Variations in root architecture traits and their association with organ mass fraction of common annual ephemeral species in the desert of northern Xinjiang.

The variation of plant traits is closely related to the trade-offs between resource acquisition and conservation, as well as the accumulation of biomass. However, there has been a lack of comprehensive insights into the variation patterns, phylogenetic conservatism, and covariation with biomass allocation of root system architecture in desert areas. We examined the root systems of 47 annual ephemeral species and evaluated their biomass allocation and six key root system architecture traits. Our results indicated that the variation in root traits mainly originated from interspecific variation (48.78%-99.76%), but intraspecific variation should not be ignored as to why the contribution rate of root tissue density (RTD) reached 51.22%. The six root traits were mainly loaded on the first and second axes of the principal component analysis (PCA), these traits mainly vary along two dimensions. The highest interspecific variation is in RTD (51.63%) and the lowest in topological index (TI; 5.92%). The intraspecific variation value and range of specific root length (SRL), specific root area (SRA), and RTD were significantly higher than TI (p < .05), and they are not limited by phylogenetic relationships (0< K < 1, p > .05). The SRA is positively correlated with SRL (r = .72, p < .001) and negatively correlated with RTD (r = -.57, p < .05). The LMF is positively correlated with SRL, and SRA demonstrated the coordination between water consumption and acquisition. The positive correlation between RMF and MRD indicated the coordination of root carbon investment with exploring soil vertical space. The multi-dimensional variation of root traits, divergence of RTDs, and convergence of TI are important ecological strategies for annual short-lived plants to adapt to heterogeneous desert habitats. Meanwhile, these plants achieve optimal access to scarce resources through the high plasticity of resource acquisition (e.g., SRL and SRA) and conservation traits (e.g., RTD), as well as the trade-offs between them and organ mass fraction.

Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders.

DNA sensing is a pivotal component of the innate immune system that is responsible for detecting mislocalized DNA and triggering downstream inflammatory pathways. Among the DNA sensors, cyclic GMP-AMP synthase (cGAS) is a primary player in detecting cytosolic DNA, including foreign DNA from pathogens and self-DNA released during cellular damage, culminating in a type I interferon (IFN-I) response through stimulator of interferon genes (STING) activation. IFN-I cytokines are essential in mediating neuroinflammation, which is widely observed in CNS injury, neurodegeneration, and aging, suggesting an upstream role for the cGAS DNA sensing pathway. In this review, we summarize the latest developments on the cGAS-STING DNA-driven immune response in various neurological diseases and conditions. Our review covers the current understanding of the molecular mechanisms of cGAS activation and highlights cGAS-STING signaling in various cell types of central and peripheral nervous systems, such as resident brain immune cells, neurons, and glial cells. We then discuss the role of cGAS-STING signaling in different neurodegenerative conditions, including tauopathies, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as aging and senescence. Finally, we lay out the current advancements in research and development of cGAS inhibitors and assess the prospects of targeting cGAS and STING as therapeutic strategies for a wide spectrum of neurological diseases.

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity.

Pathogenic tau accumulation fuels neurodegeneration in Alzheimer's disease (AD). Enhancing aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses. Previous studies have showed that mice lacking DAP12 in tauopathy mice exhibit higher tau pathology but are protected from tau-induced cognitive deficits. However, the exact mechanism remains elusive. Our current study uncovers a novel resilience mechanism via microglial interaction with oligodendrocytes. Despite higher tau inclusions, Dap12 deletion curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Specifically, removal of Dap12 abolished tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli), which are spatially correlated with tau pathology in AD brains. Our study highlights the critical role of interactions between microglia and oligodendrocytes in tau toxicity and DAP12 signaling as a promising target for enhancing resilience in AD.

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity.

Pathogenic tau accumulation fuels neurodegeneration in Alzheimer's disease (AD). Enhancing aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses. Previous studies have showed that mice lacking DAP12 in tauopathy mice exhibit higher tau pathology but are protected from tau-induced cognitive deficits. However, the exact mechanism remains elusive. Our current study uncovers a novel resilience mechanism via microglial interaction with oligodendrocytes. Despite higher tau inclusions, Dap12 deletion curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Specifically, removal of Dap12 abolished tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli), which are spatially correlated with tau pathology in AD brains. Our study highlights the critical role of interactions between microglia and oligodendrocytes in tau toxicity and DAP12 signaling as a promising target for enhancing resilience in AD.

Straw mulch improves soil carbon and nitrogen cycle by mediating microbial community structure and function in the maize field.

This study was conducted to investigate the capability of the microbial community characteristics and soil variables to promote carbon and nitrogen cycles in maize fields under straw mulch. We covered the surface soil of the maize field with different amounts of wheat straw (0 kg/ha, 2,250 kg/ha, and 4,500 kg/ha) and used 16S rRNA and ITS sequencing, Biology ECO-plate, traditional enzymology, TOC analyzer, and HPLC to measure bacterial and fungal community composition and functions, characteristics of microbial carbon source metabolism, carbon and nitrogen fraction, enzyme activity, and organic acid content in the maize rhizosphere and non-rhizosphere. The results indicated that short-term straw mulch insignificantly affected the alpha diversity of bacterial and fungal communities whereas significantly influenced their beta diversity. The results of functional prediction revealed that straw mulch considerably boosted the relative abundances of bacteria belonging to chemoheterotrophy, aerobic chemoheterotrophy, ureolysis, and nitrogen fixation and inhibited fermentation and nitrate reduction in maize rhizosphere soil. These processes primarily drove the C and N cycles in soil. Straw mulch also improved fungal saprotrophs by raising the proportion of Chaetomiaceae and Chaetosphaeriaceae. The Biology ECO-plate results illustrated that straw mulch weakened the metabolism capacity of microbial labile carbon resources. As a result, the labile C and N fractions were raised under straw mulch. Our results also showed that straw mulch primarily regulated the microbial community structure in rhizosphere soil by significantly decreasing Firmicutes and Ascomycota relative abundance while increasing Basidiomycota. The fungal community structure is more than bacterial for affecting soil microbial biomass carbon, readily oxidizable organic carbon, dissolved organic carbon, available nitrogen, ammonium, and nitrate directly and indirectly through malic acid content and cellulase, protease, and amylase activity. Overall, our findings imply that straw mulch might influence the bacterial and fungal community structures, thereby boosting the production of labile C and N components and accelerating the C and N cycle in maize fields.

De-wetting of evaporating drops on regular patterns of triangular posts.

Directional wicking and spreading of liquids can be achieved by regular micro-patterns of specifically designed topographic features that break the reflection symmetry of the underlying pattern. The present study aims to understand the formation and stability of wetting films during the evaporation of volatile liquid drops on surfaces with a micro-pattern of triangular posts arranged in a rectangular lattice. Depending on the density and aspect ratio of the posts, we observe either spherical-cap shaped drops with a mobile three-phase contact line or the formation of circular or angular drops with a pinned three-phase contact line. Drops of the latter class eventually evolve into a liquid film extending to the initial footprint of the drop and a shrinking cap-shaped drop sitting on the film. The drop evolution is controlled by the density and aspect ratio of the posts, while no influence of the orientation of the triangular posts on the contact line mobility becomes evident. Our experiments corroborate previous results of systematic numerical energy minimization, predicting that conditions for a spontaneous retraction of a wicking liquid film depend weakly on the orientation of the film edge relative to the micro-pattern.

Machine learning approaches based on fibroblast morphometry do not predict ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease with limited therapeutic options. Biomarkers are needed for early disease detection, clinical trial design, and personalized medicine. Early evidence suggests that specific morphometric features in ALS primary skin fibroblasts may be used as biomarkers; however, this hypothesis has not been rigorously tested in conclusively large fibroblast populations. Here, we imaged ALS-relevant organelles (mitochondria, endoplasmic reticulum, lysosomes) and proteins (TAR DNA-binding protein 43, Ras GTPase-activating protein-binding protein 1, heat-shock protein 60) at baseline and under stress perturbations and tested their predictive power on a total set of 443 human fibroblast lines from ALS and healthy individuals. Machine learning approaches were able to confidently predict stress perturbation states (ROC-AUC ∼0.99) but not disease groups or clinical features (ROC-AUC 0.58-0.64). Our findings indicate that multivariate models using patient-derived fibroblast morphometry can accurately predict different stressors but are insufficient to develop viable ALS biomarkers.

Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience.

Pathological hallmarks of Alzheimer's disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS-IFN-MEF2C axis to improve resilience against AD-related pathological insults.

SsCox17, a copper chaperone, is required for pathogenic process and oxidative stress tolerance of Sclerotinia sclerotiorum.

Stem rot, caused by Sclerotinia sclerotiorum has emerged as one of the major fungal pathogens of oilseed Brassica across the world. The pathogenic development is exquisitely dependent on reactive oxygen species (ROS) modulation. Cox17 is a crucial factor that shuttles copper ions from the cytosol to the mitochondria for the cytochrome c oxidase (CCO) assembly. Currently, no data is available regarding the impact of Cox17 in fungal pathogenesis. The present research was carried out to functionally characterize the role of Cox17 in S. sclerotiorum pathogenesis. SsCox17 transcripts showed high expression levels during inoculation on rapeseed. Intramitochondrial copper content and CCO activity were decreased in SsCox17 gene-silenced strains. The SsCox17 gene expression was up-regulated in the hyphae under oxidative stress and a deficiency response to oxidative stress was detected in SsCox17 gene-silenced strains. Compared to the S. sclerotiorum wild-type strain, there was a concomitant reduction in the virulence of SsCox17 gene-silenced strains. The SsCox17 overexpression strain was further found to increase copper content, CCO activity, tolerance to oxidative stress and virulence. We also observed a certain correlation of appressoria formation and SsCox17. These results provide evidence that SsCox17 is positively associated with fungal virulence and oxidative detoxification.

Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy.

Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer's disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy.

Selection and identification of a DNA aptamer for ultrasensitive and selective detection of λ-cyhalothrin residue in food.

Pyrethroid pesticides residues will not only pollute the environment, but also cause high toxicity to the human body. It is significant to establish an efficient and accurate method for pyrethroid detection in food. Considering that the common biomolecules like antibody is complicated and easy to inactivate, it is urgent to find a new type of biomolecule to specifically recognize pyrethroid pesticides. This study proposed the Capture-SELEX strategy to firstly select λ-cyhalothrin aptamer by immobilizing random ssDNA library. High-throughput sequencing was performed on the enriched ssDNA library through multiple Capture-SELEX rounds. Comprehensively inspecting structural similarity and homology, six sequences were chosen from five families for further analysis. The results showed that the aptamer (named LCT-1) could specifically recognize λ-cyhalothrin with the strongest affinity (Kd = 50.64 ± 4.33 nmol L-1). Molecular docking results revealed that the binding sites between λ-cyhalothrin and LCT-1 aptamer are mainly related to the bases A-5, C-6, C-28, A-29, C-30, G-31 and G-32. The LCT-1 aptamer was truncated to a shorter sequence (named as LCT-1-39) by removing other irrelevant bases, and its Kd value was determined as (10.27 ± 1.33) nmol·L-1 by Microscale Thermophoresis (MST). Both LCT-1 and LCT-1-39 aptamers were employed as recognition molecules to establish the colorimetric aptasensors for λ-cyhalothrin detection, which displayed good repeatability and reproducibility. The detection limit of the aptasensors were individually calculated as 0.0197 µg ml-1 and 0.0186 µg ml-1, and their recovery rate of λ-cyhalothrin in pear and cucumber samples was in the range of 82.93-95.50%. This article provides a promising application for the detection of λ-cyhalothrin.

Severe bacterial infection in young infants with pyrexia admitted to the emergency department.

ABSTRACT: The objectives of this study were to understand the clinical presentations of febrile young infants with severe bacterial infection (SBI), and to investigate the pathogen variations throughout the vaccine era and after antenatal group B Streptococcus (GBS) screening.All infants < 90 days old with a body temperature of ≥38.0°C and admitted to the emergency department were retrospectively enrolled in our study. SBI was defined as a positive culture of urine, blood, or cerebrospinal fluid. All clinical variables were analyzed and compared between the SBI group and the non-SBI group, to identify the relevant risk factors for SBI in infants with pyrexia.A total of 498 infants were studied, 279 of whom (56%) had SBI. The body temperature at triage was higher in the SBI group, and the difference was highly obvious in the neonatal group. White blood cell count and C-reactive protein levels were both significantly higher in the SBI group (P < .05), whereas neutrophil percentage and band percentage demonstrated no significant differences. Escherichia coli was the most common pathogen and plasmid-mediated extended-spectrum lactamases were detected in up to 9.1%. GBS was detected in 16 cases of bacteremia (6 cases with concurrent meningitis).The body temperature at triage may provide a clue for differentiating sick babies, especially in the neonatal group. Complete serum analysis is required for infection survey, especially white blood cell and C-reactive protein. Escherichia coli is the most common pathogen, and clinician should raise awareness of drug resistance in some patients. The prevalence of GBS infection in the young infant group remains high after routine antenatal GBS screening.

Facile Colorimetric Nanozyme Sheet for the Rapid Detection of Glyphosate in Agricultural Products Based on Inhibiting Peroxidase-Like Catalytic Activity of Porous Co3O4 Nanoplates.

The rapid and onsite detection of glyphosate herbicides in agricultural products is still a challenge. Herein, a novel colorimetric nanozyme sheet for the rapid detection of glyphosate has been successfully prepared through the physical adsorption of porous Co3O4 nanoplates on a polyester fiber membrane. Glyphosate can specifically inhibit the peroxidase-mimicking catalytic activity of porous Co3O4 nanoplates, thereby the visual detection of glyphosate can be realized by distinguishing the change in the color intensity of the established nanozyme sheet. The prepared nanozyme sheet has good sensitivity and selectivity, with a detection limit of 0.175 mg·kg-1 for glyphosate detection just by the naked eyes. It can effectively detect glyphosate within 10 min, and the color spots can maintain more than 20 min. The nanozyme sheet is not easily affected by the external environment in detection and storage. The merits of the nanozyme sheet facilitate its practical application in the large-scale preliminary screening of glyphosate residues in agricultural products.

Effect of controlled-release urea fertilizers for oilseed rape (Brassica napus L.) on soil carbon storage and CO2 emission.

Fertilizer-induced CO2 emission is a primary driver of global warming. The experiment was used to study whether controlled-release urea (CRU) application in winter oilseed rape can play a positive role in mitigating CO2 emission and promoting C utilization by soil microorganisms. Five fertilizer types consisted of N0 (0 g N plant-1), conventional CRU application (CRU100%), monotypic CRU at the 80% of conventional rate (CRU80%), co-application of CRU with uncoated urea (CRC), and organic fertilizer (CRO). Results showed that soil CO2 fluxes were significantly affected by N fertilizer types after the start of the stem growing (P < 0.05). CO2 emissions typically peaked during the seed filling period, with the highest emission of 1.99 µmol m-2 s-1 being registered for CRU100%. CRU100% had 25.00%, 30.60%, and 4.17% greater CO2 emissions than CRU80%, CRC, and CRO practices by harvest, respectively. Compared to the conventional CRU treatment, CRU80% led to a lower root volume and root mass ratio than CRU100%, which could partly contribute to the reduced CO2 emission. Conversely, CRU80% performed better in N agronomic efficiency than that of CRU100% treatment. Also, C source utilization by soil microbiomes as well as microbial diversity indices following CRU80% along with CRO applications was substantially higher than that under the conventional CRU supply. These observations suggest that opportunity exists to maintain N balance by N fertilization practices to mitigate CO2 emission from cropland. Further, a close and positive relationship between soil total nitrogen and CO2 emission also supports this. CRO-treated soils substantially elevated the contents of total carbon and readily oxidation carbon over CK. Moreover, the enzyme activity of ß-glucosidase in CRO soil was about twice as high as the CRU100%. Consequently, CRU amendments by decreasing CRU rate application and the incorporation of organic fertilizer into CRU have the potential for mitigating of CO2 emission and positive effect on the soil microbial functional diversity to improve nitrogen use efficiency of rapeseed.

A facile colorimetric sensor for ultrasensitive and selective detection of Lead(II) in environmental and biological samples based on intrinsic peroxidase-mimic activity of WS2 nanosheets.

Two-dimentional layered WS2 nanosheets with rich active edge exhibit intrinsic peroxidase-mimic activity, which make them an ideal material for sensor design. However, there is still lack of research on the catalysis and regulation mechanisms of the layered WS2 nanosheets as well as their application in the detection of hazardous substances. Herein, the regulatory effect of Pb(II) on the peroxidase-mimic activity of the layered WS2 nanosheets was firstly investigated, which enable us to construct a novel and facile colorimetric sensor for ultrasensitive and selective detection of Pb(II). To improve the performance of colorimetric sensor, some important parameters like buffer conditions, substrates and temperature have been investigated. Under the optimal conditions, the catalytic kinetics of layered WS2 nanosheets were extensively investigated. The peroxidase-mimic catalytic reaction was proved to be the "ping pong" mechanism, and the regulatory effect of Pb(II) on layered WS2 nanosheets was agreed with noncompetitive inhibition. The absorbance variation of colorimetric sensor is proportionally related to the concentration of heavy metals, which enable us to easily distinguish whether Pb(II) exceeds the permissible level in less than 20 min even by the naked eyes. The limit of detection (LOD) and the limit of quantification (LOQ) of the proposed colorimetric sensor for Pb(II) were determined as low as 4 µg L-1 and 13.3 µg L-1, and displays excellent selectivity against other competitive metal ions. Moreover, the further studies also validate the applicability of colorimetric sensor in several actual samples, indicating that our strategy may has prospective applications for Pb(II) detection in environment and biological samples.

Effects of Biochar Combined with Nitrogen Fertilizer Reduction on Rapeseed Yield and Soil Aggregate Stability in Upland of Purple Soils.

Reduction of soil fertility and production efficiency resulting from excessive application of chemical fertilizers is universal in rapeseed-growing fields. The main objective of our study was to assess the effects of biochar combined with nitrogen fertilizer reduction on soil aggregate stability and rapeseed yield and to identify the relationship between yield and soil aggregate stability. A two-factor field experiment (2017-2019) was conducted with biochar (0 (C0), 10 (C10), 20 (C20) and 40 t·ha-1 (C40)) and nitrogen fertilizer (180 (N100), 144 (N80) and 108 kg N·ha-1 (N60)). Experimental results indicated that under N100 and N80 treatments, C10 significantly increased the macro-aggregates (R0.25), mean weight diameter (MWD) and geometric mean diameter (GMD) of soil water stable aggregate by 14.28%-15.85%, 14.88%-17.08% and 36.26%-42.22%, respectively, compared with C0. Besides, the overall difference of the soil water-stable aggregate content in 2-5 mm size range among nitrogen treatments was significant under the application of C10, which increased by 17.04%-33.04% compared with C0. Total organic carbon (TOC) in R0.25 of soil mechanical-stable aggregates was basically all increased after biochar application, especially in 0.25-1 mm and 1-2 mm aggregates, and had an increasing trend with biochar increase. C10 significantly increased rapeseed yield by 22.08%-45.65% in 2019, compared with C0. However, the reduction of nitrogen fertilizer reduced the two-year average rapeseed yield, which decreased by 11.67%-31.67% compared with N100. The highest yield of rapeseed was obtained by N100C10 in two consecutive years, which had no statistical difference with N80C10. However, the two-year yields of N80C10 were all higher than those of N100C0 with increase rate of 16.11%, and which would reduce 35.43% nitrogen fertilizer in the case of small yield difference, compared with the highest yield (2.67 t·ha-1) calculated by multi-dimensional nonlinear regression models. The regression analysis indicated R0.25, MWD and GMD had the strong positive associations with rapeseed yield, whereas percentage of aggregate destruction (PAD0.25) had a significant negative correlation with rapeseed yield. This study suggests that the application of biochar into upland purple soil could improve soil structure, increase the content of TOC in macro-aggregates under nitrogen fertilizer reduction as well as replace part of nitrogen fertilizer to achieve relatively high rapeseed yield.

Shape Evolution of Droplets Growing on Linear Microgrooves.

Anisotropic spreading of liquids and elongated droplet shapes are often encountered on surfaces decorated with a periodic micropattern of linear surface topographies. Numerical calculations and wetting experiments show that the shape evolution of droplets that are slowly growing on a surface with parallel grooves can be grouped into two distinct morphological regimes. In the first regime, the liquid of the growing droplet spreads only into the direction parallel to the grooves. In the second regime, the three-phase contact line advances also perpendicular to the grooves, whereas the growing droplets approach a scale-invariant shape. Here, we demonstrate that shapes of droplets in contact with a large number of linear grooves are identical to the shapes of droplets confined to a plane chemical stripe, where this mapping of shapes is solely based on the knowledge of the cross section of the linear grooves and the material contact angle. The spectrum of interfacial shapes on the chemical stripe can be exploited to predict the particular growth mode and the asymptotic value of the base eccentricity in the limit of droplets covering a large number of grooves. The proposed model shows an excellent agreement with experimentally observed base eccentricities for droplets on grooves of various cross sections. The universality of the model is underlined by the accurate match with available literature data for droplet eccentricities on parallel chemical stripes.

Lysine Deacetylation by HDAC6 Regulates the Kinase Activity of AKT in Human Neural Progenitor Cells.

The AKT family of serine-threonine kinases functions downstream of phosphatidylinositol 3-kinase (PI3K) to transmit signals by direct phosphorylation of a number of targets, including the mammalian target of rapamycin (mTOR), glycogen synthase kinase 3ß (GSK3ß), and ß-catenin. AKT binds to phosphatidylinositol (3,4,5)-triphosphate (PIP3) generated by PI3K activation, which results in its membrane localization and subsequent activation through phosphorylation by phosphoinositide-dependent protein kinase 1 (PDK1). Together, the PI3K-AKT signaling pathway plays pivotal roles in many cellular systems, including in the central nervous system where it governs both neurodevelopment and neuroplasticity. Recently, lysine residues (Lys14 and Lys20) on AKT, located within its pleckstrin homology (PH) domain that binds to membrane-bound PIP3, have been found to be acetylated under certain cellular contexts in various cancer cell lines. These acetylation modifications are removed by the enzymatic action of the class III lysine deacetylases, SIRT1 and SIRT2, of the sirtuin family. The extent to which reversible acetylation regulates AKT function in other cell types remains poorly understood. We report here that AKT kinase activity is modulated by a class IIb lysine deacetylase, histone deacetylase 6 (HDAC6), in human neural progenitor cells (NPCs). We find that HDAC6 and AKT physically interact with each other in the neuronal cells, and in the presence of selective HDAC6 inhibition, AKT is acetylated at Lys163 and Lys377 located in the kinase domain, two novel sites distinct from the acetylation sites in the PH-domain modulated by the sirtuins. Measurement of the functional effect of HDAC6 inhibition on AKT revealed decreased binding to PIP3, a correlated decrease in AKT kinase activity, decreased phosphorylation of Ser552 on ß-catenin, and modulation of neuronal differentiation trajectories. Taken together, our studies implicate the deacetylase activity of HDAC6 as a novel regulator of AKT signaling and point to novel mechanisms for regulating AKT activity with small-molecule inhibitors of HDAC6 currently under clinical development.

Stem cell-derived neurons in the development of targeted treatment for schizophrenia and bipolar disorder.

The recent advent of induced pluripotent stem cells has enabled the study of patient-specific and disease-related neurons in vitro and has facilitated new directions of inquiry into disease mechanisms. With these approaches, we now have the possibility of correlating ex vivo cellular phenotypes with individual patient response to treatment and/or side effects, which makes targeted treatments for schizophrenia and bipolar disorder a distinct prospect in the coming years. Here, we briefly review the current state of stem cell-based models and explore studies that are providing new insights into the disease biology of schizophrenia and bipolar disorder, which are laying the foundations for the development of novel targeted therapies.