The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has ...led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.
Fibronectin, the extracellular glue Zollinger, Alicia J.; Smith, Michael L.
Matrix biology,
July 2017, 2017-Jul, 2017-07-00, 20170701, Letnik:
60-61
Journal Article
Recenzirano
Fibronectin is an extracellular matrix protein that is present during periods of change within tissues. It is upregulated and necessary in a number of developmental contexts, and it is also present ...during pathological progression of tissues and during wound healing. Thus, it has been studied in a broad number of contexts from basic science to pathology. One of the unique features of fibronectin is its ability to specifically bind a large number of molecules including other components of the extracellular matrix, signaling molecules, and cell adhesion molecules. Cellular interactions with fibronectin lead to bidirectional crosstalk that directs cell function and also leads to cell-dependent changes in the extracellular matrix. Interestingly, fibronectin exists in a functional form composed of fibers that are nm to μm in diameter that is highly interwoven, and fibronectin molecules that constitute this material have a labile molecular conformation that can be altered through binding of allosteric partners and strain resulting from application of cell contractile forces. This review focuses on summarizing the many binding partners for fibronectin such as ECM proteins, growth factors, and synthetic binding partners with a particular interest in binding partners whose adhesiveness is impacted by the molecular conformation of the fibronectin fibers.
•Fibronectin binds a large number of cell adhesion receptors, growth factors, and extracellular matrix proteins.•Fibronectin conformation is labile and can be altered by allosteric binding partners and mechanical stress.•Fibronectin conformation can be detected with conformation-sensitive monoclonal antibodies and synthetic binding partners.
Nosema ceranae, a newly introduced parasite of the honey bee, Apis mellifera, is contributing to worldwide colony losses. Other Nosema species, such as N. apis, tend to be associated with increased ...defecation and spread via a fecal-oral pathway, but because N. ceranae does not induce defecation, it may instead be spread via an oral-oral pathway. Cages that separated older infected bees from young uninfected bees were used to test whether N. ceranae can be spread during food exchange. When cages were separated by one screen, food could be passed between the older bees and the young bees, but when separated by two screens, food could not be passed between the two cages. Young uninfected bees were also kept isolated in cages, as a solitary control. After 4 days of exposure to the older bees, and 10 days to incubate infections, young bees were more likely to be infected in the 1-Screen Test treatment vs. the 2-Screen Test treatment (P=0.0097). Young bees fed by older bees showed a 13-fold increase in mean infection level relative to young bees not fed by older bees (1-Screen Test 40.8%; 2-Screen Test 3.4%; Solo Control 2.8%). Although fecal-oral transmission is still possible in this experimental design, oral-oral infectivity could help explain the rapid spread of N. ceranae worldwide.
We present a simulation of the formation of the earliest Population II stars, starting from cosmological initial conditions and ending when metals created in the first supernovae are incorporated ...into a collapsing gas cloud. This occurs after a supernova blast-wave collides with a nearby mini-halo, inducing further turbulence that efficiently mixes metals into the dense gas in the centre of the halo. The gas that first collapses has been enriched to a metallicity of Z ∼ 2 × 10−5 Z⊙. Due to the extremely low metallicity, collapse proceeds similarly to metal-free gas until dust cooling becomes efficient at high densities, causing the cloud to fragment into a large number of low-mass objects. This external enrichment mechanism provides a plausible origin for the most metal-poor stars observed, such as SMSS J031300.36-670839.3, that appear to have formed out of gas enriched by a single supernova. This mechanism operates on shorter time-scales than the time for low-mass mini-haloes (M ≤ 5 × 105 M⊙) to recover their gas after experiencing a supernova. As such, metal-enriched stars will likely form first via this channel if the conditions are right for it to occur. We identify a number of other externally enriched haloes that may form stars in this manner. These haloes have metallicities as high as 0.01 Z⊙, suggesting that some members of the first generation of metal-enriched stars may be hiding in plain sight in current stellar surveys.
Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF ...diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting ...with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10−7), SMARCC1 (p = 8.15 × 10−10), and PTCH1 (p = 1.06 × 10−6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10−4). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.
•Exome sequencing identifies novel genetic drivers of congenital hydrocephalus (CH)•De novo and inherited rare variants in four genes explain ∼10% of CH cases•All four CH genes (TRIM71, SMARCC1, PTCH1, and SHH) regulate neural stem cell fate•These data implicate aberrant neurogenesis in the pathogenesis of a subset of CH
Congenital hydrocephalus (CH) is a major cause of childhood morbidity and mortality, affecting 1 in 1,000 live births and representing up to 3% of all pediatric hospital charges. Using data from the largest CH exome sequencing study to date, Furey et al. identify four genes (TRIM71, SMARCC1, PTCH1, and SHH) not previously implicated in CH. Remarkably, all four genes regulate ventricular zone neural stem cell fate and, together, explain ∼10% of CH cases. These findings implicate impaired neurogenesis in pathogenesis of a significant number of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.
Developing a better understanding of the evolution of morphology in plastic solar cells is the key to designing new materials and structures that achieve photoconversion efficiencies greater than ...10%. In the most extensively characterized system, the poly(3‐hexyl thiophene) (P3HT):6,6‐phenyl‐C61‐butyric‐acid‐methyl‐ester (PCBM) bulk heterojunction, the origins and evolution of the blend morphology during processes such as thermal annealing are not well understood. In this work, we use a model system, a bilayer of P3HT and PCBM, to develop a more complete understanding of the miscibility and diffusion of PCBM within P3HT during thermal annealing. We find that PCBM aggregates and/or molecular species are miscible and mobile in disordered P3HT, without disrupting the ordered lamellar stacking of P3HT chains. The fast diffusion of PCBM into the amorphous regions of P3HT suggests the favorability of mixing in this system, opposing the belief that phase‐pure domains form in BHJs due to immiscibility of these two components.
Polymer/fullerene blends: Bilayers of poly(3‐hexyl thiophene) (P3HT) and 6,6‐phenyl‐C61‐butyric‐acid‐methyl‐ester (PCBM) were fabricated to investigate the miscibility and mobility of the two components during thermal annealing. It is found that aggregates and/or molecular species of PCBM are miscible and mobile in disordered P3HT without disrupting the P3HT crystallite orientation or size.
Sustained organizational performance depends on top management teams effectively exploring and exploiting. These strategic agendas are, however, associated with contradictory organizational ...architectures. Using the literature on paradox, contradictions, and conflict, we develop a model of managing strategic contradictions that is associated with paradoxical cognitionsenior leaders and/or their teams (a) articulating a paradoxical frame, (b) differentiating between the strategy and architecture for the existing product and those for innovation, and (c) integrating between those strategies and architectures. We further argue that the locus of paradox in top management teams resides either with the senior leader or with the entire team. We identify a set of top management team conditions that facilitates a teams ability to engage in paradoxical cognitive processes.
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