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Auxin regulates plant growth and development through downstream signaling pathways, including the best-known SCFTIR1/AFB-Aux/IAA-ARF pathway and several other less characterized "noncanonical" pathways. Recently, one SCFTIR1/AFB-independent noncanonical pathway, mediated by Transmembrane Kinase 1 (TMK1), was discovered through the analyses of its functions in Arabidopsis apical hook development. Asymmetric accumulation of auxin on the concave side of the apical hook triggers DAR1-catalyzed release of the C-terminal of TMK1, which migrates into the nucleus, where it phosphorylates and stabilizes IAA32/34 to inhibit cell elongation, which is essential for full apical hook formation. However, the molecular factors mediating IAA32/34 degradation have not been identified. Here, we show that proteins in the CYTOKININ INDUCED ROOT WAVING 1 (CKRW1)/WAVY GROWTH 3 (WAV3) subfamily act as E3 ubiquitin ligases to target IAA32/34 for ubiquitination and degradation, which is inhibited by TMK1c-mediated phosphorylation. This antagonistic interaction between TMK1c and CKRW1/WAV3 subfamily E3 ubiquitin ligases regulates IAA32/34 levels to control differential cell elongation along opposite sides of the apical hook. [ABSTRACT FROM AUTHOR]

Specification of Sox2+ proneurosensory progenitors within otic ectodermis a prerequisite for the production of sensory cells and neurons for hearing. However, the underlying molecular mechanisms driving this lineage specification remain unknown. Here, we show that the Brg1-based SWI/SNF chromatin-remodeling complex interacts with the neurosensory-specific transcriptional regulators Eya1/Six1 to induce Sox2 expression and promote proneurosensory-lineage specification. Ablation of the ATPase-subunit Brg1 or both Eya1/Six1 results in loss of Sox2 expression and lack of neurosensory identity, leading to abnormal apoptosis within the otic ectoderm. Brg1 binds to two of three distal 3' Sox2 enhancers occupied by Six1, and Brg1-binding to these regions depends on Eya1-Six1 activity. We demonstrate that the activity of these Sox2 enhancers in otic neurosensory cells specifically depends on binding to Six1. Furthermore, genome-wide and transcriptome profiling indicate that Brg1 may suppress apoptotic factor Map3k5 to inhibit apoptosis. Together, our findings reveal an essential role for Brg1, its downstream pathways, and their interactions with Six1/Eya1 in promoting proneurosensory fate induction in the otic ectoderm and subsequent neuronal lineage commitment and survival of otic cells. [ABSTRACT FROM AUTHOR]

Avian-origin influenza viruses overcome the bottleneck of the interspecies barrier and infect humans through the evolution of variants toward more efficient replication in mammals. The dynamic adaptation of the genetic substitutions and the correlation with the virulence of avian-origin influenza virus in patients remain largely elusive. Here, based on the one-health approach, we retrieved the original virus-positive samples from patients with H7N9 and their surrounding poultry/environment. The specimens were directly deep sequenced, and the subsequent big data were integrated with the clinical manifestations. Unlike poultry/environment-derived samples with the consistent dominance of avian signature 627E of H7N9 polymerase basic protein 2 (PB2), patient specimens had diverse ratios of mammalian signature 627K, indicating the rapid dynamics of H7N9 adaptation in patients during the infection process. In contrast, both human- and poultry/environment-related viruses had constant dominance of avian signature PB2-701D. The intra host dynamic adaptation was confirmed by the gradual replacement of 627E by 627K in H7N9 in the longitudinally collected specimens from one patient. These results suggest that host adaptation for better virus replication to new hosts, termed “genetic tuning,” actually occurred in H7N9-infected patients in vivo. Notably, our findings also demonstrate the correlation between rapid host adaptation of H7N9 PB2-E627K and the fatal outcome and disease severity in humans. The feature of H7N9 genetic tuning in vivo and its correlation with the disease severity emphasize the importance of testing for the evolution of this avian-origin virus during the course of infection. [ABSTRACT FROM AUTHOR]

Mechano-sensory hair cells within the inner ear cochlea are essential for the detection of sound. In mammals, cochlear hair cells are only produced during development and their loss, due to disease or trauma, is a leading cause of deafness. In the immature cochlea, prior to the onset of hearing, hair cell loss stimulates neighboring supporting cells to act as hair cell progenitors and produce new hair cells. However, for reasons unknown, such regenerative capacity (plasticity) is lost once supporting cells undergo maturation. Here, we demonstrate that the RNA binding protein LIN28B plays an important role in the production of hair cells by supporting cells and provide evidence that the developmental drop in supporting cell plasticity in the mammalian cochlea is, at least in part, a product of declining LIN28B-mammalian target of rapamycin (mTOR) activity. Employing murine cochlear organoid and explant cultures to model mitotic and nonmitotic mechanisms of hair cell generation, we show that loss of LIN28B function, due to its conditional deletion, or due to overexpression of the antagonistic miRNA let-7g, suppressed Akt-mTOR complex 1 (mTORC1) activity and renders young, immature supporting cells incapable of generating hair cells. Conversely, we found that LIN28B overexpression increased Akt-mTORC1 activity and allowed supporting cells that were undergoing maturation to de-differentiate into progenitor-like cells and to produce hair cells via mitotic and nonmitotic mechanisms. Finally, using the mTORC1 inhibitor rapamycin, we demonstrate that LIN28B promotes supporting cell plasticity in an mTORC1- dependent manner. [ABSTRACT FROM AUTHOR]

AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and predominantly assemble as heterotetramers in the brain. Recently, the crystal structures of homotetrameric GluA2 demonstrated that AMPARs are assembled with two pairs of conformationally distinct subunits, in a dimer of dimers formation. However, the structure of heteromeric AMPARs remains unclear. Guided by the GluA2 structure, we performed cysteine mutant cross-linking experiments in fulllength GluA1/A2, aiming to draw the heteromeric AMPAR architecture. We found that the amino-terminal domains determine the first level of heterodimer formation. When the dimers further assemble into tetramers, GluA1 and GluA2 subunits have preferred positions, possessing a 1-2-1-2 spatial assembly. By swapping the critical sequences, we surprisingly found that the spatial assembly pattern is controlled by the excisable signal peptides. Replacements with an unrelated GluK2 signal peptide demonstrated that GluA1 signal peptide plays a critical role in determining the spatial priority. Our study thus uncovers the spatial assembly of an important type of glutamate receptors in the brain and reveals a novel function of signal peptides. [ABSTRACT FROM AUTHOR]

A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ~100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ~5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability. [ABSTRACT FROM AUTHOR]

The beneficial roles of probiotics in lowering the gastrointestinal inflammation and preventing colorectal cancer have been frequently demonstrated, but their immunomodulatory effects and mechanism in suppressing the growth of extraintestinal tumors remain unexplored. Here, we adopted a mouse model and metagenome sequencing to investigate the efficacy of probiotic feeding in controlling s.c. hepatocellular carcinoma (HCC) and the underlying mechanism suppressing the tumor progression. Our result demonstrated that Prohep, a novel probiotic mixture, slows down the tumor growth significantly and reduces the tumor size and weight by 40% compared with the control. From a mechanistic point of view the down-regulated IL-17 cytokine and its major producer Th17 cells, whose levels decreased drastically, played critical roles in tumor reduction upon probiotics feeding. Cell staining illustrated that the reduced Th17 cells in the tumor of the probiotictreated group is mainly caused by the reduced frequency of migratory Th17 cells from the intestine and peripheral blood. In addition, shotgun-metagenome sequencing revealed the crosstalk between gut microbial metabolites and the HCC development. Probiotics shifted the gut microbial community toward certain beneficial bacteria, including Prevotella and Oscillibacter, that are known producers of antiinflammatory metabolites, which subsequently reduced the Th17 polarization and promoted the differentiation of antiinflammatory Treg/Tr1 cells in the gut. Overall, our study offers novel insights into the mechanism by which probiotic treatment modulates the microbiota and influences the regulation of the T-cell differentiation in the gut, which in turn alters the level of the proinflammatory cytokines in the extraintestinal tumor microenvironment. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1α (protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs. [ABSTRACT FROM AUTHOR]

The malaria parasite-resistance island (PRI) of the African mosquito vector, Anopheles gambiae, was mapped to five genomic regions containing 80 genes, using coexpression patterns of genomic blocks. High-throughput sequencing identified 347 nonsynonymous single-nucleotide polymorphisms within these genes in mosquitoes from malaria-endemic areas in Kenya. Direct association studies between nonsynonymous single-nucleotide polymorphisms and Plasmodium falciparum infection identified three naturally occurring genetic variations in each of three genes (An. gambiae adenosine deaminase, fibrinogen-related protein 30, and fibrinogen-related protein 1) that were associated significantly with parasite infection. A role for these genes in the resistance phenotype was confirmed by RNA interference knockdown assays. Silencing fibrinogen-related protein 30 increased parasite infection significantly, whereas ablation of fibrinogen-related protein 1 transcripts resulted in mosquitoes nearly free of parasites. The discovered genes and single-nucleotide polymorphisms are anticipated to be useful in the development of tools for malaria control in endemic areas in Africa. [ABSTRACT FROM AUTHOR]

It is increasingly recognized that the mechanisms underlying ischemic cell death are sexually dimorphic. Stroke-induced cell death in males is initiated by the mitochondrial release of apoptosis-inducing factor, resulting in caspase-independent cell death. In contrast, ischemic cell death in females is primarily triggered by mitochondrial cytochrome c release with subsequent caspase activation. Because X-linked inhibitor of apoptosis (XIAP) is the primary endogenous inhibitor of caspases, its regulation may play a unique role in the response to injury in females. XIAP mRNA levels were higher in females at baseline. Stroke induced a significant decrease in XIAP mRNA in females, whereas no changes were seen in the male brain. However, XIAP protein levels were decreased in both sexes after stroke. MicroRNAs (miRNAs) predominantly induce translational repression and are emerging as a major regulators of mRNA and subsequent protein expression after ischemia. The miRNA miR-23a was predicted to bind XIAP mRNA. miR-23a directly bound the 3' UTR of XIAP, and miR-23a inhibition led to an increase in XIAP mRNA in vitro, demonstrating that XIAP is a previously uncharacterized target for miR-23a. miR-23a levels differed in male and female ischemic brains, providing evidence for sex-specific miRNA expression in stroke. Embelin, a small-molecule inhibitor of XIAP, decreased the interaction between XIAP and caspase-3 and led to enhanced caspase activity. Embelin treatment significantly exacerbated stroke-induced injury in females but had no effect in males, demonstrating that XIAP is an important mediator of sex-specific responses after stroke. [ABSTRACT FROM AUTHOR]

Self-assembled capsules are nanoscale structures made up of multiple synthetic subunits held together by weak intermolecular forces. They act as host structures that can completely surround small molecule guests of the appropriate size, shape and chemical surface. Like their biological counterparts, multimeric enzymes and receptors, the subunits of the capsules are generally identical, and lead to homomeric assemblies of high symmetry. In both biological and synthetic systems small variations in structures are tolerated and lead to heteromeric assemblies with slightly different recognition properties. The synthetic capsules are dynamic, with lifetimes from milliseconds to hours, and allow the direct spectroscopic observation of smaller molecules inside, under ambient conditions at equilibrium in solution. We report here the assembly of hybrid capsules made up of 2 very different structures, both capable of forming their own homomeric capsules through hydrogen bonding. These hybrids exhibit host properties that differ markedly from the parent capsules, and suggest that other capsules may emerge from seemingly unrelated modules that have curved surfaces and are rich in hydrogen bonding capabilities. [ABSTRACT FROM AUTHOR]

NF-κB is constitutively active in many solid tumors, including breast cancer. However, the role of NF-κB in breast carcinogenesis is unknown. IkkαAA/AA ‘knockin’ mice in which activation of IκB kinase α (IKKα) is prevented by replacement of activation loop serines with alanines exhibit delayed mammary gland growth during pregnancy, because IKKα activity is required for cyclin D1 induction and proliferation of lobuloalveolar epithelial cells. Given the role of cyclin D1 in breast and mammary cancer, we examined involvement of IKKα in mammary carcinogenesis induced by oncogenes or a chemical carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA). The IkkαAA mutation retarded tumor development in response to either 7,12-dimethylbenzaanthracene or the MMTV-c-neu (ErbB2/Her2) transgene but had no effect on MMTV-v-Ha-ras-induced cancer, although both oncogenes rely on cyclin D1. Strikingly, primary IkkαAA/AA/MMTV-c-neu carcinoma cells exhibited diminished self-renewal capacity, resulting in the inability to establish secondary tumors. IkkαAA/AA/MMTV-c-neu carcinoma cells underwent premature senescence when cultured under conditions used for propagation of mammary gland stem cells. Thus, IKKα is not only a regulator of mammary epithelial proliferation, but is also an important contributor to ErbB2-induced oncogenesis, providing signals that maintain mammary tumor-initiating cells. IKKα may represent a novel and specific target for treatment of ErbB2-positive breast cancer. [ABSTRACT FROM AUTHOR]

To better understand the molecular basis of chronic obstructive pulmonary disease (COPD), we used serial analysis of gene expression (SAGE) and microarray analysis to compare the gene expression patterns of lung tissues from COPD and control smokers. A total of 59,343 tags corresponding to 26,502 transcripts were sequenced in SAGE analyses. A total of 327 genes were differentially expressed (1.5-fold up- or down-regulated). Microarray analysis using the same RNA source detected 261 transcripts that were differentially ex- pressed to a significant degree between GOLD-2 and GOLD-O smokers. We confirmed the altered expression of a select number of genes by using real-time quantitative RT-PCR. These genes encode for transcription factors (EGRI and FOS), growth factors or related proteins (CTGF, CYR61, CX3CL1, TGFB1, and PDGFRA)S and extracellular matrix protein (COLIA1). Immunofluorescence studies on the same lung specimens localized the expression of Egr-1, CTGF, and Cyr61 to alveolar epithelial cells, airway epithelial cells, and stromal and inflammatory cells of GOLD-2 smokers. Cigarette smoke extract induced Egr-1 protein expression and increased Egr-1 DNA-binding activity in human lung fibroblast cells. Cytomix (tumor necrosis factor a, IL-I fi, and IFN-y) treatment showed that the activity of matrix metalloproteinase-2 (MMP-2) was increased in lung fibroblasts from EGRI control (+ 1+) mice but not detected in that of EGRI null (-I-) mice, whereas MMP-9 was regulated by EGR1 in a reverse manner. Our study represents the first comprehensive analysis of gene expression on GOLD-2 versus GOLD-0 smokers and reveals previously unreported candidate genes that may serve as potential molecular targets in COPD. [ABSTRACT FROM AUTHOR]

SO2 (Sulfur dioxide) is the major precursor to the production of sulfuric acid (H2SO4), contributing to acid rain and atmospheric aerosols. Sulfuric acid formed from SO2 generates light-reflecting sulfate aerosol particles in the atmosphere. This property has prompted recent geoengineering proposals to inject sulfuric acid or its precursors into the Earth’s atmosphere to increase the planetary albedo to counteract global warming. SO2 oxidation in the atmosphere by the hydroxyl radical HO to form HOSO2 is a key rate-limiting step in the mechanism for forming acid rain. However, the dynamics of the HO + SO2 → HOSO2 reaction and its slow rate in the atmosphere are poorly understood to date. Herein, we use photoelectron spectroscopy of cryogenically cooled HOSO2-anion to access the neutral HOSO2 radical near the transition state of the HO+SO2 reaction. Spectroscopic and dynamic calculations are conducted on the first ab initio-based full-dimensional potential energy surface to interpret the photoelectron spectra of HOSO2-and to probe the dynamics of the HO + SO2 reaction. In addition to the finding of a unique pre-reaction complex (HO⋯SO2) directly connected to the transition state, dynamic calculations reveal that the accessible phase space for the HO + SO2 → HOSO2 reaction is extremely narrow, forming a key reaction bottleneck and slowing the reaction rate in the atmosphere, despite the low reaction barrier. This study underlines the importance of understanding the full multidimensional potential energy surface to elucidate the dynamics of complex bimolecular reactions involving polyatomic reactants. [ABSTRACT FROM AUTHOR]

Focuses on a study which assessed the importance of endocrine and autocrine/paracrine roles of insulin-like growth factor I (IGF-I) in growth and development. Generation and characterization of albumin-cre transgenic mice; Liver IGF-I expression in albumin-cre transgenic mice; Postnatal growth of mice exhibiting liver-specific deletion of IGF-I.

Reports on a study that investigated the role of liver-derived insulin-like growth factor I for postnatal body growth. Materials and methods; Results; Discussion.

The Periodic Law of Chemistry is one of the great discoveries in cultural history. Elements behaving chemically similar are empirically merged in groups G of a Periodic Table, each element with G valence electrons per neutral atom, and with upper limit G for the oxidation and valence numbers. Here, we report that among the usually mono- or di-valent s-block elements (G = 1 or 2), the heaviest members (87Fr, 88Ra, 119E, and 120E) with atomic numbers Z = 87, 88, 119, 120 form unusual 5- or 6-valent compounds at ambient conditions. Together with well-reported basic changes of valence at the end of the 6d-series, in the whole 7p-series, and for 5g6f-elements, it indicates that at the bottom of common Periodic Tables, the classic Periodic Law is not as straightforward as commonly expected. Specifically, we predict the feasible experimental synthesis of polyvalent [RaL− n] (n = 4, 6) compounds. [ABSTRACT FROM AUTHOR]

Earth’s inner core is predominantly composed of solid iron (Fe) and displays intriguing properties such as strong shear softening and an ultrahigh Poisson’s ratio. Insofar, physical mechanisms to explain these features coherently remain highly debated. Here, we have studied longitudinal and shear wave velocities of hcp-Fe (hexagonal close-packed iron) at relevant pressure–temperature conditions of the inner core using in situ shock experiments and machine learning molecular dynamics (MLMD) simulations. Our results demonstrate that the shear wave velocity of hcp-Fe along the Hugoniot in the premelting condition, defined as T/Tm (Tm: melting temperature of iron) above 0.96, is significantly reduced by ~30%, while Poisson’s ratio jumps to approximately 0.44. MLMD simulations at 230 to 330 GPa indicate that collective motion with fast diffusive atomic migration occurs in premelting hcp-Fe primarily along [100] or [010] crystallographic direction, contributing to its elastic softening and enhanced Poisson’s ratio. Our study reveals that hcp-Fe atoms can diffusively migrate to neighboring positions, forming open-loop and close-loop clusters in the inner core conditions. Hcp-Fe with collective motion at the inner core conditions is thus not an ideal solid previously believed. The premelting hcp-Fe with collective motion behaves like an extremely soft solid with an ultralow shear modulus and an ultrahigh Poisson’s ratio that are consistent with seismic observations of the region. Our findings indicate that premelting hcp-Fe with fast diffusive motion represents the underlying physical mechanism to help explain the unique seismic and geodynamic features of the inner core. [ABSTRACT FROM AUTHOR]

Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) BREA2 drives breast cancer metastasis by stabilizing the Notch1 intracellular domain (NICD1). Moreover, we reveal WW domain containing E3 ubiquitin protein ligase 2 (WWP2) as an E3 ligase for NICD1 at K1821 and a suppressor of breast cancer metastasis. Mechanistically, BREA2 impairs WWP2-- NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. BREA2 loss sensitizes breast cancer cells to inhibition of Notch signaling and suppresses the growth of breast cancer patient-derived xenograft tumors, highlighting its therapeutic potential in breast cancer. Taken together, these results reveal the lncRNA BREA2 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Reproducible quantification of large biological cohorts is critical for clinical/pharmaceutical proteomics yet remains challenging because most prevalent methods suffer from drastically declined commonly quantified proteins and substantially deteriorated quantitative quality as cohort size expands. MS2-based dataindependent acquisition approaches represent tremendous advancements in reproducible protein measurement, but often with limited depth. We developed IonStar, an MS1-based quantitative approach enabling in-depth, high-quality quantification of large cohorts by combining efficient/reproducible experimental procedures with unique data-processing components, such as efficient 3D chromatographic alignment, sensitive and selective direct ion current extraction, and stringent postfeature generation quality control. Compared with several popular label-free methods, IonStar exhibited far lower missing data (0.1%), superior quantitative accuracy/ precision [~5% intragroup coefficient of variation (CV)], the widest protein abundance range, and the highest sensitivity/specificity for identifying protein changes (<5% false altered-protein discovery) in a benchmark sample set (n = 20). We demonstrated the usage of IonStar by a large-scale investigation of traumatic injuries and pharmacological treatments in rat brains (n = 100), quantifying >7,000 unique protein groups (>99.8% without missing data across the 100 samples) with a low false discovery rate (FDR), two or more unique peptides per protein, and high quantitative precision. IonStar represents a reliable and robust solution for precise and reproducible protein measurement in large cohorts. [ABSTRACT FROM AUTHOR]

The optimal functionalities of materials often appear at phase transitions involving simultaneous changes in the electronic structure and the symmetry of the underlying lattice. It is experimentally challenging to disentangle which of the two effects--electronic or structural--is the driving force for the phase transition and to use the mechanism to control material properties. Here we report the concurrent pumping and probing of Cu2S nanoplates using an electron beam to directly manipulate the transition between two phases with distinctly different crystal symmetries and charge-carrier concentrations, and show that the transition is the result of charge generation for one phase and charge depletion for the other. We demonstrate that this manipulation is fully reversible and nonthermal in nature. Our observations reveal a phase-transition pathway in materials, where electron-induced changes in the electronic structure can lead to a macroscopic reconstruction of the crystal structure. [ABSTRACT FROM AUTHOR]

Airborne bacteria are an influential component of the Earth’s microbiomes, but their community structure and biogeographic distribution patterns have yet to be understood. We analyzed the bacterial communities of 370 air particulate samples collected from 63 sites around the world and constructed an airborne bacterial reference catalog with more than 27 million nonredundant 16S ribosomal RNA (rRNA) gene sequences. We present their biogeographic pattern and decipher the interlacing of the microbiome co-occurrence network with surface environments of the Earth. While the total abundance of global airborne bacteria in the troposphere (1.72 × 1024 cells) is 1 to 3 orders of magnitude lower than that of other habitats, the number of bacterial taxa (i.e., richness) in the atmosphere (4.71 × 108 to 3.08 × 109) is comparable to that in the hydrosphere, and its maximum occurs in midlatitude regions, as is also observed in other ecosystems. The airborne bacterial community harbors a unique set of dominant taxa (24 species); however, its structure appears to be more easily perturbed, due to the more prominent role of stochastic processes in shaping community assembly. This is corroborated by the major contribution of surface microbiomes to airborne bacteria (averaging 46.3%), while atmospheric conditions such as meteorological factors and air quality also play a role. Particularly in urban areas, human impacts weaken the relative importance of plant sources of airborne bacteria and elevate the occurrence of potential pathogens from anthropogenic sources. These findings serve as a key reference for predicting planetary microbiome responses and the health impacts of inhalable microbiomes with future changes in the environment. [ABSTRACT FROM AUTHOR]

Triplex gene editing relies on binding a stable peptide nucleic acid (PNA) sequence to a chromosomal target, which alters the helical structure of DNA to stimulate site-specific recombination with a single-strand DNA (ssDNA) donor template and elicits gene correction. Here, we assessed whether the codelivery of PNA and donor template encapsulated in Poly Lactic-co-Glycolic Acid (PLGA)-based nanoparticles can correct sickle cell disease and x-linked severe combined immunodeficiency. However, through this process we have identified a false-positive PCR artifact due to the intrinsic capability of PNAs to aggregate with ssDNA donor templates. Here, we show that the combination of PNA and donor templates but not either agent alone results in different degrees of aggregation that result in varying but highly reproducible levels of false-positive signal. We have identified this phenomenon in vitro and confirmed that the PNA sequences producing the highest supposed correction in vitro are not active in vivo in both disease models, which highlights the importance of interrogating and eliminating carryover of ssDNA donor templates in assessing various gene editing technologies such as PNA-mediated gene editing. [ABSTRACT FROM AUTHOR]

Electrostimulation has been recognized as a promising nonpharmacological treatment in orthopedics to promote bone fracture healing. However, clinical applications have been largely limited by the complexity of equipment operation and stimulation implementation. Here, we present a self-powered implantable and bioresorbable bone fracture electrostimulation device, which consists of a triboelectric nanogenerator for electricity generation and a pair of dressing electrodes for applying electrostimulations directly toward the fracture. The device can be attached to irregular tissue surfaces and provide biphasic electric pulses in response to nearby body movements. We demonstrated the operation of this device on rats and achieved effective bone fracture healing in as short as 6 wk versus the controls for more than 10 wk to reach the same healing result. The optimized electrical field could activate relevant growth factors to regulate bone microenvironment for promoting bone formation and bone remodeling to accelerate bone regeneration and maturation, with statistically significant 27%and 83%improvement over the control groups in mineral density and flexural strength, respectively. This work provided an effective implantable fracture therapy device that is self-responsive, battery free, and requires no surgical removal after fulfilling the biomedical intervention. [ABSTRACT FROM AUTHOR]

A copper-catalyzed a-functionalization of glycine derivatives and short peptides with nucleophiles is described. The present method provides ways to introduce functionalities such as aryl, vinyl, alkynyl, or indolyl specifically to the terminal glycine moieties of small peptides, which are normally difficult in peptide modifications. Furthermore, on functionalization, the configurations of other stereocenters in the peptides could be maintained. Because the functionalized peptides could easily be deprotected and carried onto the next coupling process, our approach provides a useful tool for the peptidebased biological research. [ABSTRACT FROM AUTHOR]

Cu-catalyzed cross-dehydrogenative coupling (CDC) methodologies were developed based on the oxidative activation of sp3 C-H bonds adjacent to a nitrogen atom. Various sp, sp2, and sp3 C-H bonds of pronucleophiles were used in the Cu-catalyzed CDC reactions. Based on these results, the mechanisms of the CDC reactions also are discussed. [ABSTRACT FROM AUTHOR]

Rechargeability and operational safety of commercial lithium (Li)- ion batteries demand further improvement. Plating of metallic Li on graphite anodes is a critical reason for Li-ion battery capacity decay and short circuit. It is generally believed that Li plating is caused by the slow kinetics of graphite intercalation, but in this paper, we demonstrate that thermodynamics also serves a crucial role. We show that a nonuniform temperature distribution within the battery can make local plating of Li above 0 V vs. Li0/Li+ (room temperature) thermodynamically favorable. This phenomenon is caused by temperature-dependent shifts of the equilibrium potential of Li0/Li+. Supported by simulation results, we confirm the likelihood of this failure mechanism during commercial Li-ion battery operation, including both slow and fast charging conditions. This work furthers the understanding of nonuniform Li plating and will inspire future studies to prolong the cycling lifetime of Li-ion batteries. [ABSTRACT FROM AUTHOR]

Much attention is being paid to conformational biases in the ensembles of intrinsically disordered proteins. However, it is currently unknown whether or how conformational biases within the disordered ensembles of foldable proteins affect function in vivo. Recently, we demonstrated that water can be a good solvent for unfolded polypeptide chains, even those with a hydrophobic and charged sequence composition typical of folded proteins. These results run counter to the generally accepted model that protein folding begins with hydrophobicity-driven chain collapse. Here we investigate what other features, beyond amino acid composition, govern chain collapse. We found that local clustering of hydrophobic and/or charged residues leads to significant collapse of the unfolded ensemble of pertactin, a secreted autotransporter virulence protein from Bordetella pertussis, as measured by small angle X-ray scattering (SAXS). Sequence patterns that lead to collapse also correlate with increased intermolecular polypeptide chain association and aggregation. Crucially, sequence patterns that support an expanded conformational ensemble enhance pertactin secretion to the bacterial cell surface. Similar sequence pattern features are enriched across the large and diverse family of autotransporter virulence proteins, suggesting sequence patterns that favor an expanded conformational ensemble are under selection for efficient autotransporter protein secretion, a necessary prerequisite for virulence. More broadly, we found that sequence patterns that lead to more expanded conformational ensembles are enriched across water-soluble proteins in general, suggesting protein sequences are under selection to regulate collapse and minimize protein aggregation, in addition to their roles in stabilizing folded protein structures. [ABSTRACT FROM AUTHOR]

Infrared spectroscopic study of neutral water clusters is crucial to understanding of the hydrogen-bonding networks in liquid water and ice. Here we report infrared spectra of size-selected neutral water clusters, (H2O)n (n = 3−6), in the OH stretching vibration region, based on threshold photoionization using a tunable vacuum ultraviolet free-electron laser. Distinct OH stretch vibrational fundamentals observed in the 3,500−3,600-cm−1 region of (H2O)5 provide unique spectral signatures for the formation of a noncyclic pentamer, which coexists with the global-minimum cyclic structure previously identified in the gas phase. The main features of infrared spectra of the pentamer and hexamer, (H2O)n (n = 5 and 6), span the entire OH stretching band of liquid water, suggesting that they start to exhibit the richness and diversity of hydrogen-bonding networks in bulk water. [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]

Although pain is a prevalent nonmotor symptom in Parkinson's disease (PD), it is undertreated, in part because of our limited understanding of the underlying mechanisms. Considering that the basal ganglia are implicated in pain sensation, and that their synaptic outputs are controlled by the subthalamic nucleus (STN), we hypothesized that the STN might play a critical role in parkinsonian pain hypersensitivity. To test this hypothesis, we established a unilateral parkinsonian mouse model with moderate lesions of dopaminergic neurons in the substantia nigra. The mice displayed pain hypersensitivity and neuronal hyperactivity in the ipsilesional STN and in central pain-processing nuclei. Optogenetic inhibition of STN neurons reversed pain hypersensitivity phenotypes in parkinsonian mice, while hyperactivity in the STN was sufficient to induce pain hypersensitivity in control mice. We further demonstrated that the STN differentially regulates thermal and mechanical pain thresholds through its projections to the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi)/ventral pallidum (VP), respectively. Interestingly, optogenetic inhibition of STN-GPi/STN-VP and STN-SNr projections differentially elevated mechanical and thermal pain thresholds in parkinsonian mice. In summary, our results support the hypothesis that the STN and its divergent projections play critical roles in modulating pain processing under both physiological and parkinsonian conditions, and suggest that inhibition of individual STN projections may be a therapeutic strategy to relieve distinct pain phenotypes in PD. [ABSTRACT FROM AUTHOR]

Microglial activation plays a central role in poststroke inflammation and causes secondary neuronal damage; however, it also contributes in debris clearance and chronic recovery. Microglial pro- and antiinflammatory responses (or so-called M1-M2 phenotypes) coexist and antagonize each other throughout the disease progress. As a result of this balance, poststroke immune responses alter stroke outcomes. Our previous study found microglial expression of interferon regulatory factor 5 (IRF5) and IRF4 was related to pro- and antiinflammatory responses, respectively. In the present study, we genetically modified the IRF5 and IRF4 signaling to explore their roles in stroke. Both in vitro and in vivo assays were utilized; IRF5 or IRF4 small interfering RNA (siRNA), lentivirus, and conditional knockout (CKO) techniques were employed to modulate IRF5 or IRF4 expression in microglia. We used a transient middle cerebral artery occlusion model to induce stroke and examined both acute and chronic stroke outcomes. Poststroke inflammation was evaluated with flow cytometry, RT-PCR, MultiPlex, and immunofluorescence staining. An oscillating pattern of the IRF5-IRF4 regulatory axis function was revealed. Down-regulation of IRF5 signaling by siRNA or CKO resulted in increased IRF4 expression, enhanced M2 activation, quenched proinflammatory responses, and improved stroke outcomes, whereas down-regulation of IRF4 led to increased IRF5 expression, enhanced M1 activation, exacerbated proinflammatory responses, and worse functional recovery. Up-regulation of IRF4 or IRF5 by lentivirus induced similar results. We conclude that the IRF5-IRF4 regulatory axis is a key determinant in microglial activation. The IRF5-IRF4 regulatory axis is a potential therapeutic target for neuroinflammation and ischemic stroke. [ABSTRACT FROM AUTHOR]

It is well recognized that metastasis can occur early in the course of lung adenocarcinoma (LAD) development, and yet the molecular mechanisms driving this capability of rapid metastasis remain incompletely understood. Here we reported that a long noncoding RNA, LINC00673, was up-regulated in LAD cells. Of note, we first found that LINC00673-v4 was the most abundant transcript of LINC00673 in LAD cells and its expression was associated with adverse clinical outcome of LAD. In vitro and in vivo experiments demonstrated that LINC00673-v4 enhanced invasiveness, migration, and metastasis of LAD cells. Mechanistically, LINC00673-v4 augmented the interaction between DDX3 and CK1ε and thus the phosphorylation of dishevelled, which subsequently activated WNT/β-catenin signaling and consequently caused aggressiveness of LAD. Antagonizing LINC00673-v4 suppressed LAD metastasis in vivo. Together, our data suggest that LINC00673-v4 is a driver molecule for metastasis via constitutively activating WNT/β-catenin signaling in LAD and may represent a potential therapeutic target against the metastasis of LAD. [ABSTRACT FROM AUTHOR]

Extended defects are known to have critical influences in achieving desired material performance. However, the nature of extended defect generation is highly elusive due to the presence of multiple nucleation mechanisms with close energetics. A strategy to design extended defects in a simple and clean way is thus highly desirable to advance the understanding of their role, improve material quality, and serve as a unique playground to discover new phenomena. In this work, we report an approach to create planar extended defects--antiphase boundaries (APB)--with well-defined origins via the combination of advanced growth, atomic-resolved electron microscopy, first-principals calculations, and defect theory. In La2/3Sr1/3MnO3 thin film grown on Sr2RuO4 substrate, APBs in the film naturally nucleate at the step on the substrate/film interface. For a single step, the generated APBs tend to be nearly perpendicular to the interface and propragate toward the film surface. Interestingly, when two steps are close to each other, two corresponding APBs communicate and merge together, forming a unique triangle-shaped defect domain boundary. Such behavior has been ascribed, in general, to the minimization of the surface energy of the APB. Atomic-resolved electron microscopy shows that these APBs have an intriguing antipolar structure phase, thus having the potential as a general recipe to achieve ferroelectriclike domain walls for high-density nonvolatile memory. [ABSTRACT FROM AUTHOR]

While boron forms a wide range of metal borides with important industrial applications, there has been relatively little attention devoted to lanthanide boride clusters. Here we report a joint photoelectron spectroscopy and quantum chemical study on two octa-boron di-lanthanide clusters, Ln2B8- (Ln = La, Pr). We found that these clusters form highly stable inverse sandwich structures, [Ln-B8-Ln]-, with strong Ln and B8 bonding via interactions between the Ln 5d orbitals and the delocalized σ and π orbitals on the B8 ring. A (d-p)δ bond, involving the 5dδ and the antibonding π orbital of the B8 ring, is observed to be important in the Ln-B8 interactions. The highly symmetric inverse sandwich structures are overwhelmingly more stable than any other isomers. Upon electron detachment, the (d-p)δ orbitals become half-filled, giving rise to a triplet ground state for neutral La2B8. In addition to the two unpaired electrons in the (d-p)δ orbitals upon electron detachment, the neutral Pr2B8 complex also contains two unpaired 4f electrons on each Pr center. The six unpaired spins in Pr2B8 are ferromagnetically coupled to give rise to a septuplet ground state. The current work suggests that highly magnetic Ln...B8...Ln inverse sandwiches or 1D Ln...B8...Ln nanowires may be designed with novel electronic and magnetic properties. [ABSTRACT FROM AUTHOR]

Gold (Au) catalysts exhibit a significant size effect, but its origin has been puzzling for a long time. It is generally believed that supported Au clusters are more or less rigid in working condition, which inevitably leads to the general speculation that the active sites are immobile. Here, by using atomic resolution in situ environmental transmission electron microscopy, we report size-dependent structure dynamics of single Au nanoparticles on ceria (CeO2) in CO oxidation reaction condition at room temperature. While large Au nanoparticles remain rigid in the catalytic working condition, ultrasmall Au clusters lose their intrinsic structures and become disordered, featuring vigorous structural rearrangements and formation of dynamic low-coordinated atoms on surface. Ab initio molecular-dynamics simulations reveal that the interaction between ultrasmall Au cluster and CO molecules leads to the dynamic structural responses, demonstrating that the shape of the catalytic particle under the working condition may totally differ from the shape under the static condition. The present observation provides insight on the origin of superior catalytic properties of ultrasmall gold clusters. [ABSTRACT FROM AUTHOR]

Galactose, a monosaccharide capable of assuming two possible configurational isomers (d-/l-), can exist as a six-membered ring, galactopyranose (Galp), or as a five-membered ring, galactofuranose (Galf). UDP-galactopyranose mutase (UGM) mediates the conversion of pyranose to furanose thereby providing a precursor for d-Galf. Moreover, UGM is critical to the virulence of numerous eukaryotic and prokaryotic human pathogens and thus represents an excellent antimicrobial drug target. However, the biosynthetic mechanism and relevant enzymes that drive l-Galf production have not yet been characterized. Herein we report that efforts to decipher the sugar biosynthetic pathway and tailoring steps en route to nucleoside antibiotic A201A led to the discovery of a GDP-l-galactose mutase, MtdL. Systematic inactivation of 18 of the 33 biosynthetic genes in the A201A cluster and elucidation of 10 congeners, coupled with feeding and in vitro biochemical experiments, enabled us to: (i) decipher the unique enzyme, GDP-l-galactose mutase associated with production of two unique d-mannose-derived sugars, and (ii) assign two glycosyltransferases, four methyltransferases, and one desaturase that regiospecifically tailor the A201A scaffold and display relaxed substrate specificities. Taken together, these data provide important insight into the origin of l-Galf-containing natural product biosynthetic pathways with likely ramifications in other organisms and possible antimicrobial drug targeting strategies. [ABSTRACT FROM AUTHOR]

Acute exposure to fine particle (PM2.5) induces DNA methylation changes implicated in inflammation and oxidative stress. We conducted a crossover trial to determine whether B-vitamin supplementation averts such changes. Ten healthy adults blindly received a 2-h, controlled-exposure experiment to sham under placebo, PM2.5 (250 μg/m3) under placebo, and PM2.5 (250 μg/m3) under B-vitamin supplementation (2.5 mg/d folic acid, 50 mg/d vitamin B6, and 1 mg/d vitamin B12), respectively. We profiled epigenome-wide methylation before and after each experiment using the Infinium HumanMethylation450 BeadChip in peripheral CD4+ T-helper cells. PM2.5 induced methylation changes in genes involved in mitochondrial oxidative energy metabolism. B-vitamin supplementation prevented these changes. Likewise, PM2.5 depleted 11.1% [95% confidence interval (CI), 0.4%, 21.7%; P = 0.04] of mitochondrial DNA content compared with sham, and B-vitamin supplementation attenuated the PM2.5 effect by 102% (Pinteraction = 0.01). Our study indicates that individual-level prevention may be used to complement regulations and control potential mechanistic pathways underlying the adverse PM2.5 effects, with possible significant public health benefit in areas with frequent PM2.5 peaks. [ABSTRACT FROM AUTHOR]

Inheritance of the callipyge phenotype in sheep is an example of polar overdominance inheritance, an unusual mode of inheritance. To investigate the underlying molecular mechanism, we profiled the expression of the genes located in the Delta-like 1 homolog (Dlk1)-type III iodothyronine deiodinase (Dio3) imprinting region in mice. We found that the transcripts of the microRNA (miR) 379/miR-544 cluster were highly expressed in neonatal muscle and paralleled the expression of the Dlk1. We then determined the in vivo role of the miR-379/miR-544 cluster by establishing a mouse line in which the cluster was ablated. The maternal heterozygotes of young mutant mice displayed a hypertrophic tibialis anterior muscle, extensor digitorum longus muscle, gastrocnemius muscle, and gluteus maximus muscle and elevated expression of the DLK1 protein. Reduced expression of DLK1 was mediated by miR-329, a member of this cluster. Our results suggest that maternal expression of the imprinted miR-379/miR-544 cluster regulates paternal expression of the Dlk1 gene in mice. We therefore propose a miR-based molecular working model for polar overdominance inheritance. [ABSTRACT FROM AUTHOR]

Bioinspired artificial water channels aim to combine the high permeability and selectivity of biological aquaporin (AQP) water channels with chemical stability. Here, we carefully characterized a class of artificial water channels, peptide-appended pillar[5]arenes (PAPs). The average single-channel osmotic water permeability for PAPs is 1.0(±0.3) × 10-14 cm3/s or 3.5(±1.0) × 108 water molecules per s, which is in the range of AQPs (3.4~40.3 × 108 water molecules per s) and their current synthetic analogs, carbon nanotubes (CNTs, 9.0 × 108 water molecules per s). This permeability is an order of magnitude higher than first-generation artificial water channels (20 to ~107 water molecules per s). Furthermore, within lipid bilayers, PAP channels can self-assemble into 2D arrays. Relevant to permeable membrane design, the pore density of PAP channel arrays (~2.6 × 105 pores per μm2) is two orders of magnitude higher than that of CNT membranes (0.1~2.5 × 103 pores per μm2). PAP channels thus combine the advantages of biological channels and CNTs and improve upon them through their relatively simple synthesis, chemical stability, and propensity to form arrays. [ABSTRACT FROM AUTHOR]

The Pictet-Spengler (PS) reaction constructs plant alkaloids such as morphine and camptothecin, but it has not yet been noticed in the fungal kingdom. Here, a silent fungal Pictet-Spenglerase (FPS) gene of Chaetomium globosum 1C51 residing in Epinephelus drummondhayi guts is described and ascertained to be activable by 1-methyl-L-tryptophan (1-MT). The activated FPS expression enables the PS reaction between 1-MT and flavipin (fungal aldehyde) to form "unnatural" natural products with unprecedented skeletons, of which chaetoglines B and F are potently antibacterial with the latter inhibiting acetylcholinesterase. A gene-implied enzyme inhibition (GIEI) strategy has been introduced to address the key steps for PS product diversifications. In aggregation, the work designs and validates an innovative approach that can activate the PS reaction-based fungal biosynthetic machinery to produce unpredictable compounds of unusual and novel structure valuable for new biology and biomedicine. [ABSTRACT FROM AUTHOR]

The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domain-containing adapter inducing IFN-β, respectively. This form of cell death has been implicated in the host-defense system. However, the molecular mechanisms that drive the activation of RIP3 by a variety of pathogens, other than the above-mentioned receptors, are largely unknown. Here, we report that human herpes simplex virus 1 (HSV-1) infection triggers RIP3-dependent necrosis. This process requires MLKL but is independent of TNF receptor, TLR3, cylindromatosis, and host RIP homotypic interaction motif-containing protein DNA-dependent activator of IFN regulatory factor. After HSV-1 infection, the viral ribonucleotide reductase large subunit (ICP6) interacts with RIP3. The formation of the ICP6–RIP3 complex requires the RHIM domains of both proteins. An HSV-1 ICP6 deletion mutant failed to cause effective necrosis of HSV-1–infected cells. Furthermore, ectopic expression of ICP6, but not RHIM mutant ICP6, directly activated RIP3/MLKL-mediated necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. Therefore, this study reveals a previously uncharacterized host antipathogen mechanism. [ABSTRACT FROM AUTHOR]

Axon pathology has been widely reported in Alzheimer's disease (AD) patients and AD mouse models. Herein we report that increased miR-342-5p down-regulates the expression of ankyrin G (AnkG), a protein known to play a critical role in establishing selective filtering machinery at the axon initial segment (AIS). Diminished AnkG expression leads to defective AIS filtering in cultured hippocampal neurons from AD mouse models, as monitored by selective exclusion of large macromolecules from the axons. Furthermore, AnkG-deficiency impairs AIS localization of Nav 1.6 channels and confines NR2B to the somatodendritic compartments. The expression of exogenous AnkG improved the cognitive performance of 12-mo-old APP/PS1 mice; thus, our data suggest that AnkG and impairment of AIS filtering may play important roles in AD pathology. [ABSTRACT FROM AUTHOR]

Animals exploit different germ-line-encoded proteins with various domain structures to detect the signature molecules of pathogenic microbes. These molecules are known as pathogen-associated molecular patterns (PAMPs), and the host proteins that react with PAMPs are called pattern recognition proteins (PRPs). Here, we present a novel type of protein domain structure capable of binding to bacterial peptidoglycan (PGN) and the minimal PGN motif muramyl dipeptide (GvlDP). This domain is designated as apextrin C-terminal domain (ApeC), and its presence was confirmed in several invertebrate phyla and subphyla. Two apextrin-like proteins (ALP1 and ALP2) were identified in a basal chordate, the Japanese amphioxus Branchiostoma japonicum (bj). bjALPI is a mucosal effector secreted into the gut lumen to agglutinate the Gram-positive bacterium Staphylococcus aureus via PGN binding. Neutralization of secreted bjALP1 by anti-bjALP1 monoclonal antibodies caused serious damage to the gut epithelium and rapid death of the animals after bacterial infection. bjALP2 is an intracellular PGN sensor that binds to TNF receptor-associated factor 6 (TRAF6) and prevents TRAF6 from self-ubiquitination and hence from NF-κB activation. MDP was found to compete with TRAF6 for bjALP2, which released TRAF6 to activate the NF-κB pathway. BjALPI and bjALP2 therefore play distinct and complementary functions in amphioxus gut mucosal immunity. In conclusion, discovery of the ApeC domain and the functional analyses of amphioxus ALP1 and ALP2 allowed us to define a previously undocumented type of PRP that is represented across different animal phyla. [ABSTRACT FROM AUTHOR]

We report the development of an all-fiber-optic scanning endomicroscope capable of highresolution second harmonic generation (SHG) imaging of biological tissues and demonstrate its utility for monitoring the remodeling of cervical collagen during gestation in mice. The endomicroscope has an overall 2.0 mm diameter and consists of a single customized doubledad fiber, a compact rapid two-dimensional beam scanner, and a miniature compound objective lens for excitation beam delivery, scanning, focusing, and efficient SHG signal collection. Endomicroscopic SHG images of murine cervical tissue sections at different stages of normal pregnancy reveal progressive, quantifiable changes in cervical collagen morphology with resolution similar to that of benchtop SHG microscopy. SHG endomicroscopic imaging of ex vivo murine and human cervical tissues through intact epithelium has also been performed. Our findings demonstrate the feasibility of SHG endomicroscopy technology for staging normal pregnancy, and suggest its potential application as a minimally invasive tool for clinical assessment of abnormal cervical remodeling associated with preterm birth. [ABSTRACT FROM AUTHOR]

It is generally understood that foxtail millet and broomcorn millet were initially domesticated in Northern China where they eventually became the dominant plant food crops. The rarity of older archaeological sites and archaeobotanical work in the region, however, renders both the origins of these plants and their processes of domestication poorly understood. Here we present ancient starch grain assemblages recovered from cultural deposits, including carbonized residues adhering to an early pottery sherd as well as grinding stone tools excavated from the sites of Nanzhuangtou (11.5-11.0 cal kyBP) and Donghulin (11.0-9.5 cal kyBP) in the North China Plain. Our data extend the record of millet use in China by nearly 1,000 y, and the record of foxtail millet in the region by at least two millennia. The patterning of starch residues within the samples allow for the formulation of the hypothesis that foxtail millets were cultivated for an extended period of two millennia, during which this crop plant appears to have been undergoing domestication. Future research in the region will help clarify the processes in place. [ABSTRACT FROM AUTHOR]

Abscisic acid (ABA) is an essential hormone that controls plant growth, development, and responses to abiotic stresses. Central for ABA signaling is the ABA-mediated autoactivation of three monomeric Snf1-related kinases (SnRK2.2, -2.3, and -2.6). In the absence of ABA, SnRK2s are kept in an inactive state by forming physical complexes with type 2C protein phosphatases (PP2Cs). Upon relief of this inhibition, SnRK2 kinases can autoactivate through unknown mechanisms. Here, we report the crystal structures of full-length Arabidopsis thaliana SnRK2.3 and SnRK2.6 at 1.9- and 2.3-Å resolution, respectively. The structures, in combination with biochemical studies, reveal a two-step mechanism of intramolecular kinase activation that resembles the intermolecular activation of cyclin-dependent kinases. First, release of inhibition by PP2C allows the SnRK2s to become partially active because of an intramolecular stabilization of the catalytic domain by a conserved helix in the kinase regulatory domain. This stabilization enables SnRK2s to gain full activity by activation loop autophosphorylation. Autophosphorylation is more efficient in SnRK2.6, which has higher stability than SnRK2.3 and has well-structured activation loop phosphate acceptor sites that are positioned next to the catalytic site. Together, these data provide a structural framework that links ABA-mediated release of PP2C inhibition to activation of SnRK2 kinases. [ABSTRACT FROM AUTHOR]

The K+ channel KCa3.1 is required for Ca2+ influx and the subsequent activation of CD4 T cells. The class II phosphatidylinositol 3 kinase C2β (PI3KC2β) is activated by the T-cell receptor (TCR) and is critical for KCa3.1 channel activation. Tripartite motif containing protein 27 (TRIM27) is a member of a large family of proteins that function as Really Interesting New Gene (RING) E3 ubiquitin ligases. We now show that TRIM27 functions as an E3 ligase and mediates lysine 48 polyubiquitination of PI3KC2β, leading to a decrease in PI3K enzyme activity. By inhibiting PI3KC2β, TRIM27 also functions to negatively regulate CD4 T cells by inhibiting KCa3.1 channel activity and TCR-stimulated Ca2+ influx and cytokine production in Jurkat, primary human CD4 T cells, and Th0, Th1, and Th2 CD4 T cells generated from TRIM27-/- mice. These findings provide a unique mechanism for regulating class II PI3Ks, and identify TRIM27 as a previously undescribed negative regulator of CD4 T cells. [ABSTRACT FROM AUTHOR]

Chemistry of the actinide elements represents a challenging yet vital scientific frontier. Development of actinide chemistry requires fundamental understanding of the relative roles of actinide valence-region orbitals and the nature of their chemical bonding. We report here an experimental and theoretical investigation of the uranium methylidyne molecules X3UCH (X = F, Cl, Br), F2CIUCH, and F3UCF formed through reactions of laser-ablated uranium atoms and trihalomethanes or carbon tetrafluoride in excess argon. By using matrix infrared spectroscopy and relativistic quantum chemistry calculations, we have shown that these actinide complexes possess relatively strong UC triple bonds between the U 6d-5f hybrid orbitals and carbon 2s-2p orbitals. Electron-with- drawing ligands are critical in stabilizing the U(Vl) oxidation state and sustaining the formation of uranium multiple bonds. These unique UC-bearing molecules are examples of the long-sought actinide-alkylidynes. This discovery opens the door to the rational synthesis of triple-bonded actinide-carbon compounds. [ABSTRACT FROM AUTHOR]

Demonstrates that lack of insulin-like growth factor I (IGF-I) in knockout mice prevents normal retinal vascular growth, despite the presence of vascular endothelial growth factor. Comparison with studies in premature infants; Blinding disease retinopathy of prematurity caused by IGF-I insufficiency.