Microglia interact with neurons to facilitate synapse plasticity; however, signal(s) contributing to microglia activation for synapse elimination in pathology are not fully understood. Here, using in ...vitro organotypic hippocampal slice cultures and transient middle cerebral artery occlusion (MCAO) in genetically engineered mice in vivo, we report that at 24 hours after ischemia, microglia release brain-derived neurotrophic factor (BDNF) to downregulate glutamatergic and GABAergic synapses within the peri-infarct area. Analysis of the cornu ammonis 1 (CA1) in vitro shows that proBDNF and mBDNF downregulate glutamatergic dendritic spines and gephyrin scaffold stability through p75 neurotrophin receptor (p75
) and tropomyosin receptor kinase B (TrkB) receptors, respectively. After MCAO, we report that in the peri-infarct area and in the corresponding contralateral hemisphere, similar neuroplasticity occurs through microglia activation and gephyrin phosphorylation at serine-268 and serine-270 in vivo. Targeted deletion of the
gene in microglia or
S268A/S270A (phospho-null) point mutations protects against ischemic brain damage, neuroinflammation, and synapse downregulation after MCAO.
ADNP is essential for embryonic development. As such, de novo ADNP mutations lead to an intractable autism/intellectual disability syndrome requiring investigation.
Mimicking humans, CRISPR ...(clustered regularly interspaced short palindromic repeats)–Cas9 editing produced mice carrying heterozygous Adnp p.Tyr718∗ (Tyr), a paralog of the most common ADNP syndrome mutation. Phenotypic rescue was validated by treatment with the microtubule/autophagy-protective ADNP fragment NAPVSIPQ (NAP).
RNA sequencing of spleens, representing a peripheral biomarker source, revealed Tyr-specific sex differences (e.g., cell cycle), accentuated in females (with significant effects on antigen processing and cellular senescence) and corrected by NAP. Differentially expressed, NAP-correctable transcripts, including the autophagy and microbiome resilience–linked FOXO3, were also deregulated in human patient-derived ADNP-mutated lymphoblastoid cells. There were also Tyr sex-specific microbiota signatures. Phenotypically, Tyr mice, similar to patients with ADNP syndrome, exhibited delayed development coupled with sex-dependent gait defects. Speech acquisition delays paralleled sex-specific mouse syntax abnormalities. Anatomically, dendritic spine densities/morphologies were decreased with NAP amelioration. These findings were replicated in the Adnp+/− mouse, including Foxo3 deregulation, required for dendritic spine formation. Grooming duration and nociception threshold (autistic traits) were significantly affected only in males. Early-onset tauopathy was accentuated in males (hippocampus and visual cortex), mimicking humans, and was paralleled by impaired visual evoked potentials and correction by acute NAP treatment.
Tyr mice model ADNP syndrome pathology. The newly discovered ADNP/NAP target FOXO3 controls the autophagy initiator LC3 (microtubule-associated protein 1 light chain 3), with known ADNP binding to LC3 augmented by NAP, protecting against tauopathy. NAP amelioration attests to specificity, with potential for drug development targeting accessible biomarkers.
Following its discovery more than 30 years ago, the enhanced permeability and retention (EPR) effect has become the guiding principle for cancer nanomedicine development. Over the years, the ...tumor-targeted drug delivery field has made significant progress, as evidenced by the approval of several nanomedicinal anticancer drugs. Recently, however, the existence and the extent of the EPR effect - particularly in patients - have become the focus of intense debate. This is partially due to the disbalance between the huge number of preclinical cancer nanomedicine papers and relatively small number of cancer nanomedicine drug products reaching the market. To move the field forward, we have to improve our understanding of the EPR effect, of its cancer type-specific pathophysiology, of nanomedicine interactions with the heterogeneous tumor microenvironment, of nanomedicine behavior in the body, and of translational aspects that specifically complicate nanomedicinal drug development. In this virtual special issue, 24 research articles and reviews discussing different aspects of the EPR effect and cancer nanomedicine are collected, together providing a comprehensive and complete overview of the current state-of-the-art and future directions in tumor-targeted drug delivery.
In the initial stage of relativistic heavy-ion collisions, strong magnetic fields appear due to the large velocity of the colliding charges. The evolution of these fields appears as a novel and ...intriguing feature in the fluid-dynamical description of heavy-ion collisions. In this work, we study analytically the one-dimensional, longitudinally boost-invariant motion of an ideal fluid in the presence of a transverse magnetic field. Interestingly, we find that, in the limit of ideal magnetohydrodynamics, i.e., for infinite conductivity, and irrespective of the strength of the initial magnetization, the decay of the fluid energy density e with proper time τ is the same as for the time-honoured “Bjorken flow” without magnetic field. Furthermore, when the magnetic field is assumed to decay ∼τ−a, where a is an arbitrary number, two classes of analytic solutions can be found depending on whether a is larger or smaller than one. In summary, the analytic solutions presented here highlight that the Bjorken flow is far more general than formerly thought. These solutions can serve both to gain insight on the dynamics of heavy-ion collisions in the presence of strong magnetic fields and as testbeds for numerical codes.
Inspired by the highly parallel processing power and low energy consumption of the biological nervous system, the development of a neuromorphic computing paradigm to mimic brain‐like behaviors with ...electronic components based artificial synapses may play key roles to eliminate the von Neumann bottleneck. Random resistive access memory (RRAM) is suitable for artificial synapse due to its tunable bidirectional switching behavior. In this work, a biological spiking synapse is developed with solution processed Au@Ag core–shell nanoparticle (NP)‐based RRAM. The device shows highly controllable bistable resistive switching behavior due to the favorable Ag ions migration and filament formation in the composite film, and the good charge trapping and transport property of Au@Ag NPs. Moreover, comprehensive synaptic functions of biosynapse including paired‐pulse depression, paired‐pulse facilitation, post‐tetanic potentiation, spike‐time‐dependent plasticity, and the transformation from short‐term plasticity to long‐term plasticity are emulated. This work demonstrates that the solution processed bimetal core–shell nanoparticle‐based biological spiking synapse provides great potential for the further creation of a neuromorphic computing system.
A biological spiking synapse constructed from solution processed bimetal core–shell nanoparticle based composites is reported. The device can emulate important synaptic behaviors including spike‐rate‐dependent plasticity, spike‐time‐dependent plasticity, and transformation from short‐term plasticity to long‐term plasticity. This work demonstrates that the polymer–metal nanoparticles composites based artificial synapse have great potential for the realization of next‐generation neuromorphic computing system.
•Traffic impacts evaluated from roadside and urban increments.•Trends viewed with deweathered data for PM, NO2 and other pollutants.•Traffic increments are reducing in developed world cities.•Traffic ...still makes major contribution to urban air pollution.•Mitigation measures need to take careful account of local circumstances.
Road traffic emissions are considered a major contributor to urban air pollution, but clean air actions have led to a huge reduction in emissions per vehicle. This raises a pressing question on the potential to further reduce road traffic emissions to improve air quality. Here, we analysed ~11 million real-world data to estimate the contribution of road traffic to roadside and urban concentrations for several major cities. Our results confirm that road traffic remains a dominant source of nitrogen dioxide and a significant source of primary coarse particulate matter in the European cities. However, it now represents a relatively small component of overall PM2.5 at urban background locations in cities with strong controls on traffic emissions (including European cities and Beijing) and many roadside sites will exceed the WHO guideline (10 μg m−3 annual mean) even when this source is eliminated. This suggests that further controls on traffic emissions, including the transition to a battery-electric fleet, are needed to reduce NO2 concentrations, but this will have limited benefit to reduce the concentration of fine particles, except in countries where the use of diesel particle filters is not mandatory. There are substantial differences between cities and the optimal solution will differ from one to another.
At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available and timelines are tight. A miniaturized automation ...platform enabling high-throughput experimentation for synthetic route scouting to identify conditions for preparative reaction scale-up would be a transformative advance. Because automated, miniaturized chemistry is difficult to carry out in the presence of solids or volatile organic solvents, most of the synthetic "toolkit" cannot be readily miniaturized. Using palladium-catalyzed cross-coupling reactions as a test case, we developed automation-friendly reactions to run in dimethyl sulfoxide at room temperature. This advance enabled us to couple the robotics used in biotechnology with emerging mass spectrometry–based high-throughput analysis techniques. More than 1500 chemistry experiments were carried out in less than a day, using as little as 0.02 milligrams of material per reaction.
Smart cancer nanomedicine van der Meel, Roy; Sulheim, Einar; Shi, Yang ...
Nature nanotechnology,
11/2019, Letnik:
14, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Nanomedicines are extensively employed in cancer therapy. We here propose four strategic directions to improve nanomedicine translation and exploitation. (1) Patient stratification has become common ...practice in oncology drug development. Accordingly, probes and protocols for patient stratification are urgently needed in cancer nanomedicine, to identify individuals suitable for inclusion in clinical trials. (2) Rational drug selection is crucial for clinical and commercial success. Opportunistic choices based on drug availability should be replaced by investments in modular (pro)drug and nanocarrier design. (3) Combination therapies are the mainstay of clinical cancer care. Nanomedicines synergize with pharmacological and physical co-treatments, and should be increasingly integrated in multimodal combination therapy regimens. (4) Immunotherapy is revolutionizing the treatment of cancer. Nanomedicines can modulate the behaviour of myeloid and lymphoid cells, thereby empowering anticancer immunity and immunotherapy efficacy. Alone and especially together, these four directions will fuel and foster the development of successful cancer nanomedicine therapies.
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