Spinal cord injury can lead to severe motor, sensory and autonomic dysfunction. Currently, there is no effective treatment for the injured spinal cord. The transplantation of Schwann cells, neural ...stem cells or progenitor cells, olfactory ensheathing cells, oligodendrocyte precursor cells and mesenchymal stem cells has been investigated as potential therapies for spinal cord injury. However, little is known about the mechanisms through which these individual cell types promote repair and functional improvements. The five most commonly proposed mechanisms include neuroprotection, immunomodulation, axon regeneration, neuronal relay formation and myelin regeneration. A better understanding of the mechanisms whereby these cells promote functional improvements, as well as an appreciation of the obstacles in implementing these therapies and effectively modeling spinal cord injury, will be important to make cell transplantation a viable clinical option and may lead to the development of more targeted therapies.
In the adult mammalian central nervous system (CNS), neurons typically fail to regenerate their axons after injury. During development, by contrast, neurons extend axons effectively. A variety of ...intracellular mechanisms mediate this difference, including changes in gene expression, the ability to form a growth cone, differences in mitochondrial function/axonal transport and the efficacy of synaptic transmission. In turn, these intracellular processes are linked to extracellular differences between the developing and adult CNS. During development, the extracellular environment directs axon growth and circuit formation. In adulthood, by contrast, extracellular factors, such as myelin and the extracellular matrix, restrict axon growth. Here, we discuss whether the reactivation of developmental processes can elicit axon regeneration in the injured CNS.
We systematically investigate the excitonic dephasing of three representative transition-metal dichalcogenides, namely, MoS_{2}, MoSe_{2}, and WSe_{2} atomic monolayer thick and bulk crystals, in ...order to gain a proper understanding of the factors that determine the optical coherence in these materials. Coherent nonlinear optical spectroscopy and temperature dependent absorption, combined with theoretical calculations of the phonon spectra, indicate electron-phonon interactions, to be the limiting factor. Surprisingly, the excitonic dephasing, differs only slightly between atomic monolayers and high quality bulk crystals, which indicates that material imperfections are not the limiting factor in atomically thin monolayer samples. The temperature dependence of the electronic band gap and the excitonic linewidth combined with "ab initio" calculations of the phonon energies and the phonon density of states reveal a strong interaction with the E' and E" phonon modes.
Mixed lineage kinase domain-like (MLKL) is a component of the “necrosome,” the multiprotein complex that triggers tumor necrosis factor (TNF)-induced cell death by necroptosis. To define the specific ...role and molecular mechanism of MLKL action, we generated MLKL-deficient mice and solved the crystal structure of MLKL. Although MLKL-deficient mice were viable and displayed no hematopoietic anomalies or other obvious pathology, cells derived from these animals were resistant to TNF-induced necroptosis unless MLKL expression was restored. Structurally, MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation. Structure-guided mutation of the MLKL pseudoactive site resulted in constitutive, RIPK3-independent necroptosis, demonstrating that modification of MLKL is essential for propagation of the necroptosis pathway downstream of RIPK3.
•The crystal structure of MLKL reveals an unusual pseudoactive site•The MLKL pseudokinase domain binds ATP but is not catalytically active•MLKL-deficient cells are resistant to TNF-induced necroptosis•MLKL pseudoactive site mutations cause caspase- and RIPK3-independent necroptosis
Skeletal stem cells (SSCs) are postulated to provide a continuous supply of osteoblasts throughout life. However, under certain conditions, the SSC population can become incorrectly specified or is ...not maintained, resulting in reduced osteoblast formation, decreased bone mass, and in severe cases, osteoporosis. Glutamine metabolism has emerged as a critical regulator of many cellular processes in diverse pathologies. The enzyme glutaminase (GLS) deaminates glutamine to form glutamate—the rate-limiting first step in glutamine metabolism. Using genetic and metabolic approaches, we demonstrate GLS and glutamine metabolism are required in SSCs to regulate osteoblast and adipocyte specification and bone formation. Mechanistically, transaminase-dependent α-ketoglutarate production is critical for the proliferation, specification, and differentiation of SSCs. Collectively, these data suggest stimulating GLS activity may provide a therapeutic approach to expand SSCs in aged individuals and enhance osteoblast differentiation and activity to increase bone mass.
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•Skeletal stem cells increase glutamine metabolism during osteoblast differentiation•Glutamine metabolism regulates osteoblast and adipocyte specification•Mice unable to metabolize glutamine have less bone and increased marrow fat•Amino acid transaminase-derived α-ketoglutarate is critical for SSC proliferation
Skeletal stem cells (SSCs) provide a reservoir of bone-forming osteoblasts throughout life. Yu et al. investigate glutamine metabolism in SSCs. Glutamine-derived α-ketoglutarate supports amino acid biosynthesis and proliferation in SSCs. Inhibiting glutamine metabolism in SSCs results in low bone mass and increased marrow adiposity in mice.
Cytopenias are key prognostic indicators of life-threatening infection, contributing to immunosuppression and mortality. Here we define a role for Caspase-1-dependent death, known as pyroptosis, in ...infection-induced cytopenias by studying inflammasome activation in hematopoietic progenitor cells. The NLRP1a inflammasome is expressed in hematopoietic progenitor cells and its activation triggers their pyroptotic death. Active NLRP1a induced a lethal systemic inflammatory disease that was driven by Caspase-1 and IL-1β but was independent of apoptosis-associated speck-like protein containing a CARD (ASC) and ameliorated by IL-18. Surprisingly, in the absence of IL-1β-driven inflammation, active NLRP1a triggered pyroptosis of hematopoietic progenitor cells resulting in leukopenia at steady state. During periods of hematopoietic stress induced by chemotherapy or lymphocytic choriomeningitis virus (LCMV) infection, active NLRP1a caused prolonged cytopenia, bone marrow hypoplasia, and immunosuppression. Conversely, NLRP1-deficient mice showed enhanced recovery from chemotherapy and LCMV infection, demonstrating that NLRP1 acts as a cellular sentinel to alert Caspase-1 to hematopoietic and infectious stress.
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► Systemic NLRP1 inflammasome activation induces lethal inflammation ► IL-18 ameliorates inflammation induced by NLRP1 ► NLRP1 activation in progenitor cells induces cytopenia and immunosuppression ► NLRP1 deficiency accelerates recovery from viral infection and chemotherapy
Many interesting but practically intractable problems can be reduced to that of finding the ground state of a system of interacting spins; however, finding such a ground state remains computationally ...difficult. It is believed that the ground state of some naturally occurring spin systems can be effectively attained through a process called quantum annealing. If it could be harnessed, quantum annealing might improve on known methods for solving certain types of problem. However, physical investigation of quantum annealing has been largely confined to microscopic spins in condensed-matter systems. Here we use quantum annealing to find the ground state of an artificial Ising spin system comprising an array of eight superconducting flux quantum bits with programmable spin-spin couplings. We observe a clear signature of quantum annealing, distinguishable from classical thermal annealing through the temperature dependence of the time at which the system dynamics freezes. Our implementation can be configured in situ to realize a wide variety of different spin networks, each of which can be monitored as it moves towards a low-energy configuration. This programmable artificial spin network bridges the gap between the theoretical study of ideal isolated spin networks and the experimental investigation of bulk magnetic samples. Moreover, with an increased number of spins, such a system may provide a practical physical means to implement a quantum algorithm, possibly allowing more-effective approaches to solving certain classes of hard combinatorial optimization problems.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Our research examined effective ways of presenting true descriptive norm information about sustainable consumption in a realistic online shopping environment, even when the current norms for ...purchasing green products are low. In Experiment 1, participants presented with both “strong” and “weak” formulations of descriptive norms purchased more eco-labeled products and spent more money in comparison with a control condition. Using a different population, Experiment 2 confirmed these results for strong norms, but not for weak ones, and eliminated product salience and differential recall of norms as explanations for these effects. Overall, these findings suggest that even though current levels of green consumption may be relatively low, they can be truthfully described in ways that promote sustainable consumption in a shopping environment with real incentives. These methods can be easily adopted by supermarket chains and department stores.
•We used descriptive norms about sustainable consumption in a virtual shop.•These norms had a positive effect on eco-products purchasing.•Participants presented with these norms also spent more money on eco-products.•Experiment 2 confirmed these results for strong norms.•Even description of low levels of consumption can promote sustainable consumption.
Coxsackievirus B3 (CVB3), a member of the picornavirus family and enterovirus genus, causes viral myocarditis, aseptic meningitis, and pancreatitis in humans. We genetically engineered a unique ...molecular marker, "fluorescent timer" protein, within our infectious CVB3 clone and isolated a high-titer recombinant viral stock (Timer-CVB3) following transfection in HeLa cells. "Fluorescent timer" protein undergoes slow conversion of fluorescence from green to red over time, and Timer-CVB3 can be utilized to track virus infection and dissemination in real time. Upon infection with Timer-CVB3, HeLa cells, neural progenitor and stem cells (NPSCs), and C2C12 myoblast cells slowly changed fluorescence from green to red over 72 hours as determined by fluorescence microscopy or flow cytometric analysis. The conversion of "fluorescent timer" protein in HeLa cells infected with Timer-CVB3 could be interrupted by fixation, suggesting that the fluorophore was stabilized by formaldehyde cross-linking reactions. Induction of a type I interferon response or ribavirin treatment reduced the progression of cell-to-cell virus spread in HeLa cells or NPSCs infected with Timer-CVB3. Time lapse photography of partially differentiated NPSCs infected with Timer-CVB3 revealed substantial intracellular membrane remodeling and the assembly of discrete virus replication organelles which changed fluorescence color in an asynchronous fashion within the cell. "Fluorescent timer" protein colocalized closely with viral 3A protein within virus replication organelles. Intriguingly, infection of partially differentiated NPSCs or C2C12 myoblast cells induced the release of abundant extracellular microvesicles (EMVs) containing matured "fluorescent timer" protein and infectious virus representing a novel route of virus dissemination. CVB3 virions were readily observed within purified EMVs by transmission electron microscopy, and infectious virus was identified within low-density isopycnic iodixanol gradient fractions consistent with membrane association. The preferential detection of the lipidated form of LC3 protein (LC3 II) in released EMVs harboring infectious virus suggests that the autophagy pathway plays a crucial role in microvesicle shedding and virus release, similar to a process previously described as autophagosome-mediated exit without lysis (AWOL) observed during poliovirus replication. Through the use of this novel recombinant virus which provides more dynamic information from static fluorescent images, we hope to gain a better understanding of CVB3 tropism, intracellular membrane reorganization, and virus-associated microvesicle dissemination within the host.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Emerging immune therapy, such as with the anti-programmed cell death-1 (anti-PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from ...cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1-/-) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1-/- mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1-/- mice. Consistently, these beneficial effects in Pd1-/- mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti-PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.
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