damage induced by bedaquiline and moxifloxacin through secondary effects downstream from their main target pathways. We implemented MorphEUS to correctly classify three compounds in a blinded study and identified an off-target effect for one compound that was not readily apparent in previous studies. We anticipate that the ability of MorphEUS to rapidly identify pathways of drug action and the proximal cause of cellular damage in tubercle bacilli will make it applicable to other pathogens and cell types where morphological responses are subtle and heterogeneous. [ABSTRACT FROM AUTHOR]

Temperature is a fundamental parameter for all forms of lives. Natural evolution has resulted in organisms which have excellent thermoregulation capabilities in extreme climates. Bioinspired materials that mimic biological solution for thermoregulation have proven promising for passive radiative cooling. However, scalable production of artificial photonic radiators with complex structures, outstanding properties, high throughput, and low cost is still challenging. Herein, we design and demonstrate biologically inspired photonic materials for passive radiative cooling, after discovery of longicorn beetles' excellent thermoregulatory function with their dual-scale fluffs. The natural fluffs exhibit a finely structured triangular cross-section with two thermoregulatory effects which effectively reflects sunlight and emits thermal radiation, thereby decreasing the beetles' body temperature. Inspired by the finding, a photonic film consisting of a micropyramid-arrayed polymer matrix with random ceramic particles is fabricated with high throughput. The film reflects ~95% of solar irradiance and exhibits an infrared emissivity >0.96. The effective cooling power is found to be ~90.8 W·m-2 and a temperature decrease of up to 5.1 °C is recorded under direct sunlight. Additionally, the film exhibits hydrophobicity, superior flexibility, and strong mechanical strength, which is promising for thermal management in various electronic devices and wearable products. Our work paves the way for designing and fabrication of high-performance thermal regulation materials. [ABSTRACT FROM AUTHOR]

Directional cell migration involves signaling cascades that stimulate actin assembly at the leading edge, and additional pathways must inhibit actin polymerization at the rear. During neuroblast migration in Caenorhabditis elegans, the transmembrane protein MIG-13/Lrp12 acts through the Arp2/3 nucleation-promoting factors WAVE and WASP to guide the anterior migration. Here we show that a tyrosine kinase, SRC-1, directly phosphorylates MIG-13 and promotes its activity on actin assembly at the leading edge. In GFP knockin animals, SRC-1 and MIG-13 distribute along the entire plasma membrane of migrating cells. We reveal that a receptor-like tyrosine phosphatase, PTP-3, maintains the F-actin polarity during neuroblast migration. Recombinant PTP-3 dephosphorylates SRC-1-dependent MIG-13 phosphorylation in vitro. Importantly, the endogenous PTP-3 accumulates at the rear of the migrating neuroblast, and its extracellular domain is essential for directional cell migration. We provide evidence that the asymmetrically localized tyrosine phosphatase PTP-3 spatially restricts MIG-13/Lrp12 receptor activity in migrating cells. [ABSTRACT FROM AUTHOR]

Ten-eleven translocation (TET) family enzymes (TET1, TET2, and TET3) oxidize 5-methylcytosine (5mC) and generate 5-hydroxymethylcytosine (5hmC) marks on the genome. Each TET protein also interacts with specific binding partners and partly plays their role independent of catalytic activity. Although the basic role of TET enzymes is well established now, the molecular mechanism and specific contribution of their catalytic and noncatalytic domains remain elusive. Here, by combining in silico and biochemical screening strategy, we have identified a small molecule compound, C35, as a first-in-class TET inhibitor that specifically blocks their catalytic activities. Using this inhibitor, we explored the enzymatic function of TET proteins during somatic cell reprogramming. Interestingly, we found that C35-mediated TET inactivation increased the efficiency of somatic cell programming without affecting TET complexes. Using high-throughput mRNA sequencing, we found that by targeting 5hmC repressive marks in the promoter regions, C35-mediated TET inhibition activates the transcription of the BMP-SMAD-ID signaling pathway, which may be responsible for promoting somatic cell reprogramming. These results suggest that C35 is an important tool for inducing somatic cell reprogramming, as well as for dissecting the other biological functions of TET enzymatic activities without affecting their other nonenzymatic roles. [ABSTRACT FROM AUTHOR]

The 2016, moment magnitude (Mw) 7.8, Kaikoura earthquake generated the most complex surface ruptures ever observed. Although likely linked with kinematic changes in central New Zealand, the driving mechanisms of such complexity remain unclear. Here, we propose an interpretation accounting for the most puzzling aspects of the 2016 rupture. We examine the partitioning of plate motion and coseismic slip during the 2016 event in and around Kaikoura and the large-scale fault kinematics, volcanism, seismicity, and slab geometry in the broader Tonga-Kermadec region. We find that the plate motion partitioning near Kaikoura is comparable to the coseismic partitioning between strike-slip motion on the Kekerengu fault and subperpendicular thrusting along the offshore West-Hikurangi megathrust. Together with measured slip rates and paleoseismological results along the Hope, Kekerengu, and Wairarapa faults, this observation suggests that the West-Hikurangi thrust and Kekerengu faults bound the southernmost tip of the Tonga-Kermadec sliver plate. The narrow region, around Kaikoura, where the 3 fastest-slipping faults of New Zealand meet, thus hosts a fault- fault-trench (FFT) triple junction, which accounts for the particularly convoluted 2016 coseismic deformation. That triple junction appears to have migrated southward since the birth of the sliver plate (around 5 to 7 million years ago). This likely drove southward stepping of strike-slip shear within the Marlborough fault system and propagation of volcanism in the North Island. Hence, on a multimillennial time scale, the apparently distributed faulting across southern New Zealand may reflect classic plate-tectonic triple-junction migration rather than diffuse deformation of the continental lithosphere. [ABSTRACT FROM AUTHOR]

Our understanding of the mechanisms of neural circuit assembly is far from complete. Identification of wiring molecules with novel mechanisms of action will provide insights into how complex and heterogeneous neural circuits assemble during development. In the Drosophila olfactory system, 50 classes of olfactory receptor neurons (ORNs) make precise synaptic connections with 50 classes of partner projection neurons (PNs). Here, we performed an RNA interference screen for cell surface molecules and identified the leucine-rich repeat-containing transmembrane protein known as Fish-lips (Fili) as a novel wiring molecule in the assembly of the Drosophila olfactory circuit. Fili contributes to the precise axon and dendrite targeting of a small subset of ORN and PN classes, respectively. Cell-type-specific expression and genetic analyses suggest that Fili sends a transsynaptic repulsive signal to neurites of nonpartner classes that prevents their targeting to inappropriate glomeruli in the antennal lobe. [ABSTRACT FROM AUTHOR]

Metastases constitute the greatest causes of deaths from cancer. However, no effective therapeutic options currently exist for cancer patients with metastasis. Estrogen receptor β (ERβ), as a member of the nuclear receptor superfamily, shows potent tumor-suppressive activities in many cancers. To investigate whether modulation of ERβ could serve as a therapeutic strategy for cancer metastasis, we examined whether the selective ERβ agonist LY500307 could suppress lung metastasis of triple-negative breast cancer (TNBC) and melanoma. Mechanistically, while we observed that LY500307 potently induced cell death of cancer cells metastasized to lung in vivo, it does not mediate apoptosis of cancer cells in vitro, indicating that the cell death-inducing effects of LY500307 might be mediated by the tumor microenvironment. Pathological examination combined with flow cytometry assays indicated that LY500307 treatment induced significant infiltration of neutrophils in the metastatic niche. Functional experiments demonstrated that LY500307-treated cancer cells show chemotactic effects for neutrophils and that in vivo neutrophil depletion by Ly6G antibody administration could reverse the effects of LY500307-mediated metastasis suppression. RNA sequencing analysis showed that LY500307 could induce up-regulation of IL-1β in TNBC and melanoma cells, which further triggered antitumor neutrophil chemotaxis. However, the therapeutic effects of LY500307 treatment for suppression of lung metastasis was attenuated in IL1B-/- murine models, due to failure to induce antitumor neutrophil infiltration in the metastatic niche. Collectively, our study demonstrated that pharmacological activation of ERβ could augment innate immunity to suppress cancer metastatic colonization to lung, thus providing alternative therapeutic options for cancer patients with metastasis. [ABSTRACT FROM AUTHOR]

Skeletal muscles harbor quiescent muscle-specific stem cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targetsMuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromisesmuscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1. Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes muscle repair and strength. Through such gain- or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent. [ABSTRACT FROM AUTHOR]

Neisseria meningitidis (Nm) clonal complex 11 (cc11) lineage is a hypervirulent pathogen responsible for outbreaks of invasivemeningococcal disease, including among men who have sex with men, and is increasingly associated with urogenital infections. Recently, clusters of Nm urethritis have emerged primarily among heterosexual males in the United States. We determined that nonencapsulated meningococcal isolates from an ongoing Nm urethritis outbreak among epidemiologically unrelated men in Columbus, Ohio, are linked to increased Nm urethritis cases in multiple US cities, including Atlanta and Indianapolis, and that they form a unique clade (the US Nm urethritis clade, US_NmUC). The isolates belonged to the cc11 lineage 11.2/ET-15 with fine type of PorA P1.5-1, 10-8; FetA F3-6; PorB 2-2 and express a unique FHbp allele. A common molecular fingerprint of US_NmUC isolates was an IS1301 element in the intergenic region separating the capsule ctr-css operons and adjacent deletion of cssA/B/C and a part of csc, encoding the serogroup C capsule polymerase. This resulted in the loss of encapsulation and intrinsic lipooligosaccharide sialylation that may promote adherence to mucosal surfaces. Furthermore, we detected an IS1301-mediated inversion of an ~20-kb sequence near the cps locus. Surprisingly, these isolates had acquired by gene conversion the complete gonococcal denitrification norB-aniA gene cassette, and strains grow well anaerobically. The cc11 US_NmUC isolates causing urethritis clusters in the United States may have adapted to a urogenital environment by loss of capsule and gene conversion of the Neisseria gonorrheae norB-aniA cassette promoting anaerobic growth. [ABSTRACT FROM AUTHOR]

In this paper we describe the antibacterial effect of methylene blue, MB, and silver nitrate reacting alone and in combination against five bacterial strains including Serratia marcescens and Escherichia coli bacteria. The data presented suggest that when the two components are combined and react together against bacteria, the effects can be up to three orders ofmagnitude greater than that of the sum of the two components reacting alone against bacteria. Analysis of the experimental data provides proof that a synergistic mechanism is operative within a dose range when the two components react together, and additive when reacting alone against bacteria. [ABSTRACT FROM AUTHOR]

Intracellular accumulation of wild-type tau is a hallmark of sporadic Alzheimer's disease (AD), but the molecular mechanisms underlying tau-induced synapse impairment and memory deficit are poorly understood. Here we found that overexpression of human wild-type full-length tau (termed hTau) induced memory deficits with impairments of synaptic plasticity. Both in vivo and in vitro data demonstrated that hTau accumulation caused remarkable dephosphorylation of cAMP response element binding protein (CREB) in the nuclear fraction. Simultaneously, the calcium-dependent protein phosphatase calcineurin (CaN) was up-regulated, whereas the calcium/ calmodulin-dependent protein kinase IV (CaMKIV) was suppressed. Further studies revealed that CaN activation could dephosphorylate CREB and CaMKIV, and the effect of CaN on CREB dephosphorylation was independent of CaMKIV inhibition. Finally, inhibition of CaN attenuated the hTau-induced CREB dephosphorylation with improved synapse and memory functions. Together, these data indicate that the hTau accumulation impairs synapse and memory by CaN-mediated suppression of nuclear CaMKIV/CREB signaling. Our findings not only reveal new mechanisms underlying the hTau-induced synaptic toxicity, but also provide potential targets for rescuing tauopathies. [ABSTRACT FROM AUTHOR]

Printed electronics are considered for wireless electronic tags and sensors within the future Internet-of-things (loT) concept. As a consequence of the low charge carrier mobility of present printable organic and inorganic semiconductors, the operational frequency of printed rectifiers is not high enough to enable direct communication and powering between mobile phones and printed e-tags. Here, we report an all-printed diode operating up to 1.6 GHz. The device, based on two stacked layers of Si and NbSi2 particles, is manufactured on a flexible substrate at low temperature and in ambient atmosphere. The high charge carrier mobility of the Si microparticles allows device operation to occur in the charge injection-limited regime. The asymmetry of the oxide layers in the resulting device stack leads to rectification of tunneling current. Printed diodes were combined with antennas and electrochromic displays to form an all-printed e-tag. The harvested signal from a Global System for Mobile Communications mobile phone was used to update the display. Our findings demonstrate a new communication pathway for printed electronics within loT applications. [ABSTRACT FROM AUTHOR]

LETTER REPLY TO MA AND WANG: Reliabilityofvariousinvitroactivityassayson SARS-CoV-2mainproteaseinhibitors Zhe Li a,1 , Yuxi Lin b,c,1, Yi-You Huang a,1, Runduo Liu a , Chang-Guo Zhan d,e,2 , Xin Wang b,f,2 , and Hai-Bin Luo a,g,2  Ma and Wang (1) tested our recently reported severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) main protease (M pro) noncovalent inhibitors (2) using their in vitro assays, and they obtained negligible or much lower inhibitory activities compared to ours. Notably,thefluorescence resonanceenergytransfer(FRET)-basedenzymaticassay used by Ma and Wang (1) is different from our FRETbased enzymatic assay in the M pro protein (discussed below) and the FRET substrate [longer than the more popularly used substrate (3, 4) utilized in our assay]. Ma and Wang (1) also used native mass spectrometry (MS) and thermal shift assays (TSA) to detect the protein-ligand binding. [Extracted from the article]

Ceramide transfer protein (CERT) transfers ceramide from the endoplasmic reticulum to the Golgi complex, a process critical in synthesis and maintenance of normal levels of sphingolipids in mammalian cells. However, how its function is integrated into development and physiology of the animal is less clear. Here, me report the in vivo consequences of loss of functional CERT protein. We generated Drosophila melanogaster mutant flies lacking a functional CERT (Dcert) protein using chemical mutagenesis and a Western blot-based genetic screen. The mutant flies die early between days 10 and 30, whereas controls lived between 75 and 90 days. They display >70% decrease in ceramide phosphoethanolamine (the sphingomyelin analog in Drosophila) and ceramide. These changes resulted in increased plasma membrane fluidity than renders them susceptible to reactive oxygen species and results in enhanced oxidative damage to cellular proteins. Consequently, the flies showed reduced thermal tolerance that was exacerbated with aging and metabolic compromise such as decreasing ATP and increasing glucose levels, reminiscent of premature aging. Our studies demonstrate that maintenance of physiological levels of ceramide phosphoethanolamine by CERT in viva is required to prevent oxidative damages to cellular components that are critical for viability and normal lifespan of the animal. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinases (CDKs) are crucial regulators of the eukaryotic cell cycle whose activities are controlled by associated cyclins. PFTK1 shares limited homology to CDKs, but its ability to associate with any cyclins and its biological functions remain largely unknown. Here, we report the functional characterization of human PFTK1 as a CDK. PFTK1 specifically interacted with cyclin D3 (CCND3) and formed a ternary complex with the cell cycle inhibitor p21Cip1 in mammalian cells. We demonstrated that the kinase activity of PFTK1 depended on CCND3 and was negatively regulated by p21Cip1. Moreover, we identified the tumor suppressor Rb as a potential downstream substrate for the PFTK1/CCND3 complex. Importantly, knocking down PFTK1 expression by using siRNA caused cell cycle arrest at G1, whereas ectopic expression of PFTK1 promoted cell proliferation. Taken together, our data strongly suggest that PFTK1 acts as a CDK that regulates cell cycle progression and cell proliferation. [ABSTRACT FROM AUTHOR]