The human proteome is rich with protein kinases, and this richness has made the kinase of crucial importance in initiating and maintaining cell behavior. Elucidating cell signaling networks and manipulating their components to understand and alter behavior require well designed inhibitors. These inhibitors are needed in culture to cause and study network perturbations, and the same compounds can be used as drugs to treat disease. Understanding the structural biology of protein kinases in detail, including their commonalities, differences and modes of substrate interaction, is necessary for designing high quality inhibitors that will be of true use for cell biology and disease therapy. To this end, we here report on a structural analysis of all available active-conformation protein kinases, discussing residue conservation, the novel features of such conservation, unique properties of atypical kinases and variability in the context of substrate binding. We also demonstrate how this information can be used for structure prediction. Our findings will be of use not only in understanding protein kinase function and evolution, but they highlight the flaws inherent in kinase drug design as commonly practiced and dictate an appropriate strategy for the sophisticated design of specific inhibitors for use in the laboratory and disease therapy.

Sevoflurane preconditioning (SPC) can provide myocardial protective effects similar to ischemic preconditioning. However, the exact mechanism of SPC remains unclear. Previous studies indicate that vascular endothelial growth factor receptor 1 (VEGFR-1) is involved in ischemic preconditioning-mediated cardioprotection. This study was designed to determine the significance of VEGFR-1 signaling in SPC-mediated cardioprotection.

Accurate nodal staging is crucial for esophageal cancer. A prospective study was performed to assess the value of [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) for diagnosing cervical lymph node metastasis (LNM) of esophageal squamous cell carcinoma.

Federated Learning (FL) enables multiple clients to train a shared model collaboratively without sharing any personal data. However, selecting a model and adapting it quickly to meet user expectations in a large-scale FL application with heterogeneous devices is challenging. In this paper, we propose a model selection and adaptation system for Federated Learning (FedMSA), which includes a hardware-aware model selection algorithm that trades-off model training efficiency and model performance base on FL developers' expectation. Meanwhile, considering the expected model should be achieved by dynamic model adaptation, FedMSA supports full automation in building and deployment of the FL task to different hardware at scale. Experiments on benchmark and real-world datasets demonstrate the effectiveness of the model selection algorithm of FedMSA in real devices (e.g., Raspberry Pi and Jetson nano).

The production of reactive oxygen species (ROS) is a ubiquitous defense response in plants. Adapted pathogens evolved mechanisms to counteract the deleterious effects of host-derived ROS and promote infection. How plant pathogens regulate this elaborate response against ROS burst remains unclear. Using the rice blast fungus Magnaporthe oryzae, we uncovered a self-balancing circuit controlling response to ROS in planta and virulence. During infection, ROS induces phosphorylation of the high osmolarity glycerol pathway kinase MoOsm1 and its nuclear translocation. There, MoOsm1 phosphorylates transcription factor MoAtf1 and dissociates MoAtf1-MoTup1 complex. This releases MoTup1-mediated transcriptional repression on oxidoreduction-pathway genes and activates the transcription of MoPtp1/2 protein phosphatases. In turn, MoPtp1/2 dephosphorylate MoOsm1, restoring the circuit to its initial state. Balanced interactions among proteins centered on MoOsm1 provide a means to counter host-derived ROS. Our findings thereby reveal new insights into how M. oryzae utilizes a phosphor-regulatory circuitry to face plant immunity during infection.

MicroRNAs (miRNAs) have been demonstrated to exhibit important regulatory roles in multiple malignancies, including hepatocellular carcinoma (HCC). hsa-miR-497-5p was reported to involve in cancer progression and poor prognosis in many kinds of tumors. However, the expression and its clinical significance of hsa-miR-497-5p in HCC remain unclear.

Postoperative cognitive dysfunction in elderly patients has been related to neurodegenerative disorders and mortality. Sevoflurane anesthesia has been implicated in both postoperative cognitive dysfunction and neurotoxicity. Given the advantages of using inhaled anesthetics like sevoflurane, it is important to understand how their usage results in neurotoxicity and subsequently devise ways to circumvent or attenuate the anesthetic-mediated induction in neurotoxicity. We have used an aged rat model to investigate the molecular mechanisms by which sevoflurane inhalation results in neurotoxicity and whether modulation of these molecular mechanisms can inhibit or attenuate neurotoxicity and cognitive learning and memory impairment in these animals. Low- or high-dose of sevoflurane resulted in reactive oxygen species generation, increased NADPH oxidase protein expression, apoptosis and autophagy. Sevoflurane inhalation resulted in significant inhibition of brain derived neurotrophic factor (BDNF) and cognitive impairment. And the activation of PI3K/Akt/mTOR signaling pathways are attenuated in sevoflurane-mediated anesthesia. Adeno-associated virus (AAV)-mediated expression of Bdnf, but not controls EGFP, attenuated sevoflurane-induced oxidative stress and cognitive impairment in the rats. Our results highlight that AAV-mediated gene therapy might offer a potential therapeutic opportunity to treat post-operative cognitive impairment resulting from inhaled anesthetics.

We built a prediction model of mortality risk in patients the with Acinetobacter baumannii (AB)-caused hospital-acquired (HAP) and ventilator-associated pneumonia (VAP).

CXCL13 is a B lymphocyte chemoattractant and activates CXCR5 receptor in the immune system. Here we investigated whether CXCL13/CXCR5 mediates inflammatory pain in dorsal root ganglia (DRG) and the underlying mechanisms. Peripheral injection of complete Freund's Adjuvant (CFA) increased the expression of CXCL13 and CXCR5 in DRG neurons. In Cxcr5-/- mice, CFA-induced pain hypersensitivity were attenuated. Whole-cell patch-clamp recording showed that the excitability of dissociated DRG neurons was increased after CFA injection or CXCL13 incubation from wild-type (WT) mice, but not from Cxcr5-/- mice. Additionally, sodium channel Nav1.8 was co-expressed with CXCR5 in dissociated DRG neurons, and the increased neuronal excitability induced by CFA or CXCL13 was reduced by Nav1.8 blocker. Intrathecal injection of Nav1.8 blocker also attenuated intrathecal injection of CXCL13-induced pain hypersensitivity. Furthermore, CXCL13 increased Nav1.8 current density in DRG neurons, which was inhibited by p38 MAP kinase inhibitor. CFA and CXCL13 increased p38 phosphorylation in the DRG of WT mice but not Cxcr5-/- mice. Finally, intrathecal p38 inhibitor alleviated CXCL13-induced pain hypersensitivity. Taken together, these results demonstrated that CXCL13, upregulated by peripheral inflammation, acts on CXCR5 on DRG neurons and activates p38, which increases Nav1.8 current density and further contributes to the maintenance of inflammatory pain.

Drosophila Dscam encodes a vast family of immunoglobulin (Ig)-containing proteins that exhibit isoform-specific homophilic binding. This diversity is essential for cell recognition events required for wiring the brain. Each isoform binds to itself but rarely to other isoforms. Specificity is determined by "matching" of three variable Ig domains within an approximately 220 kD ectodomain. Here, we present the structure of the homophilic binding region of Dscam, comprising the eight N-terminal Ig domains (Dscam(1-8)). Dscam(1-8) forms a symmetric homodimer of S-shaped molecules. This conformation, comprising two reverse turns, allows each pair of the three variable domains to "match" in an antiparallel fashion. Structural, genetic, and biochemical studies demonstrate that, in addition to variable domain "matching," intramolecular interactions between constant domains promote homophilic binding. These studies provide insight into how "matching" at all three pairs of variable domains in Dscam mediates isoform-specific recognition.

A series of fluorescent coumarin derivatives 2a-e were systematically designed, synthesized and studied for their Cu2+ sensing performance in aqueous media. The sensitivities and selectivities of the on-to-off fluorescent Cu2+ sensing signal were in direct correlation with the relative arrangements of the heteroatoms within the coordinating moieties of these coumarins. Probes 2b and 2d exhibited Cu2+ concentration dependent and selective fluorescence quenching, with linear ranges of 0-80 μM and 0-10 μM, and limits of detection of 0.14 μM and 0.38 μM, respectively. Structural changes of 2b upon Cu2+ coordination were followed by fluorescence titration, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), mass spectrometry, and single crystal X-ray diffraction on the isolated Cu2+-coumarin complex. The results revealed a 1:1 stoichiometry between 2b and Cu2+, and that the essential structural features for Cu2+-selective coordination are the coumarin C=O and a three-bond distance between the amide NH and heterocyclic N. Probe 2b was also used to determine copper (II) levels in aqueous soil extracts, with recovery rates over 80% when compared to the standard soil analysis method: inductively coupled plasma-mass spectrometry (ICP-MS).

99m Tc bone scintigraphy (BS) is still the most common approach for the evaluation of bone metastasis in China. The purpose of this study was to investigate the necessity of BS as part of a routine preoperative workup for patients with cT1N0 subsolid lung cancer.

During plant-pathogenic fungi and host plants interactions, numerous pathogen-derived proteins are secreted resulting in the activation of the unfolded protein response (UPR) pathway. For efficient trafficking of secretory proteins, including those important in disease progression, the cytoplasmic coat protein complex II (COPII) exhibits a multifunctional role whose elucidation remains limited. Here, we discovered that the COPII cargo receptor MoErv29 functions as a target of MoHac1, a previously identified transcription factor of the UPR pathway. In Magnaporthe oryzae, deletion of MoERV29 severely affected the vegetative growth, conidiation and biotrophic invasion of the fungus in susceptible rice hosts. We demonstrated that MoErv29 is required for the delivery of secreted proteins through recognition and binding of the amino-terminal tripeptide motifs following the signal peptide. By using bioinformatics analysis, we predicted a cargo spectrum of MoErv29 and found that MoErv29 is required for the secretion of many proteins, including extracellular laccases and apoplastic effectors. This secretion is mediated through the conventional endoplasmic reticulum-Golgi secretion pathway and is important for conferring host recognition and disease resistance. Taken together, our results revealed how MoErv29 operates on effector secretion, and our findings provided a critical link between COPII vesicle trafficking and the UPR pathway.

Protein phosphatases are critical regulators in eukaryotic cells. For example, the budding yeast Saccharomyces cerevisiae dual specificity protein phosphatase (DSP) ScYvh1 regulates growth, sporulation, and glycogen accumulation. Despite such importance, functions of Yvh1 proteins in filamentous fungi are not well understood. In this study, we characterized putative protein phosphatase MoYvh1, an Yvh1 homolog in the rice blast fungus Magnaporthe oryzae. Deletion of the MoYVH1 gene resulted in significant reductions in vegetative growth, conidial production, and virulence. The ΔMoyvh1 mutant also displayed defects in cell-wall integrity and was hyposensitive to the exogenous osmotic stress. Further examination revealed that the ΔMoyvh1 mutant had defects in appressorium function and invasive hyphae growth, resulting attenuated pathogenicity. Interestingly, we found that MoYvh1 affects the scavenging of host-derived reactive oxygen species that promotes M. oryzae infection. Finally, overexpression of the phosphodiesterase MoPDEH suppressed the defects in conidia formation and pathogenicity of the ΔMoyvh1 mutant, suggesting MoYvh1 could regulate MoPDEH for its function. Our study reveals not only the importance of MoYvh1 proteins in growth, differentiation, and virulence of the rice blast fungus but, also, a genetic link between MoYvh1 and MoPDEH-cAMP signaling in this fungus.

The accumulation of the reactive oxygen species (ROS) in rice is important in its interaction with the rice blast fungus Magnaporthe oryzae during which the pathogen scavenges ROS through the production of extracellular enzymes that promote blast. We previously characterized the MoYvh1 protein phosphatase from M. oryzae that plays a role in scavenging of ROS. To understand the underlying mechanism, we found that MoYvh1 is translocated into the nucleus following oxidative stress and that this translocation is dependent on MoSsb1 and MoSsz1 that are homologous to heat-shock protein 70 (Hsp70) proteins. In addition, we established a link between MoYvh1 and MoMrt4, a ribosome maturation factor homolog whose function also involves shuttling between the cytoplasm and the nucleus. Moreover, we found that MoYvh1 regulates the production of extracellular proteins that modulate rice-immunity. Taking together, our evidence suggests that functions of MoYvh1 in regulating ROS scavenging require its nucleocytoplasmic shuttling and the partner proteins MoSsb1 and MoSsz1, as well as MoMrt4. Our findings provide novel insights into the mechanism by which M. oryzae responds to and subverts host immunity through the regulation of ribosome biogenesis and protein biosynthesis.

Hepatocellular cancer (HCC) has been reported to belong to one of the highly vascularized solid tumours accompanied with angiogenesis of human umbilical vein endothelial cells (HUVECs). KDM5A, an attractive drug target, plays a critical role in diverse physiological processes. Thus, this study aims to investigate its role in angiogenesis and underlying mechanisms in HCC. ChIP-qPCR was utilized to validate enrichment of H3K4me3 and KDM5A on the promotor region of miR-433, while dual luciferase assay was carried out to confirm the targeting relationship between miR-433 and FXYD3. Scratch assay, transwell assay, Edu assay, pseudo-tube formation assay and mice with xenografted tumours were conducted to investigate the physiological function of KDM5A-miR-433-FXYD3-PI3K-AKT axis in the progression of HCC after loss- and gain-function assays. KDM5A p-p85 and p-AKT were highly expressed but miR-433 was down-regulated in HCC tissues and cell lines. Depletion of KDM5A led to reduced migrative, invasive and proliferative capacities in HCC cells, including growth and a lowered HUVEC angiogenic capacity in vitro. Furthermore, KDM5A suppressed the expression of miR-433 by demethylating H3K4me3 on its promoterregion. miR-433 negatively targeted FXYD3. Depleting miR-433 or re-expressing FXYD3 restores the reduced migrative, invasive and proliferative capacities, and lowers the HUVEC angiogenic capacity caused by silencing KDM5A. Therefore, KDM5A silencing significantly suppresses HCC tumorigenesis in vivo, accompanied with down-regulated miR-433 and up-regulated FXYD3-PI3K-AKT axis in tumour tissues. Lastly, KDM5A activates the FXYD3-PI3K-AKT axis to enhance angiogenesis in HCC by suppressing miR-433.

Lentinan (LNT) is a complex fungal component that possesses effective antitumor and immunostimulating properties. However, there is a paucity of studies regarding the effects and mechanisms of LNT on type 1 diabetes.

In the era of big data, industrial process data are often generated rapidly in the form of streams. Thus, how to process such sequential and high-speed stream data in real time and provide critical quality variable predictions has become a critical issue for facilitating efficient process control and monitoring in the process industry. Traditionally, soft sensor models are usually built through offline batch learning, which remain unchanged during the online implementation phase. Once the process state changes, soft sensors built from historical data cannot provide accurate predictions. In practice, industrial process data streams often exhibit characteristics such as nonlinearity, time-varying behavior, and label scarcity, which pose great challenges for building high-performance soft sensor models. To address this issue, an online-dynamic-clustering-based soft sensor (ODCSS) is proposed for industrial semi-supervised data streams. The method achieves automatic generation and update of clusters and samples deletion through online dynamic clustering, thus enabling online dynamic identification of process states. Meanwhile, selective ensemble learning and just-in-time learning (JITL) are employed through an adaptive switching prediction strategy, which enables dealing with gradual and abrupt changes in process characteristics and thus alleviates model performance degradation caused by concept drift. In addition, semi-supervised learning is introduced to exploit the information of unlabeled samples and obtain high-confidence pseudo-labeled samples to expand the labeled training set. The proposed method can effectively deal with nonlinearity, time-variability, and label scarcity issues in the process data stream environment and thus enable reliable target variable predictions. The application results from two case studies show that the proposed ODCSS soft sensor approach is superior to conventional soft sensors in a semi-supervised data stream environment.

Magnaporthe oryzae causes rice blasts posing serious threats to food security worldwide. During infection, M. oryzae utilizes several transmembrane receptor proteins that sense cell surface cues to induce highly specialized infectious structures called appressoria. However, little is known about the mechanisms of intracellular receptor tracking and their function. Here, we described that disrupting the coat protein complex II (COPII) cargo protein MoErv14 severely affects appressorium formation and pathogenicity as the ΔMoerv14 mutant is defective not only in cAMP production but also in the phosphorylation of the mitogen-activated protein kinase (MAPK) MoPmk1. Studies also showed that either externally supplementing cAMP or maintaining MoPmk1 phosphorylation suppresses the observed defects in the ΔMoerv14 strain. Importantly, MoErv14 is found to regulate the transport of MoPth11, a membrane receptor functioning upstream of G-protein/cAMP signaling, and MoWish and MoSho1 function upstream of the Pmk1-MAPK pathway. In summary, our studies elucidate the mechanism by which the COPII protein MoErv14 plays an important function in regulating the transport of receptors involved in the appressorium formation and virulence of the blast fungus.