Genetic mutations in TAR DNA-binding protein 43 (TARDBP, also known as TDP-43) cause amyotrophic lateral sclerosis (ALS), and an increase in the presence of TDP-43 (encoded by TARDBP) in the ...cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 and ND6, impair their expression and specifically cause complex I disassembly. The suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration.
Immunosurveillance is a critical mechanism guarding against tumor development and progression. Checkpoint inhibitors have shown significant success in cancer treatment, but expression of key factors ...such as PD-L1 in putative cancer stem cell (CSC) populations in squamous cell carcinoma has been inconclusive, suggesting that CSCs may have developed other mechanisms to escape immune surveillance. Here we show that CSCs upregulate the immune checkpoint molecule CD276 (B7-H3) to evade host immune responses. CD276 is highly expressed by CSCs in mouse and human head and neck squamous cell carcinoma (HNSCC) and can be used to prospectively isolate tumorigenic CSCs. Anti-CD276 antibodies eliminate CSCs in a CD8+ T cell-dependent manner, inhibiting tumor growth and lymph node metastases in a mouse HNSCC model. Single-cell RNA sequencing (RNA-seq) showed that CD276 blockade remodels SCC heterogeneity and reduces epithelial-mesenchymal transition. These results show that CSCs utilize CD276 for immune escape and suggest that targeting CD276 may reduce CSCs in HNSCC.
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•CSCs use CD276 to evade immune surveillance in SCC initiation and metastasis•CD276 is a functional cell surface marker to isolate CSCs from SCC•CD276 blockade remodels SCC heterogeneity with decrease of pEMT•CD276 blockade kills CSCs in a CD8+ T cell-dependent manner
Wang et al. show that cancer stem cells (CSCs) utilize the immune checkpoint molecule CD276 (B7-H3) to evade immune surveillance during HNSCC initiation, development, and metastasis. CD276 blockade eliminates CSCs and inhibits tumor growth and metastasis by increasing anti-tumor immunity.
Lytic polysaccharide monooxygenases (LPMOs) are copper-dependent enzymes for the degradation of recalcitrant polysaccharides such as chitin and cellulose. Unlike classical hydrolytic enzymes ...(cellulases), LPMOs catalyze the cleavage of the glycosidic bond via an oxidative mechanism using oxygen and a reductant. The full enzymatic molecular mechanisms, starting from the initial electron transfer from a reductant to oxygen activation and hydrogen peroxide formation, are not yet understood. Using quantum mechanics/molecular mechanics (QM/MM) metadynamics simulations, we have uncovered the oxygen activation mechanisms by LPMO in the presence of ascorbic acid, one of the most-used reductants in LPMOs assays. Our simulations capture the sequential formation of Cu(II)-O2 – and Cu(II)-OOH– intermediates via facile H atom abstraction from ascorbate. By investigating all the possible reaction pathways from the Cu(II)–OOH– intermediate, we ruled out Cu(II)-O• – formation via direct O–O cleavage of Cu(II)-OOH–. Meanwhile, we identified a possible pathway in which the proximal O atom of Cu(II)–OOH– abstracts a hydrogen atom from ascorbate, leading to Cu(I) and H2O2. The in-situ-generated H2O2 either converts to LPMO-Cu(II)-O• – via a homolytic reaction, or diffuses into the bulk water in an uncoupled pathway. The competition of these two pathways is strongly dependent on the binding of the carbohydrate substrate, which plays a role in barricading the in-situ-generated H2O2 molecule, preventing its diffusion from the active site into the bulk water. Based on the present results, we propose a catalytic cycle of LPMOs that is consistent with the experimental information available. In particular, it explains the enigmatic substrate dependence of the reactivity of the LPMO with H2O2.
The increasing awareness of the energy–environment nexus is compelling the development of technologies that reduce environmental impacts during energy production as well as energy consumption during ...environmental remediation. Countries spend billions in pollution cleanup projects, and new technologies with low energy and chemical consumption are needed for sustainable remediation practice. This perspective review provides a comprehensive summary on the mechanisms of the new bioelectrochemical system (BES) platform technology for efficient and low cost remediation, including petroleum hydrocarbons, chlorinated solvents, perchlorate, azo dyes, and metals, and it also discusses the potential new uses of BES approach for some emerging contaminants remediation, such as CO2 in air and nutrients and micropollutants in water. The unique feature of BES for environmental remediation is the use of electrodes as non-exhaustible electron acceptors, or even donors, for contaminant degradation, which requires minimum energy or chemicals but instead produces sustainable energy for monitoring and other onsite uses. BES provides both oxidation (anode) and reduction (cathode) reactions that integrate microbial–electro-chemical removal mechanisms, so complex contaminants with different characteristics can be removed. We believe the BES platform carries great potential for sustainable remediation and hope this perspective provides background and insights for future research and development.
Analyses of pairwise relatedness represent a key component to addressing many topics in biology. However, such analyses have been limited because most available programs provide a means to estimate ...relatedness based on only a single estimator, making comparison across estimators difficult. Second, all programs to date have been platform specific, working only on a specific operating system. This has the undesirable outcome of making choice of relatedness estimator limited by operating system preference, rather than being based on scientific rationale. Here, we present a new R package, called related, that can calculate relatedness based on seven estimators, can account for genotyping errors, missing data and inbreeding, and can estimate 95% confidence intervals. Moreover, simulation functions are provided that allow for easy comparison of the performance of different estimators and for analyses of how much resolution to expect from a given data set. Because this package works in R, it is platform independent. Combined, this functionality should allow for more appropriate analyses and interpretation of pairwise relatedness and will also allow for the integration of relatedness data into larger R workflows.
Abstract
Harmonic generation is a general characteristic of driven nonlinear systems, and serves as an efficient tool for investigating the fundamental principles that govern the ultrafast nonlinear ...dynamics. Here, we report on terahertz-field driven high-harmonic generation in the three-dimensional Dirac semimetal Cd
3
As
2
at room temperature. Excited by linearly-polarized multi-cycle terahertz pulses, the third-, fifth-, and seventh-order harmonic generation is very efficient and detected via time-resolved spectroscopic techniques. The observed harmonic radiation is further studied as a function of pump-pulse fluence. Their fluence dependence is found to deviate evidently from the expected power-law dependence in the perturbative regime. The observed highly non-perturbative behavior is reproduced based on our analysis of the intraband kinetics of the terahertz-field driven nonequilibrium state using the Boltzmann transport theory. Our results indicate that the driven nonlinear kinetics of the Dirac electrons plays the central role for the observed highly nonlinear response.
Visible-light photocatalytic conversion of CO2-to-fuels for green electricity is sustainably attractive for alleviating carbon emissions. Photocatalytic CO2-to-CO frequently suffered from relatively ...low yields, mainly due to ineffective charge transfer rates. A new approach for photocatalytic CO2-to-CO enhanced with effective H+ from H2O-to-H2O2 through the water oxidation reaction (WOR) has been studied in the present work. Here, the nano palladium (9 wt %), serving as a cocatalyst, dispersed on the g-C3N4/Cu2O heterojunctions (i.e., g-C3N4/Cu2O–Pd) has been prepared to facilitate charge separation for the two-electron reduction of CO2 to CO. Experimentally, the g-C3N4/Cu2O–Pd heterojunctions have a higher photocatalytic H2O-to-H2O2 yield than the g-C3N4/Cu2O heterojunction by 5.3 times. The photocatalytic WOR provides sufficient electrons (e–) and H+ (2H2O → H2O2 + 2H+) for CO2-to-CO (CO2(aq) + 2H+ + 2e– → CO(g) + H2O(l)). Relatively high photocatalytic yields of H2O2 (34.0 μmol/mg) and CO (14.6 μmol/mg) affected by the heterojunctions can be achieved. Also, the heterojunctions have a high photostability with a photocatalytic generated CO/H2 ratio of 1.75 approximately. This visible-light photocatalytic CO2-to-CO and H2O-to-H2O2 by the new g-C3N4/Cu2O–Pd S-scheme heterojunctions demonstrates the feasibility of the zero carbon emission approach with additional green oxidant (H2O2) generation.
Schematic representation of the stereolithographic additive manufacturing of preceramic polymers into intricately patterned thermosets assisted by thiol-ene click chemistry and their subsequent ...conversion into ceramics.
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•A stereolithographic approach based on thiol-ene click chemistry is developed to 3D print preceramic polymers into infusible thermosets.•Three classes of preceramic polymers, including siloxane, carbosilane and carbosilazane, are additively manufactured.•Upon pyrolysis, thermosets transform into glassy ceramics with uniform shrinkage and high density.•A fabricated SiOC honeycomb exhibits a significantly higher compressive strength to weight ratio in comparison to other porous ceramics.
Here we introduce a versatile stereolithographic route to produce three different kinds of Si-containing thermosets that yield high performance ceramics upon thermal treatment. Our approach is based on a fast and inexpensive thiol-ene free radical addition that can be applied for different classes of preceramic polymers with carbon-carbon double bonds. Due to the rapidity and efficiency of the thiol-ene click reactions, this additive manufacturing process can be effectively carried out using conventional light sources on benchtop printers. Through light initiated cross-linking, the liquid preceramic polymers transform into stable infusible thermosets that preserve their shape during the polymer-to-ceramic transformation. Through pyrolysis the thermosets transform into glassy ceramics with uniform shrinkage and high density. The obtained ceramic structures are nearly fully dense, have smooth surfaces, and are free from macroscopic voids and defects. A fabricated SiOC honeycomb was shown to exhibit a significantly higher compressive strength to weight ratio in comparison to other porous ceramics.
The iron nanoparticle technology has received considerable attention for its potential applications in groundwater treatment and site remediation. Recent studies have demonstrated the efficacy of ...zero-valent iron nanoparticles for the transformation of halogenated organic contaminants and heavy metals. In this work, we present a systematic characterization of the iron nanoparticles prepared with the method of ferric iron reduction by sodium borohydride. Particle size, size distribution and surface composition were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), high-resolution X-ray photoelectron spectroscopy (HR-XPS), X-ray absorption near edge structure (XANES) and acoustic/electroacoustic spectrometry. BET surface area, zeta (
ζ) potential, iso-electric point (IEP), solution Eh and pH were also measured. Methods and results presented may foster better understanding, facilitate information exchange, and contribute to further research and development of iron nanoparticles for environmental and other applications.
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