Phosphorylation of ADF7-Mediated by AGC1.7 Regulates Pollen Germination in Arabidopsis thaliana.

Actin depolymerizing factors (ADFs), like other actin-binding proteins (ABPs), are modified by phosphorylation to regulate the dynamics of the actin filaments, thereby functioning in various processes throughout the plant lifecycle. In this study, we found that the Arabidopsis thaliana cytoplasmic kinase AGC1.7 interacts with ADF7 in vitro and in vivo. AGC1.7 phosphorylates ADF7 at its Ser-6, Ser-103 and Ser-104 residues in vitro, while replacing these residues with alanine promotes ADF7-mediated actin depolymerization in vitro. Expression of the phosphorylation-mimetic mutant protein ADF7S6/103/104D driven by the pollen-specific LAT52 promoter fully rescues the defects in germination rate, silique length and seeds per silique in both adf7-2 and agc1.5 agc1.7 (agcdm) mutants. Our data establish a model whereby AGC1.7-mediated ADF7 phosphorylation plays an important role in pollen germination and pollen tube growth.

Landsat-based spatiotemporal estimation of subtropical forest aboveground carbon storage using machine learning algorithms with hyperparameter tuning.

Introduction: The aboveground carbon storage (AGC) in forests serves as a crucial metric for evaluating both the composition of the forest ecosystem and the quality of the forest. It also plays a significant role in assessing the quality of regional ecosystems. However, current technical limitations introduce a degree of uncertainty in estimating forest AGC at a regional scale. Despite these challenges, remote sensing technology provides an accurate means of monitoring forest AGC. Furthermore, the implementation of machine learning algorithms can enhance the precision of AGC estimates. Lishui City, with its rich forest resources and an approximate forest coverage rate of 80%, serves as a representative example of the typical subtropical forest distribution in Zhejiang Province. Methods: Therefore, this study uses Landsat remote sensing images, employing backpropagation neural network (BPNN), random forest (RF), and categorical boosting (CatBoost) to model the forest AGC of Lishui City, selecting the best model to estimate and analyze its forest AGC spatiotemporal dynamics over the past 30 years (1989-2019). Results: The study shows that: (1) The texture information calculated based on 9×9 and 11×11 windows is an important variable in constructing the remote sensing estimation model of the forest AGC in Lishui City; (2) All three machine learning techniques are capable of estimating forest AGC in Lishui City with high precision. Notably, the CatBoost algorithm outperforms the others in terms of accuracy, achieving a model training accuracy and testing accuracy R2 of 0.95 and 0.83, and RMSE of 2.98 Mg C ha-1 and 4.93 Mg C ha-1, respectively. (3) Spatially, the central and southwestern regions of Lishui City exhibit high levels of forest AGC, whereas the eastern and northeastern regions display comparatively lower levels. Over time, there has been a consistent increase in the total forest AGC in Lishui City over the past three decades, escalating from 1.36×107 Mg C in 1989 to 6.16×107 Mg C in 2019. Discussion: This study provided a set of effective hyperparameters and model of machine learning suitable for subtropical forests and a reference data for improving carbon sequestration capacity of subtropical forests in Lishui City.

SPARK regulates AGC kinases central to the Toxoplasma gondii asexual cycle.

Apicomplexan parasites balance proliferation, persistence, and spread in their metazoan hosts. AGC kinases, such as PKG, PKA, and the PDK1 ortholog SPARK, integrate environmental signals to toggle parasites between replicative and motile life stages. Recent studies have cataloged pathways downstream of apicomplexan PKG and PKA; however, less is known about the global integration of AGC kinase signaling cascades. Here, conditional genetics coupled to unbiased proteomics demonstrates that SPARK complexes with an elongin-like protein to regulate the stability of PKA and PKG in the model apicomplexan Toxoplasma gondii. Defects attributed to SPARK depletion develop after PKG and PKA are down-regulated. Parasites lacking SPARK differentiate into the chronic form of infection, which may arise from reduced activity of a coccidian-specific PKA ortholog. This work delineates the signaling topology of AGC kinases that together control transitions within the asexual cycle of this important family of parasites.

Molecular insights into the regulatory landscape of PKC-related kinase-2 (PRK2/PKN2) using targeted small compounds.

The PKC-related kinases (PRKs, also termed PKNs) are important in cell migration, cancer, hepatitis C infection, and nutrient sensing. They belong to a group of protein kinases called AGC kinases that share common features like a C-terminal extension to the catalytic domain comprising a hydrophobic motif. PRKs are regulated by N-terminal domains, a pseudosubstrate sequence, Rho-binding domains, and a C2 domain involved in inhibition and dimerization, while Rho and lipids are activators. We investigated the allosteric regulation of PRK2 and its interaction with its upstream kinase PDK1 using a chemical biology approach. We confirmed the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF)-mediated docking interaction of PRK2 with PDK1 and showed that this interaction can be modulated allosterically. We showed that the polypeptide PIFtide and a small compound binding to the PIF-pocket of PRK2 were allosteric activators, by displacing the pseudosubstrate PKL region from the active site. In addition, a small compound binding to the PIF-pocket allosterically inhibited the catalytic activity of PRK2. Together, we confirmed the docking interaction and allostery between PRK2 and PDK1 and described an allosteric communication between the PIF-pocket and the active site of PRK2, both modulating the conformation of the ATP-binding site and the pseudosubstrate PKL-binding site. Our study highlights the allosteric modulation of the activity and the conformation of PRK2 in addition to the existence of at least two different complexes between PRK2 and its upstream kinase PDK1. Finally, the study highlights the potential for developing allosteric drugs to modulate PRK2 kinase conformations and catalytic activity.

Improving load frequency controller tuning with rat swarm optimization and porpoising feature detection for enhanced power system stability.

Load frequency control (LFC) plays a critical role in ensuring the reliable and stable operation of power plants and maintaining a quality power supply to consumers. In control engineering, an oscillatory behavior exhibited by a system in response to control actions is referred to as "Porpoising". This article focused on investigating the causes of the porpoising phenomenon in the context of LFC. This paper introduces a novel methodology for enhancing the performance of load frequency controllers in power systems by employing rat swarm optimization (RSO) for tuning and detecting the porpoising feature to ensure stability. The study focuses on a single-area thermal power generating station (TPGS) subjected to a 1% load demand change, employing MATLAB simulations for analysis. The proposed RSO-based PID controller is compared against traditional methods such as the firefly algorithm (FFA) and Ziegler-Nichols (ZN) technique. Results indicate that the RSO-based PID controller exhibits superior performance, achieving zero frequency error, reduced negative peak overshoot, and faster settling time compared to other methods. Furthermore, the paper investigates the porpoising phenomenon in PID controllers, analyzing the location of poles in the s-plane, damping ratio, and control actions. The RSO-based PID controller demonstrates enhanced stability and resistance to porpoising, making it a promising solution for power system control. Future research will focus on real-time implementation and broader applications across different control systems.

The mitochondrial aspartate/glutamate carrier does not transport GABA.

É£-aminobutyric acid (GABA) is a four­carbon amino acid acting as the main inhibitory transmitter in the invertebrate and vertebrate nervous systems. The metabolism of GABA is well compartmentalized in the cell and the uptake of cytosolic GABA into the mitochondrial matrix is required for its degradation. A previous study carried out in the fruit fly Drosophila melanogaster indicated that the mitochondrial aspartate/glutamate carrier (AGC) is responsible for mitochondrial GABA accumulation. Here, we investigated the transport of GABA catalysed by the human and D. melanogaster AGC proteins through a well-established method for the study of the substrate specificity and the kinetic parameters of the mitochondrial carriers. In this experimental system, the D. melanogaster spliced AGC isoforms (Aralar1-PA and Aralar1-PE) and the human AGC isoforms (AGC1/aralar1 and AGC2/citrin) are unable to transport GABA both in homo- and in hetero-exchange with either glutamate or aspartate, i.e. the canonical substrates of AGC. Moreover, GABA has no inhibitory effect on the exchange activities catalysed by the investigated AGCs. Our data demonstrate that AGC does not transport GABA and the molecular identity of the GABA transporter in human and D. melanogaster mitochondria remains unknown.

Immune checkpoint inhibitors combined with paclitaxel-based chemotherapy versus chemotherapy alone as first-line treatment in HER2-negative advanced gastric cancer: result of a multicenter retrospective study.

Background: Platinum-based chemotherapy combined with immune checkpoint inhibitors (ICIs) is now becoming the standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (AGC). In China, paclitaxel has shown good efficacy and tolerability in AGC as an alternative for first-line therapy. Combining ICIs with paclitaxel-based chemotherapy may lead to improved tumor immune microenvironment, but evidence in paclitaxel combing with ICIs as first-line regimen is lacking. This multicenter, retrospective research aims to compare effectiveness and tolerability of paclitaxel-based chemotherapy combined with ICIs versus chemotherapy alone as a first-line treatment of HER2-negative AGC in a real-world setting. Methods: Eighty-six patients with HER2-negative AGC were included from 2017 to 2022. Among them, 57 patients received paclitaxel-based chemotherapy plus ICIs, and 29 patients received paclitaxel-based chemotherapy alone. We compared the efficacy and incidence of adverse events between the two therapy options. Results: Significant improvements in median progression-free survival (PFS) (8.77 versus 7.47 months; P=0.04) and median overall survival (OS) (15.70 versus 14.33 months; P=0.04) were observed in the ICIs combined with paclitaxel-based chemotherapy group. The use of ICIs also significantly prolonged the duration of response (DOR) (7.47 versus 4.59 months; P=0.02). Meanwhile, the ICIs plus chemotherapy group demonstrated significantly improved objective response rate (ORR) (50.9% vs. 27.6%; P=0.03) and disease control rate (DCR) (98.3% vs. 82.8%; P=0.01), and the side effects were tolerable. Conclusions: In summary, for HER2-negative AGC, ICIs plus paclitaxel-based chemotherapy is effective with mild toxicities, which should be considered as an alternative first-line therapy regimen.

Fuzzy analytic hierarchy process based generation management for interconnected power system.

Decision makers consistently face the challenge of simultaneously assessing numerous attributes, determining their respective importance, and selecting an appropriate method for calculating their weights. This article addresses the problem of automatic generation control (AGC) in a two area power system (2-APS) by proposing fuzzy analytic hierarchy process (FAHP), an multi-attribute decision-making (MADM) technique, to determine weights for sub-objective functions. The integral-time-absolute-errors (ITAE) of tie-line power fluctuation, frequency deviations and area control errors, are defined as the sub-objectives. Each of these is given a weight by the FAHP method, which then combines them into an single final objective function. This objective function is then used to design a PID controller. To improve the optimization of the objective function, the Jaya optimization algorithm (JOA) is used in conjunction with other optimization techniques such as sine cosine algorithm (SCA), Luus-Jaakola algorithm (LJA), Nelder-Mead simplex algorithm (NMSA), symbiotic organism search algorithm (SOSA) and elephant herding optimization algorithm (EHOA). Six distinct experimental cases are conducted to evaluate the controller's performance under various load conditions, with data plotted to show responses corresponding to fluctuations in frequency and tie-line exchange. Furthermore, statistical analysis is performed to gain a better understanding of the effectiveness of the JOA-based PID controller. For non-parametric evaluation, Friedman rank test is also used to validate the performance of the proposed JOA-based controller.

Investigation of rank order centroid method for optimal generation control.

Multi-criteria decision-making (MCDM) presents a significant challenge in decision-making processes, aiming to ascertain optimal choice by considering multiple criteria. This paper proposes rank order centroid (ROC) method, MCDM technique, to determine weights for sub-objective functions, specifically, addressing issue of automatic generation control (AGC) within two area interconnected power system (TAIPS). The sub-objective functions include integral time absolute errors (ITAE) for frequency deviations and control errors in both areas, along with ITAE of fluctuation in tie-line power. These are integrated into an overall objective function, with ROC method systematically assigning weights to each sub-objective. Subsequently, a PID controller is designed based on this objective function. To further optimize objective function, Jaya optimization algorithm (JOA) is implemented, alongside other optimization algorithms such as teacher-learner based optimization algorithm (TLBOA), Luus-Jaakola algorithm (LJA), Nelder-Mead simplex algorithm (NMSA), elephant herding optimization algorithm (EHOA), and differential evolution algorithm (DEA). Six distinct case analyses are conducted to evaluate controller's performance under various load conditions, plotting data to illustrate responses to frequency and tie-line exchange fluctuations. Additionally, statistical analysis is performed to provide further insights into efficacy of JOA-based PID controller. Furthermore, to prove the efficacy of JOA-based proposed controller through non-parametric test, Friedman rank test is utilized.

AGC1-mediated Metabolic Reprogramming and Autophagy Sustain Survival of Hepatocellular Carcinoma Cells under Glutamine Deprivation.

The dependence of hepatocellular carcinoma (HCC) cells on glutamine suggests the feasibility of targeting glutamine metabolism for therapy. However, drugs inhibiting glutamine uptake and breakdown have not shown promising outcomes. Therefore, investigating the mechanism of glutamine metabolism reprogramming in HCC cells is crucial. We used bioinformatics approaches to investigate the metabolic flux of glutamine in HCC cells and validated it using qRT-PCR and western blotting. HCC cells were cultured in glutamine-deprived medium, and changes in glutamate and ATP levels were monitored. Western blotting was employed to assess the expression of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and autophagy-related proteins. The impact of Solute carrier family 25 member 12 (AGC1) on HCC cell proliferation was studied using CCK-8 and colony formation assays. Furthermore, the effects of AGC1 knockdown via siRNA on metabolic reprogramming and energy supply during glutamine deprivation in HCC were explored. During glutamine deprivation, HCC cells sustain cytosolic asparagine synthesis and ATP production through AGC1. Low ATP levels activate AMPK and inhibit mTOR activation, inducing autophagy to rescue HCC cell survival. Knockdown of AGC1 inhibits mitochondrial aspartate output and continuously activates autophagy, rendering HCC cells more sensitive to glutamine deprivation. AGC1 serves as a critical node in the reprogramming of glutamine metabolism and energy supply in HCC cells. This study provides theoretical support for overcoming resistance to drugs targeting glutamine metabolism.

Transcriptional and metabolic effects of aspartate-glutamate carrier isoform 1 (AGC1) downregulation in mouse oligodendrocyte precursor cells (OPCs).

Aspartate-glutamate carrier isoform 1 (AGC1) is a carrier responsible for the export of mitochondrial aspartate in exchange for cytosolic glutamate and is part of the malate-aspartate shuttle, essential for the balance of reducing equivalents in the cells. In the brain, mutations in SLC25A12 gene, encoding for AGC1, cause an ultra-rare genetic disease, reported as a neurodevelopmental encephalopathy, whose symptoms include global hypomyelination, arrested psychomotor development, hypotonia and seizures. Among the biological components most affected by AGC1 deficiency are oligodendrocytes, glial cells responsible for myelination processes, and their precursors [oligodendrocyte progenitor cells (OPCs)]. The AGC1 silencing in an in vitro model of OPCs was documented to cause defects of proliferation and differentiation, mediated by alterations of histone acetylation/deacetylation. Disrupting AGC1 activity could possibly reduce the availability of acetyl groups, leading to perturbation of many biological pathways, such as histone modifications and fatty acids formation for myelin production. Here, we explore the transcriptome of mouse OPCs partially silenced for AGC1, reporting results of canonical analyses (differential expression) and pathway enrichment analyses, which highlight a disruption in fatty acids synthesis from both a regulatory and enzymatic stand. We further investigate the cellular effects of AGC1 deficiency through the identification of most affected transcriptional networks and altered alternative splicing. Transcriptional data were integrated with differential metabolite abundance analysis, showing downregulation of several amino acids, including glutamine and aspartate. Taken together, our results provide a molecular foundation for the effects of AGC1 deficiency in OPCs, highlighting the molecular mechanisms affected and providing a list of actionable targets to mitigate the effects of this pathology.

Partially knocking out NtPDK1a/1b/1c/1d simultaneously in Nicotiana tabacum using CRISPR/CAS9 technology results in auxin-related developmental defects.

The eukaryotic AGC protein kinase subfamily (protein kinase A/ protein kinase G/ protein kinase C-family) is involved in regulating numerous biological processes across kingdoms, including growth and development, and apoptosis. PDK1(3-phosphoinositide-dependent protein kinase 1) is a conserved serine/threonine kinase in eukaryotes, which is both a member of AGC kinase and a major regulator of many other downstream AGC protein kinase family members. Although extensively investigated in model plant Arabidopsis, detailed reports for tobacco PDK1s have been limited. To better understand the functions of PDK1s in tobacco, CRISPR/CAS9 transgenic lines were generated in tetraploid N. tabacum, cv. Samsun (NN) with 5-7 of the 8 copies of 4 homologous PDK1 genes in tobacco genome (NtPDK1a/1b/1c/1d homologs) simultaneously knocked out. Numerous developmental defects were observed in these NtPDK1a/1b/1c/1d CRISPR/CAS9 lines, including cotyledon fusion leaf shrinkage, uneven distribution of leaf veins, convex veins, root growth retardation, and reduced fertility, all of which reminiscence of impaired polar auxin transport. The severity of these defects was correlated with the number of knocked out alleles of NtPDK1a/1b/1c/1d. Consistent with the observation in Arabidopsis, it was found that the polar auxin transport, and not auxin biosynthesis, was significantly compromised in these knockout lines compared with the wild type tobacco plants. The fact that no homozygous plant with all 8 NtPDK1a/1b/1c/1d alleles being knocked out suggested that knocking out 8 alleles of NtPDK1a/1b/1c/1d could be lethal. In conclusion, our results indicated that NtPDK1s are versatile AGC kinases that participate in regulation of tobacco growth and development via modulating polar auxin transport. Our results also indicated that CRISPR/CAS9 technology is a powerful tool in resolving gene redundancy in polyploidy plants.

Atypical glandular cells in Pap tests: cytology-histology correlation and risk assessment with human papillopmavirus (HPV) testing.

INTRODUCTION: Atypical glandular cells (AGC) represent less than 1% of Pap test cases and include a variety of lesions in both the cervix and endometrium. The study aimed to investigate the cytology-histology correlation in AGC patients and to evaluate the clinical utility of hrHPV testing in this diagnostic context. MATERIALS AND METHODS: We identified 491 atypical glandular cells (AGC) cases in our quality analysis (QA) database of 336,064 Pap tests interpreted between March 1, 2013 and July 12, 2016. Of these, 251 cases had follow-up biopsies with hrHPV tests in 148 cases. RESULTS: The most common histologic diagnosis associated with AGC was normal/benign or low-grade lesions, comprising 55% of cervical biopsies and 24% of endometrial biopsies. High-grade lesions were identified in 21% of follow-up biopsies. In patients with AGC cytology, a positive hrHPV test significantly increased the likelihood of cervical HSIL or above lesions on biopsy by 26.4 times (OR = 26.4, 95% CI: 5.8-119.4, P < 0.0001). A positive genotyping result for HPV 16 dramatically increased the likelihood of cervical HSIL or above lesions on biopsy (OR = 84, 95% CI: 12.0-590.5, P < 0.0001). The HPV test had a negative predictive value of 97% (CI: 85%-100%). CONCLUSIONS: Our study confirms that AGC is a significant diagnosis with an overall risk for high-grade cervical or endometrial lesions as high as 21%. hrHPV testing with genotyping is an effective tool for identifying high-risk individuals within the AGC population, with excellent positive and negative predictive values. This approach is valuable for clinical risk stratification and differential diagnosis in patients with AGC cytology.

Core-Shell Nanocables Decorated with Carbon Spherical Shells and Silver Nanoparticles for Sensing Ethinylestradiol Hormone in Water Sources and Pills.

The selective, rapid detection of low levels of hormones in drinking water and foodstuffs requires materials suitable for inexpensive sensing platforms. We report on core-shell Ag@C nanocables (NCs) decorated with carbon spherical shells (CSSs) and silver nanoparticles (AgNPs) by using a hydrothermal green approach. Sensors were fabricated with homogeneous, porous films on screen-printed electrodes, which comprised a 115 nm silver core covered by a 122 nm thick carbon layer and CSSs with 168 nm in diameter. NCs and CSSs were also decorated with 10-25 nm AgNPs. The NC/CSS/AgNP sensor was used to detect ethinylestradiol using square wave voltammetry in 0.1 M phosphate buffer (pH 7.0) over the 1.0-10.0 µM linear range with a detection limit of 0.76 µM. The sensor was then applied to detect ethinylestradiol in tap water samples and a contraceptive pill with recovery percentages between 93 and 101%. The high performance in terms of sensitivity and selectivity for hormones is attributed to the synergy between the carbon nanomaterials and AgNPs, which not only increased the sensor surface area and provided sites for electron exchange but also imparted an increased surface area.

An essential Trypanosoma brucei protein kinase: a functional analysis of regulation and the identification of inhibitors.

Introduction: The protein serine/threonine kinase AEK1 is essential in the pathogenic stage of Trypanosoma brucei, the causative agent of African trypanosomiasis. AEK1 is a member of the AGC protein kinase family, although it is not closely related to a specific human AGC kinase. Our previous chemical genetic studies showed that targeted inhibition of AEK1 in parasites expressing analog-sensitive AEK1 blocked parasite growth and enhanced survival of infected mice. Methods: To further validate AEK1 as a drug target, we used the chemical genetic system to determine the effect of a 24 hour loss of AEK1 activity on cell viability at the clonal level. A panel of 429 protein kinase inhibitors were screened against the wild-type protein for binding, using time-resolved fluorescence energy transfer (TR-FRET). The role of phosphorylation sites and motifs was probed by determining whether expression of proteins harboring mutations in these sequences could rescue AEK1 conditional knockout parasites. To determine the effect that mutations in the phosphosites have on the kinase activity of cellular AEK1 we compared the in vitro kinase activity of mutant and wild-type proteins immunoprecipitated from parasite lysates using the exogenous substrate MBP. Finally, the tagged AEK1 protein was localized by deconvolution microscopy. Results: After a 24 hour exposure to an AEK1 inhibitory analog in the chemical genetic system, less than five percent of the remaining live cells can clonally expand, further validating AEK1 as a drug target. In the AEK1 inhibitor screening assay, we identified 17 hit compounds. Complementation studies showed that of the two known phosphorylation sites in the activation loop; mutation of one abolished function while mutation of the other had no discernable effect. Mutation of the other two AEK1 phosphosites gave intermediate phenotypes. Mutations in either the hydrophobic motif at the C-terminus of the protein or in the region of AEK1 predicted to bind the hydrophobic motif were also required for function. All parasites with defective AEK1 showed reduced proliferation and defects in cytokinesis, although the tested mutations differed in terms of the extent of cell death. Kinase activity of immunoprecipitated AEK1 phosphosite mutants largely paralleled the effects seen in complementation studies, although the mutation of the phosphosite adjacent to the hydrophobic motif had a greater impact on activity than predicted by the complementation studies. AEK1 was localized to cytoplasmic puncta distinct from glycosomes and acidocalcisomes. Discussion: The rapid loss of viability of cells inhibited for AEK1 supports the idea that a short course of treatment that target AEK1 may be sufficient for treatment of people or animals infected with T. brucei. Key regulatory elements between AEK1 and its closest mammalian homolog appear to be largely conserved despite the vast evolutionary distance between mammals and T. brucei. The presence of AEK1 in cytoplasmic puncta raises the possibility that its localization may also play a role in functional activity.

AGC kinase inhibitors regulate STING signaling through SGK-dependent and SGK-independent mechanisms.

Type 1 IFN expression is critical in the innate immune response, but aberrant expression is associated with autoimmunity and cancer. Here, we identify N-[4-(1H46 pyrazolo[3,4-b] pyrazin-6-yl)-phenyl]-sulfonamide (Sanofi-14h), a compound with preference for inhibition of the AGC family kinase SGK3, as an inhibitor of Ifnb1 gene expression in response to STING stimulation of macrophages. Sanofi-14h abrogated SGK activity and also impaired activation of the critical TBK1/IRF3 pathway downstream of STING activation, blocking interaction of STING with TBK1. Deletion of SGK1/3 in a macrophage cell line did not block TBK1/IRF3 activation but decreased expression of transcription factors, such as IRF7 and STAT1, required for the innate immune response. Other AGC kinase inhibitors blocked TBK1 and IRF3 activation suggesting common action on a critical regulatory node in the STING pathway. These studies reveal both SGK-dependent and SGK-independent mechanisms in the innate immune response and indicate an approach to block aberrant Ifnb1 expression.

Structure-preserving low-dose computed tomography image denoising using a deep residual adaptive global context attention network.

Background: Low-dose computed tomography (LDCT) scans can effectively reduce the radiation damage to patients, but this is highly detrimental to CT image quality. Deep convolutional neural networks (CNNs) have shown their potential in improving LDCT image quality. However, the conventional CNN-based approaches rely fundamentally on the convolution operations, which are ineffective for modeling the correlations among nonlocal similar structures and the regionally distinct statistical properties in CT images. This modeling deficiency hampers the denoising performance for CT images derived in this manner. Methods: In this paper, we propose an adaptive global context (AGC) modeling scheme to describe the nonlocal correlations and the regionally distinct statistics in CT images with negligible computation load. We further propose an AGC-based long-short residual encoder-decoder (AGC-LSRED) network for efficient LDCT image noise artifact-suppression tasks. Specifically, stacks of residual AGC attention blocks (RAGCBs) with long and short skip connections are constructed in the AGC-LSRED network, which allows valuable structural and positional information to be bypassed through these identity-based skip connections and thus eases the training of the deep denoising network. For training the AGC-LSRED network, we propose a compound loss that combines the L1 loss, adversarial loss, and self-supervised multi-scale perceptual loss. Results: Quantitative and qualitative experimental studies were performed to verify and validate the effectiveness of the proposed method. The simulation experiments demonstrated the proposed method exhibits the best result in terms of noise suppression [root-mean-square error (RMSE) =9.02; peak signal-to-noise ratio (PSNR) =33.17] and fine structure preservation [structural similarity index (SSIM) =0.925] compared with other competitive CNN-based methods. The experiments on real data illustrated that the proposed method has advantages over other methods in terms of radiologists' subjective assessment scores (averaged scores =4.34). Conclusions: With the use of the AGC modeling scheme to characterize the structural information in CT images and of residual AGC-attention blocks with long and short skip connections to ease the network training, the proposed AGC-LSRED method achieves satisfactory results in preserving fine anatomical structures and suppressing noise in LDCT images.

Activation of σ1-Receptors by R-Ketamine May Enhance the Antidepressant Effect of S-Ketamine.

Ketamine is a racemic mixture composed of two enantiomers, S-ketamine and R-ketamine. In preclinical studies, both enantiomers have exhibited antidepressant effects, but these effects are attributed to distinct pharmacological activities. The S-enantiomer acts as an NMDA-channel blocker and as an opioid µ-receptor agonist, whereas the R-enantiomer binds to σ1-receptors and is believed to act as an agonist. As racemate, ketamine potentially triggers four biochemical pathways involving the AGC-kinases, PKA, Akt (PKB), PKC and RSK that ultimately lead to inhibitory phosphorylation of GSK3ß in microglia. In patients with major depressive disorder, S-ketamine administered as a nasal spray has shown clear antidepressant activity. However, when compared to intravenously infused racemic ketamine, the response rate, duration of action and anti-suicidal activity of S-ketamine appear to be less pronounced. The σ1-protein interacts with µ-opioid and TrkB-receptors, whereas in preclinical experiments σ1-agonists reduce µ-receptor desensitization and improve TrkB signal transduction. TrkB activation occurs as a response to NMDA blockade. So, the σ1-activity of R-ketamine may not only enhance two pathways via which S-ketamine produces an antidepressant response, but it furthermore provides an antidepressant activity in its own right. These two factors could explain the apparently superior antidepressant effect observed with racemic ketamine compared to S-ketamine alone.

The choreography of protein kinase PDK1 and its diverse substrate dance partners.

The protein kinase PDK1 phosphorylates at least 24 distinct substrates, all of which belong to the AGC protein kinase group. Some substrates, such as conventional PKCs, undergo phosphorylation by PDK1 during their synthesis and subsequently get activated by DAG and Calcium. On the other hand, other substrates, including members of the Akt/PKB, S6K, SGK, and RSK families, undergo phosphorylation and activation downstream of PI3-kinase signaling. This review presents two accepted molecular mechanisms that determine the precise and timely phosphorylation of different substrates by PDK1. The first mechanism involves the colocalization of PDK1 with Akt/PKB in the presence of PIP3. The second mechanism involves the regulated docking interaction between the hydrophobic motif (HM) of substrates and the PIF-pocket of PDK1. This interaction, in trans, is equivalent to the molecular mechanism that governs the activity of AGC kinases through their HMs intramolecularly. PDK1 has been instrumental in illustrating the bi-directional allosteric communication between the PIF-pocket and the ATP-binding site and the potential of the system for drug discovery. PDK1's interaction with substrates is not solely regulated by the substrates themselves. Recent research indicates that full-length PDK1 can adopt various conformations based on the positioning of the PH domain relative to the catalytic domain. These distinct conformations of full-length PDK1 can influence the interaction and phosphorylation of substrates. Finally, we critically discuss recent findings proposing that PIP3 can directly regulate the activity of PDK1, which contradicts extensive in vitro and in vivo studies conducted over the years.

Master kinase PDK1 in tumorigenesis.

3-phosphoinositide-dependent protein kinase 1 (PDK1) is considered as master kinase regulating AGC kinase family members such as AKT, SGK, PLK, S6K and RSK. Although autophosphorylation regulates PDK1 activity, accumulating evidence suggests that PDK1 is manipulated by many other mechanisms, including S6K-mediated phosphorylation, and the E3 ligase SPOP-mediated ubiquitination and degradation. Dysregulation of these upstream regulators or downstream signals involves in cancer development, as PDK1 regulating cell growth, metastasis, invasion, apoptosis and survival time. Meanwhile, overexpression of PDK1 is also exposed in a plethora of cancers, whereas inhibition of PDK1 reduces cell size and inhibits tumor growth and progression. More importantly, PDK1 also modulates the tumor microenvironments and markedly influences tumor immunotherapies. In summary, we comprehensively summarize the downstream signals, upstream regulators, mouse models, inhibitors, tumor microenvironment and clinical treatments for PDK1, and highlight PDK1 as a potential cancer therapeutic target.