Angiogenin, a 14-kDa multifunctional pro-angiogenic growth factor, is upregulated in several types of cancers. Anti-angiogenin monoclonal antibodies used as antagonists inhibited the establishment, progression and metastasis of human cancer cells in athymic mice (Olson et al., 1994). Silencing angiogenin and inhibition of angiogenin's nuclear translocation blocked cell survival and induced ...

Pancreatic ductal adenocarcinoma (PDA) has one of the worst prognoses of all cancers. Mucin 1 (MUC1), a transmembrane mucin glycoprotein, is a key modulator of several signaling pathways that affect oncogenesis, motility and metastasis. Its expression is known to be associated with poor prognosis in patients. However, the precise mechanism ...

Although the overall prognosis in childhood acute lymphoblastic leukemia (ALL) is good, outcome after relapse is poor. Recurrence is frequently characterized by the occurrence of disease at extramedullary sites, such as the central nervous system and testes. Subpopulations of blasts able to migrate to such areas may have a survival ...

Mdm2 is the major negative regulator of p53 tumor-suppressor activity. This oncoprotein is overexpressed in many human tumors that retain the wild-type p53 allele. As such, targeted inhibition of Mdm2 is being considered as a therapeutic anticancer strategy. The N-terminal hydrophobic pocket of Mdm2 binds to p53 and thereby inhibits ...

Vesicular structures called microvesicles (MVs) that are shed from the surfaces of cancer cells are capable of transferring oncogenic cargo to recipient cancer cells, as well as to normal cells, sending mitogenic signals that greatly enhance tumor growth. Because MVs are stable in the circulation, they also may have a ...

Reactivation of the androgen receptor (AR) during androgen depletion therapy (ADT) underlies castration-resistant prostate cancer (CRPCa). Alternative splicing of the AR gene and synthesis of constitutively active COOH-terminally truncated AR variants lacking the AR ligand-binding domain has emerged as an important mechanism of ADT resistance in CRPCa. In a previous ...

Intersectin 1 (ITSN1) is a scaffold protein that regulates diverse cellular pathways, including endocytosis and several signal transduction pathways, including phosphatidylinositol 3-kinase, Class IIβ (PI3K-C2β). ITSN1's transforming potential in vitro suggests that this scaffold protein may be involved in human tumorigenesis. Herein, we demonstrate that ITSN1 is expressed in primary ...

We examined the utility of cognitive evaluation to predict instrumental activities of daily living (IADLs) and decisional ability in Mild Cognitive Impairment (MCI). Sixty-seven individuals with single-domain amnestic MCI were administered the Dementia Rating Scale-2 (DRS-2) as well as the Everyday Cognition assessment form to assess functional ability. The DRS-2 ...

Serial assessments are commonplace in neuropsychological practice and used to document cognitive trajectory for many clinical conditions. However, true change scores may be distorted by measurement error, repeated exposure to the assessment instrument, or person variables. The present study provides reliable change indices (RCI) for the Boston Naming Test, derived ...

Stem cell niches, the discrete microenvironments in which the stem cells reside, play a dominant part in regulating stem cell activity and behaviours. Recent studies suggest that committed stem cell progeny become indispensable components of the niche in a wide range of stem cell systems. These unexpected niche inhabitants provide ...

G-protein-coupled receptors (GPCRs) mediate many important physiological functions and are considered as one of the most successful therapeutic targets for a broad spectrum of diseases. The design and implementation of high-throughput GPCR assays that allow the cost-effective screening of large compound libraries to identify novel drug candidates are critical in ...

Lipophilic cations such as phosphonium salts penetrate the hydrophobic barriers of the plasma and mitochondrial membranes and accumulate in mitochondria in response to the negative inner-transmembrane potentials. Thus, as newly developed noninvasive imaging agents, [¹⁸F]-labeled phosphonium salts may serve as molecular "voltage sensor" probes to investigate the role of mitochondria, ...

Neuropathic pain is a debilitating condition for which the development of effective treatments has been limited by an incomplete understanding of its chemical basis. We show by using untargeted metabolomics that sphingomyelin-ceramide metabolism is altered in the dorsal horn of rats with neuropathic pain and that the upregulated, endogenous metabolite ...

The reactive thiol in cysteine is used for coupling maleimide linkers in the generation of antibody conjugates. To assess the impact of the conjugation site, we engineered cysteines into a therapeutic HER2/neu antibody at three sites differing in solvent accessibility and local charge. The highly solvent-accessible site rapidly lost conjugated ...

We report that graphene coatings do not significantly disrupt the intrinsic wetting behaviour of surfaces for which surface-water interactions are dominated by van der Waals forces. Our contact angle measurements indicate that a graphene monolayer is wetting-transparent to copper, gold or silicon, but not glass, for which the wettability is dominated by ...

Fic proteins that are defined by the ubiquitous FIC (filamentation induced by cyclic AMP) domain are known to catalyse adenylylation (also called AMPylation); that is, the transfer of AMP onto a target protein. In mammalian cells, adenylylation of small GTPases through Fic proteins injected by pathogenic bacteria can cause collapse ...

Bilayer graphene is an attractive platform for studying new two-dimensional electron physics, because its flat energy bands are sensitive to out-of-plane electric fields and these bands magnify electron-electron interaction effects. Theory predicts a variety of interesting broken symmetry states when the electron density is at the carrier neutrality point, and ...

We report on the first observation of carbon-induced nano-faceting of a Re single crystal and its application in synthesizing a nanostructured model Pt electrocatalyst investigated using multiple surface science techniques, including low energy electron diffraction (LEED), Auger electron spectroscopy (AES), X-ray photoelectron spectroscopy (XPS), low energy ion scattering (LEIS), and ...

The majority of agronomic traits are controlled by multiple genes that cause minor phenotypic effects, making the identification of these genes difficult. Here we introduce MutMap, a method based on whole-genome resequencing of pooled DNA from a segregating population of plants that show a useful phenotype. In MutMap, a mutant ...

Cbls are RING ubiquitin ligases that attenuate receptor tyrosine kinase (RTK) signal transduction. Cbl ubiquitination activity is stimulated by phosphorylation of a linker helix region (LHR) tyrosine residue. To elucidate the mechanism of activation, we determined the structures of human CBL, a CBL-substrate peptide complex and a phosphorylated-Tyr371-CBL-E2-substrate peptide complex, ...

In animals, maternal gene products deposited into eggs regulate embryonic development before activation of the zygotic genome. In plants, an analogous period of prolonged maternal control over embryogenesis is thought to occur based on some gene-expression studies. However, other gene-expression studies and genetic analyses show that some transcripts must derive ...

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause ...

Electroanalytical procedures are often subjected to oxygen interferences. However, achieving anaerobic conditions in field analytical chemistry is difficult. In this work, novel enzymatic systems were designed to maintain oxygen-free solutions in open, small volume electrochemical cells and implemented under field conditions. The oxygen removal system consists of an oxidase enzyme, ...

Abstract Abstract: Cocaine is a potent vasoconstrictor and longstanding use can result in an acquired palatal cleft. Similar to congenital cases, this palatal defect can cause nasal emission and hypernasal speech. The goals of palate repair include optimizing palatal function for speech and feeding while avoiding dehiscence or postoperative fistulae. ...

Combinations of nucleoside and non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT) are widely used in anti-AIDS therapies. Five NNRTIs, including nevirapine, are clinical drugs; however, the molecular mechanism of inhibition by NNRTIs is not clear. We determined the crystal structures of RT-DNA-nevirapine, RT-DNA, and RT-DNA-AZT-triphosphate complexes at 2.85-, 2.70- ...

Understanding and treatment of spinal cord pathology is limited in part by a lack of time-lapse in vivo imaging strategies at the cellular level. We developed a chronically implanted spinal chamber and surgical procedure suitable for time-lapse in vivo multiphoton microscopy of mouse spinal cord without the need for repeat ...

A series of neutral C3-symmetric acyclic artificial receptors incorporating amide functionality has been designed, synthesized and fully characterized. Upon protonation these conformationally flexible N-bridged tripodal podands 1-5 forms in situ cone shape conformation through hydrogen bonding and C-H…pi interactions. The protonation-induced interior pre-organized cavity is capable of entrapping nitrate anion ...

Nuocytes are essential in innate type 2 immunity and contribute to the exacerbation of asthma responses. Here we found that nuocytes arose in the bone marrow and differentiated from common lymphoid progenitors, which indicates they are distinct, previously unknown members of the lymphoid lineage. Nuocytes required interleukin 7 (IL-7), IL-33 ...

The ubiquitination cascade has a key role in the assembly of repair and signaling proteins at sites of double-strand DNA breaks. The E3 ubiquitin ligase RING finger protein 8 (RNF8) triggers the initial ubiquitination at double-strand DNA breaks, whereas sustained ubiquitination requires the downstream E3 ligase RING finger protein 168 ...

Adult-onset diseases can be associated with in utero events, but mechanisms for this remain unknown(1,2). The Polycomb histone methyltransferase Ezh2 stabilizes transcription by depositing repressive marks during development that persist into adulthood(3-9), but its function in postnatal organ homeostasis is unknown. We show that Ezh2 stabilizes cardiac gene expression and ...

Protein serine-threonine kinase casein kinase II (CK2) is involved in a myriad of cellular processes including cell growth and proliferation through its phosphorylation of hundreds of substrates, yet how CK2 function is regulated is poorly understood. Here we report that the CK2 catalytic subunit CK2α is modified by O-linked β-N-acetyl-glucosamine ...

Chromatography combined with spectral analysers provides great separation powers. However, the amount of data provided makes analysis difficult and laborious. The Automated Peak Extraction and Quantification (APEQ) method is a novel method for targeted and untargeted analysis. The method extracts retention times (tR), spectra and signal intensity from data from ...

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the ...

Computational enzyme design holds promise for the production of renewable fuels, drugs and chemicals. De novo enzyme design has generated catalysts for several reactions, but with lower catalytic efficiencies than naturally occurring enzymes. Here we report the use of game-driven crowdsourcing to enhance the activity of a computationally designed enzyme ...

Nanoelectromechanical systems can be operated as ultrasensitive mass sensors and ultrahigh-frequency resonators, and can also be used to explore fundamental physical phenomena such as nonlinear damping and quantum effects in macroscopic objects. Various dissipation mechanisms are known to limit the mechanical quality factors of nanoelectromechanical systems and to induce aging ...

Aim To identify aspects of health in postmenopausal Brazilian women using a health-related educational program provided by a multidisciplinary team as part of the primary care approach for early and late postmenopausal symptoms. Design A prospective cohort was formed with 69 postmenopausal women; they were divided into groups corresponding to ...

The 15 known Fanconi anemia proteins cooperate in a pathway that regulates DNA interstrand cross-link repair. Recent studies indicate that the Fanconi anemia pathway also controls Rev1-mediated translesion DNA synthesis (TLS). We identified Fanconi anemia-associated protein (FAAP20), an integral subunit of the multisubunit Fanconi anemia core complex. FAAP20 binds to ...

The wide spectrum of exotic properties exhibited by transition-metal oxides stems from the complex competition between several quantum interactions. The capacity to select the emergence of specific phases at will is nowadays extensively recognized as key for the design of diverse new devices with tailored functionalities. In this context, interface ...

Cytosine methylation in DNA was determined by an enzyme linked immunosorbent assay (ELISA) with electrochemiluminescence (ECL) detection and employed for the DNA methylation assay of a long and real genomic sample for the first time. The developed method employed an anti-methyl cytosine antibody labeled with acetylcholinesterase, which was added to ...

Cell-fate diversity can be generated by the unequal segregation of the Notch regulator Numb at mitosis in both vertebrates and invertebrates. Whereas the mechanisms underlying unequal inheritance of Numb are understood, how Numb antagonizes Notch has remained unsolved. Live imaging of Notch in sensory organ precursor cells revealed that nuclear ...

We investigated the impact of thalamus on ongoing cortical activity in the awake, behaving mouse. We demonstrate that the desynchronized cortical state during active behavior is driven by a centrally generated increase in thalamic action potential firing, which can also be mimicked by optogenetic stimulation of the thalamus. The thalamus ...

The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene (p-PriC6H4Me) ruthenium building blocks and 2,5-dioxydo-1,4-benzoquinonato (dobq) or 5,8-dioxydo-1,4-naphthoquinonato (donq) bridges, in the presence of a pyrenyl-nucleoside derivatives (pyrene-R), affords the triangular prismatic host-guest compounds [(pyrene-R)Ru6(p-PriC6H4Me)6(tpt)2(dobq)3]6+ ([(pyrene-R)1]6+) and [(pyrene-R)Ru6(p-PriC6H4Me)6(tpt)2(donq)3]6+ ([(pyrene-R)2]6+), respectively. The inclusion of six mono-substituted pyrenyl-nucleosides (pyrene-R1 = 5'-(1-pyrenyl butanoate)-2'-deoxyuridne, ...

Cue-triggered recall of learned temporal sequences is an important cognitive function that has been attributed to higher brain areas. Here recordings in both anesthetized and awake rats demonstrate that after repeated stimulation with a moving spot that evoked sequential firing of an ensemble of primary visual cortex (V1) neurons, just ...

Atrial natriuretic peptide (ANP) may be a useful molecule for the treatment of cardiovascular diseases due to its potent natriuretic effects. In an effort to prolong the short in vivo half-life of ANP, fusions of the peptide to the Fc domain of IgG were generated using a semi-synthetic methodology. Synthetic ...

The transcription factor cyclic AMP-response element binding protein (CREB) is a key regulator of many neuronal processes, including brain development, circadian rhythm and long-term memory. Studies of CREB have focused on its phosphorylation, although the diversity of CREB functions in the brain suggests additional forms of regulation. Here we expand ...

Channelrhodopsins (ChRs) are light-gated cation channels derived from algae that have shown experimental utility in optogenetics; for example, neurons expressing ChRs can be optically controlled with high temporal precision within systems as complex as freely moving mammals. Although ChRs have been broadly applied to neuroscience research, little is known about ...

Synthetic molecular motors can be fuelled by the hydrolysis or hybridization of DNA. Such motors can move autonomously and programmably, and long-range transport has been observed on linear tracks. It has also been shown that DNA systems can compute. Here, we report a synthetic DNA-based system that integrates long-range transport ...

Accumulating evidence has shown that dysfunctional mitochondria can be selectively removed by mitophagy. Dysregulation of mitophagy is implicated in the development of neurodegenerative disease and metabolic disorders. How individual mitochondria are recognized for removal and how this process is regulated remain poorly understood. Here we report that FUNDC1, an integral ...

Production of the proinflammatory cytokine interleukin 1β (IL-1β) by dendritic cells is crucial in host defense. Here we identify a previously unknown role for dectin-1 in the activation of a noncanonical caspase-8 inflammasome in response to fungi and mycobacteria. Dectin-1 induced both the production and maturation of IL-1β through signaling ...

Granules of mast cells (MCs) enhance adaptive immunity when, on activation, they are released as stable particles. Here we show that submicrometre particles modelled after MC granules augment immunity when used as adjuvants in vaccines. The synthetic particles, which consist of a carbohydrate backbone with encapsulated inflammatory mediators such as ...