Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.

Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 Å from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.

Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening.

Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca2+-permeable AMPA receptor upregulation, L-type Ca2+ channel activation, enhanced spine Ca2+ transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed ∼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.

Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells.

Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF). This repair capacity is overwhelmed when cytosolic THF hyperaccumulates in the absence of mitochondrially produced formate, leading to THF degradation. Unexpectedly, we also find that the classic antifolate methotrexate, by inhibiting its well-known target DHFR, causes even more extensive folate degradation in nearly all tested cancer cell lines. These findings shed light on design features of folate metabolism, provide a biochemical basis for clinically observed folate deficiency in QDPR-deficient patients, and reveal a hitherto unknown and unexplored cellular effect of methotrexate.

Lactate is an epigenetic metabolite that drives survival in model systems of glioblastoma.

Lactate accumulates to a significant amount in glioblastomas (GBMs), the most common primary malignant brain tumor with an unfavorable prognosis. However, it remains unclear whether lactate is metabolized by GBMs. Here, we demonstrated that lactate rescued patient-derived xenograft (PDX) GBM cells from nutrient-deprivation-mediated cell death. Transcriptome analysis, ATAC-seq, and ChIP-seq showed that lactate entertained a signature of oxidative energy metabolism. LC/MS analysis demonstrated that U-13C-lactate elicited substantial labeling of TCA-cycle metabolites, acetyl-CoA, and histone protein acetyl-residues in GBM cells. Lactate enhanced chromatin accessibility and histone acetylation in a manner dependent on oxidative energy metabolism and the ATP-citrate lyase (ACLY). Utilizing orthotopic PDX models of GBM, a combined tracer experiment unraveled that lactate carbons were substantially labeling the TCA-cycle metabolites. Finally, pharmacological blockage of oxidative energy metabolism extended overall survival in two orthotopic PDX models in mice. These results establish lactate metabolism as a novel druggable pathway for GBM.

γCaMKII shuttles Ca²âº/CaM to the nucleus to trigger CREB phosphorylation and gene expression.

Activity-dependent CREB phosphorylation and gene expression are critical for long-term neuronal plasticity. Local signaling at CaV1 channels triggers these events, but how information is relayed onward to the nucleus remains unclear. Here, we report a mechanism that mediates long-distance communication within cells: a shuttle that transports Ca(2+)/calmodulin from the surface membrane to the nucleus. We show that the shuttle protein is γCaMKII, its phosphorylation at Thr287 by ßCaMKII protects the Ca(2+)/CaM signal, and CaN triggers its nuclear translocation. Both ßCaMKII and CaN act in close proximity to CaV1 channels, supporting their dominance, whereas γCaMKII operates as a carrier, not as a kinase. Upon arrival within the nucleus, Ca(2+)/CaM activates CaMKK and its substrate CaMKIV, the CREB kinase. This mechanism resolves long-standing puzzles about CaM/CaMK-dependent signaling to the nucleus. The significance of the mechanism is emphasized by dysregulation of CaV1, γCaMKII, ßCaMKII, and CaN in multiple neuropsychiatric disorders.

Unipolar Solution Flow in Calcium-Organic Frameworks for Seawater-Evaporation-Induced Electricity Generation.

Seawater-flow- and -evaporation-induced electricity generation holds significant promise in advancing next-generation sustainable energy technologies. This method relies on the electrokinetic effect but faces substantial limitations when operating in a highly ion-concentrated environment, for example, natural seawater. We present herein a novel solution using calcium-based metal-organic frameworks (MOFs, C12H6Ca2O19·2H2O) for seawater-evaporation-induced electricity generation. Remarkably, Ca-MOFs show an open-circuit voltage of 0.4 V and a short-circuit current of 14 µA when immersed in seawater under natural conditions. Our experiments and simulations revealed that sodium (Na) ions selectively transport within sub-nanochannels of these synthetic superhydrophilic MOFs. This selective ion transport engenders a unipolar solution flow, which drives the electricity generation behavior in seawater. This work not only showcases an effective Ca-MOF for electricity generation through seawater flow/evaporation but also contributes significantly to our understanding of water-driven energy harvesting technologies and their potential applications beyond this specific context.

Correction: Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain.

[This corrects the article DOI: 10.1371/journal.pbio.2002457.].

An effective disease diagnostic model related to pyroptosis in ischemic cardiomyopathy.

Pyroptosis is involved in ischemic cardiomyopathy (ICM). The study aimed to investigate the pyroptosis-related genes and clarify their diagnostic value in ICM. The bioinformatics method identified the differential pyroptosis genes between the normal control and ICM samples from online datasets. Then, protein-protein interaction (PPI) and function analysis were carried out to explore the function of these genes. Following, subtype analysis was performed using ConsensusClusterPlus, functions, immune score, stromal score, immune cell proportion and human leukocyte antigen (HLA) genes between subtypes were investigated. Moreover, optimal pyroptosis genes were selected using the least absolute shrinkage and selection operator (LASSO) analysis to construct a diagnostic model and evaluate its effectiveness using receiver operator characteristic (ROC) analysis. Twenty-one differential expressed pyroptosis genes were identified, and these genes were related to immune and pyroptosis. Subtype analysis identified two obvious subtypes: sub-1 and sub-2. And LASSO identified 13 optimal genes used to construct the diagnostic model. The diagnostic model in ICM diagnosis with the area under ROC (AUC) was 0.965. Our results suggested that pyroptosis was tightly associated with ICM.

m6A-related bioinformatics analysis and functional characterization reveals that METTL3-mediated NPC1L1 mRNA hypermethylation facilitates progression of atherosclerosis via inactivation of the MAPK pathway.

OBJECTIVE: Accumulating evidence has demonstrated that N6-methyladenosine (m6A) plays important roles in many major diseases, including atherosclerosis (AS). In the present study, we aimed to explore the transcriptomic m6A landscape of endothelial function-associated genes and identify potential regulators in AS progression. METHODS: The GEO data (GSE142386) from MeRIP-seq in human umbilical vein endothelial cells (HUVECs) with METTL3 knocked down or not were analyzed. RNA-seq was performed to identify differences in gene expression. Gene ontology (GO) functional and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses were conducted to evaluate the potential functions of the differentially expressed genes. MeRIP-qPCR was used to measure the m6A and mRNA levels of the top 8 downregulated genes, and NPC1L1 was selected as the candidate gene. Oxidized low-density lipoprotein (ox-LDL) was used to stimulate HUVECs, and METTL3 or NPC1L1 was silenced in ox-LDL-treated cells. And Transwell, ELISA, and cell apoptosis assays were performed to assess cell functional injury. ApoE-/- mice were fed with high-fat diet for 8 weeks to establish an AS model, and adenovirus-mediated NPC1L1 shRNA or NC shRNA was injected into the mice through the tail vein. Mouse aortic tissue damage and plaque deposition were evaluated by H&E, Oil Red O, and TUNEL staining. RESULTS: One hundred and ninety-four hypermethylated m6A peaks and 222 hypomethylated peaks were detected in response to knockdown of METTL3. Genes with altered m6A peaks were significantly involved in the histone modification, enzyme activity, and formation of multiple complexes and were predominantly enriched in the MAPK pathway. NPC1L1 was a most significantly downregulated transcript in response to knockdown of METTL3. Moreover, knockdown of NPC1L1 or de-m6A (METTL3 knockdown)-mediated downregulation of NPC1L1 could improve ox-LDL-induced dysfunction of HUVECs in vitro and high-fat diet-induced atherosclerotic plaque in vivo, which was associated with the inactivation of the MAPK pathway. CONCLUSION: METTL3-mediated NPC1L1 mRNA hypermethylation facilitates AS progression by regulating the MAPK pathway, and NPC1L1 may be a novel target for the treatment of AS.

An anchor-tether 'hindered' HCN1 inhibitor is antihyperalgesic in a rat spared nerve injury neuropathic pain model.

BACKGROUND: Neuropathic pain impairs quality of life, is widely prevalent, and incurs significant costs. Current pharmacological therapies have poor/no efficacy and significant adverse effects; safe and effective alternatives are needed. Hyperpolarisation-activated cyclic nucleotide-regulated (HCN) channels are causally implicated in some forms of peripherally mediated neuropathic pain. Whilst 2,6-substituted phenols, such as 2,6-di-tert-butylphenol (26DTB-P), selectively inhibit HCN1 gating and are antihyperalgesic, the development of therapeutically tolerable, HCN-selective antihyperalgesics based on their inverse agonist activity requires that such drugs spare the cardiac isoforms and do not cross the blood-brain barrier. METHODS: In silico molecular dynamics simulation, in vitro electrophysiology, and in vivo rat spared nerve injury methods were used to test whether 'hindered' variants of 26DTB-P (wherein a hydrophilic 'anchor' is attached in the para-position of 26DTB-P via an acyl chain 'tether') had the desired properties. RESULTS: Molecular dynamics simulation showed that membrane penetration of hindered 26DTB-Ps is controlled by a tethered diol anchor without elimination of head group rotational freedom. In vitro and in vivo analysis showed that BP4L-18:1:1, a variant wherein a diol anchor is attached to 26DTB-P via an 18-carbon tether, is an HCN1 inverse agonist and an orally available antihyperalgesic. With a CNS multiparameter optimisation score of 2.25, a >100-fold lower drug load in the brain vs blood, and an absence of adverse cardiovascular or CNS effects, BP4L-18:1:1 was shown to be poorly CNS penetrant and cardiac sparing. CONCLUSIONS: These findings provide a proof-of-concept demonstration that anchor-tethered drugs are a new chemotype for treatment of disorders involving membrane targets.

Highly sensitive temperature and refractive index sensor based on no-core fiber cascaded with a balloon-shaped bent single-mode fiber.

A highly sensitive temperature and refractive index (RI) sensor based on no-core fiber (NCF) cascaded with a balloon-shaped bent single-mode fiber (BSBSF) is proposed and demonstrated. The NCF can excite higher-order modes which will be concentrated and transmitted into the BSBSF due to the characteristic of self-imaging effect. The BSBSF has an excellent temperature performance due to the high thermo-optical coefficient and thermal expansion coefficient of the polymer coating. The NCF and BSBSF are both conducive to the excitation of higher-order modes, which induces the sensitivity of the sensor with an efficiency improvement. The experimental results show that the maximum temperature sensitivity is -3.19n m/ ∘ C in the range of 22°C-83°C, which is the highest temperature sensitivity in the cascaded BSBSF structure to our best knowledge. In addition, the maximum RI sensitivity is 232.16 nm/RIU when the RI changes from 1.3234 to 1.3512. Compared with other cascaded BSBSF structures, this sensor has a higher temperature sensitivity and can be applicated in the prospects of food, biology, and environmental monitoring.

Protection of laryngeal mucosa and function in laryngeal burns by heat absorption of perilaryngeal tissue.

OBJECTIVE: The laryngeal tissue carries most of the heat during inhalation injury. This study aims to explore the heat transfer process and the severity of injury inside laryngeal tissue by horizontally studying the temperature rise process at various anatomical layers of the larynx and observing the thermal damage in various parts of the upper respiratory tract. METHODS: The 12 healthy adult beagles were randomly divided into four groups, and inhaled room temperature air (control group), dry hot air of 80 °C (group I), 160 °C (group II), and 320 °C (group III) for 20 min, respectively. The temperature changes of the glottic mucosal surface, the inner surface of the thyroid cartilage, the external surface of the thyroid cartilage, and subcutaneous tissue were measured every minute. All animals were immediately sacrificed after injury, and pathological changes in various parts of laryngeal tissue were observed and evaluated under a microscope. RESULTS: After inhaling hot air of 80 °C, 160 °C and 320 °C, the increase of laryngeal temperature in each group was ΔT = 3.57 ± 0.25 °C, 7.83 ± 0.15 °C, 11.93 ± 0.21 °C. The tissue temperature was approximately uniformly distributed, and the difference was not statistically significant. The average laryngeal temperature-time curve showed that the laryngeal tissue temperature in group I and group II showed a trend of "first decrease and then increase", except that the temperature of group III directly increased with time. The prominent pathological changes after thermal burns mainly concluded necrosis of epithelial cells, loss of the mucosal layer, atrophy of submucosal glands, vasodilatation, erythrocytes exudation, and degeneration of chondrocytes. Mild degeneration of cartilage and muscle layers was also observed in mild thermal injury. Pathological scores indicated that the pathological severity of laryngeal burns increased significantly with the increase of temperature, and all layers of laryngeal tissue were seriously damaged by 320 °C hot air. CONCLUSIONS: The high efficiency of tissue heat conduction enabled the larynx to quickly transfer heat to the laryngeal periphery, and the heat-bearing capacity of perilaryngeal tissue has a certain degree of protective effect on laryngeal mucosa and function in mild to moderate inhalation injury. The laryngeal temperature distribution was in accordance with the pathological severity, and the pathological changes of laryngeal burns provided a theoretical basis for the early clinical manifestations and treatment of inhalation injury.

T-cell activation is associated with high-grade serous ovarian cancer survival.

AIM: High-grade serous ovarian cancer (HGSOC) is an aggressive disease that is largely resistant to today's immunotherapies. Here, we aimed to investigate the prognostic significance of CTLA4, PD-1, and T-cell activation status in HGSOC. METHODS: Using a publicly accessed microarray dataset including 260 HGSOC samples, we calculated Kaplan-Meier survival curves for overall survival (OS), evaluated associations with multivariate Cox regression models to evaluate the associations, and summarized using a hazard ratio (HR). The correlations between PD-1 gene expression and that of other genes were calculated by Pearson correlation. RESULTS: Multivariate survival analyses showed that high PD-1 expression but not CTLA4 was associated with longer OS (HR = 0.69; 95% confidence interval [CI] = 0.52-0.91; p = 0.01), and that higher T-cell activation score was associated with better outcome (HR = 0.74; 95% confidence interval [CI] = 0.58-0.95; p = 0.02). The top three PD-1 highly correlated genes were SIRPG (r = 0.90, p < 2E-16), FASL (r = 0.89, p < 2E-16), and CD8a (r = 0.87, p < 2E-16). HGSOC patients' OS is positively associated T-cell activation score and PD-1 expression but not CTLA4. CONCLUSION: T cell activation score may serve as a candidate for personalized immunotherapy in HGSOC. The application of anti-PD-1 therapy to HGSOC should be cautious.

Pkm2 Regulates Cardiomyocyte Cell Cycle and Promotes Cardiac Regeneration.

BACKGROUND: The adult mammalian heart has limited regenerative capacity, mostly attributable to postnatal cardiomyocyte cell cycle arrest. In the last 2 decades, numerous studies have explored cardiomyocyte cell cycle regulatory mechanisms to enhance myocardial regeneration after myocardial infarction. Pkm2 (Pyruvate kinase muscle isoenzyme 2) is an isoenzyme of the glycolytic enzyme pyruvate kinase. The role of Pkm2 in cardiomyocyte proliferation, heart development, and cardiac regeneration is unknown. METHODS: We investigated the effect of Pkm2 in cardiomyocytes through models of loss (cardiomyocyte-specific Pkm2 deletion during cardiac development) or gain using cardiomyocyte-specific Pkm2 modified mRNA to evaluate Pkm2 function and regenerative affects after acute or chronic myocardial infarction in mice. RESULTS: Here, we identify Pkm2 as an important regulator of the cardiomyocyte cell cycle. We show that Pkm2 is expressed in cardiomyocytes during development and immediately after birth but not during adulthood. Loss of function studies show that cardiomyocyte-specific Pkm2 deletion during cardiac development resulted in significantly reduced cardiomyocyte cell cycle, cardiomyocyte numbers, and myocardial size. In addition, using cardiomyocyte-specific Pkm2 modified RNA, our novel cardiomyocyte-targeted strategy, after acute or chronic myocardial infarction, resulted in increased cardiomyocyte cell division, enhanced cardiac function, and improved long-term survival. We mechanistically show that Pkm2 regulates the cardiomyocyte cell cycle and reduces oxidative stress damage through anabolic pathways and ß-catenin. CONCLUSIONS: We demonstrate that Pkm2 is an important intrinsic regulator of the cardiomyocyte cell cycle and oxidative stress, and highlight its therapeutic potential using cardiomyocyte-specific Pkm2 modified RNA as a gene delivery platform.

Bortezomib potentiates antitumor activity of mitoxantrone through dampening Wnt/ß-catenin signal pathway in prostate cancer cells.

BACKGROUND: Bortezomib (BZM), alone or in combination with other chemotherapies, has displayed strong anticancer effects in several cancers. The efficacy of the combination of BZM and mitoxantrone (MTX) in treating prostate cancer remains unknown. METHODS: Anticancer effects of combination of BZM and MTX were determined by apoptosis and proliferation assay in vivo and in vitro. Expression of ß-Catenin and its target genes were characterized by western blot and Real-time PCR. RESULTS: BZM significantly enhanced MTX-induced antiproliferation in vivo and in vitro. Mice administered a combination of BZM and MTX displayed attenuated tumor growth and prolonged survival. BZM significantly attenuated MTX-induced apoptosis. Moreover, the combination of BZM and MTX contributed to inhibition of the Wnt/ß-Catenin signaling pathway compared to monotherapy. CONCLUSIONS: This study demonstrates that BZM enhances MTX-induced anti-tumor effects by inhibiting the Wnt/ß-Catenin signaling pathway in prostate cancer cells.

Combining the advantages of prokaryotic expression and T7 phage display systems to obtain antigens for antibody preparation.

The gene encoding the phage major capsid protein 10A was cloned into the prokaryotic expression vector pET24a, and a 6XHis-tag was fused to the 3'-end of the 10A gene to verify complete expression. The recombinant plasmid was transformed into Escherichia coli (E. coli) BL21 (DE3) cells, and 10A expression was induced by IPTG. SDS-PAGE and Western blot were used to confirm the target protein expression. The T7Select10-3b vector was added to the cultured bacteria expressing 10A at a multiplicity of infection (MOI) ranging from 0.01 to 0.1, and complete lysis of the bacteria was monitored by absorbance changes in the medium. The recombinant phage (reP) was harvested by PEG/NaCl sedimentation and resuspended in PBS. ELISA was performed to verify the presence of the 6XHis-tag on the surface of reP. The 10A-fusion expression vectors (pET10A-flag, pET10A-egfp, and pET10A-pct) were constructed, and fusion proteins were expressed and detected by the same method. The corresponding rePs (reP-Flag, reP-EGFP, and reP-PCT) were prepared by T7Select10-3b infection. After the expression of the peptides/proteins on the reP surfaces was confirmed, reP-Flag and reP-PCT were used to immunize mice to prepare anti-Flag and anti-PCT antibodies. The results showed that rePs prepared using the 10A-fusion vector and T7Select10-3b can be used as antigens to immunize mice and prepare antibodies. This method may be able to meet the rapid antigen preparation requirements for antibody production. Notably, the recombinant phage (reP) described in this study was obtained by the sedimentation method from T7Select10-3b-infected E. coli BL21 (DE3) cells carrying the major capsid protein 10A expression vector or 10A-fusion protein vector.

Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53.

Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is an epigenetic mark generally associated with transcriptional activation, yet the global functions of H2Bub1 remain poorly understood. Ferroptosis is a form of non-apoptotic cell death characterized by the iron-dependent overproduction of lipid hydroperoxides, which can be inhibited by the antioxidant activity of the solute carrier family member 11 (SLC7A11/xCT), a component of the cystine/glutamate antiporter. Whether nuclear events participate in the regulation of ferroptosis is largely unknown. Here, we show that the levels of H2Bub1 are decreased during erastin-induced ferroptosis and that loss of H2Bub1 increases the cellular sensitivity to ferroptosis. H2Bub1 epigenetically activates the expression of SLC7A11. Additionally, we show that the tumor suppressor p53 negatively regulates H2Bub1 levels independently of p53's transcription factor activity by promoting the nuclear translocation of the deubiquitinase USP7. Moreover, our studies reveal that p53 decreases H2Bub1 occupancy on the SLC7A11 gene regulatory region and represses the expression of SLC7A11 during erastin treatment. These data not only suggest a noncanonical role of p53 in chromatin regulation but also link p53 to ferroptosis via an H2Bub1-mediated epigenetic pathway. Overall, our work uncovers a previously unappreciated epigenetic mechanism for the regulation of ferroptosis.

Fenofibrate prevents skeletal muscle loss in mice with lung cancer.

The cancer anorexia cachexia syndrome is a systemic metabolic disorder characterized by the catabolism of stored nutrients in skeletal muscle and adipose tissue that is particularly prevalent in nonsmall cell lung cancer (NSCLC). Loss of skeletal muscle results in functional impairments and increased mortality. The aim of the present study was to characterize the changes in systemic metabolism in a genetically engineered mouse model of NSCLC. We show that a portion of these animals develop loss of skeletal muscle, loss of adipose tissue, and increased inflammatory markers mirroring the human cachexia syndrome. Using noncachexic and fasted animals as controls, we report a unique cachexia metabolite phenotype that includes the loss of peroxisome proliferator-activated receptor-α (PPARα) -dependent ketone production by the liver. In this setting, glucocorticoid levels rise and correlate with skeletal muscle degradation and hepatic markers of gluconeogenesis. Restoring ketone production using the PPARα agonist, fenofibrate, prevents the loss of skeletal muscle mass and body weight. These results demonstrate how targeting hepatic metabolism can prevent muscle wasting in lung cancer, and provide evidence for a therapeutic strategy.

Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain.

Extracellular phosphorylation of proteins was suggested in the late 1800s when it was demonstrated that casein contains phosphate. More recently, extracellular kinases that phosphorylate extracellular serine, threonine, and tyrosine residues of numerous proteins have been identified. However, the functional significance of extracellular phosphorylation of specific residues in the nervous system is poorly understood. Here we show that synaptic accumulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) and pathological pain are controlled by ephrin-B-induced extracellular phosphorylation of a single tyrosine (p*Y504) in a highly conserved region of the fibronectin type III (FN3) domain of the receptor tyrosine kinase EphB2. Ligand-dependent Y504 phosphorylation modulates the EphB-NMDAR interaction in cortical and spinal cord neurons. Furthermore, Y504 phosphorylation enhances NMDAR localization and injury-induced pain behavior. By mediating inducible extracellular interactions that are capable of modulating animal behavior, extracellular tyrosine phosphorylation of EphBs may represent a previously unknown class of mechanism mediating protein interaction and function.

Energy-Optimal Latency-Constrained Application Offloading in Mobile-Edge Computing.

Mobile-edge computation offloading (MECO) is a promising emerging technology for battery savings in mobile devices (MD) and/or in latency reduction in the execution of applications by (either total or partial) offloading highly demanding applications from MDs to nearby servers such as base stations. In this paper, we provide an offloading strategy for the joint optimization of the communication and computational resources by considering the blue trade-off between energy consumption and latency. The strategy is formulated as the solution to an optimization problem that minimizes the total energy consumption while satisfying the execution delay limit (or deadline). In the solution, the optimal transmission power and rate and the optimal fraction of the task to be offloaded are analytically derived to meet the optimization objective. We further establish the conditions under which the binary decisions (full-offloading and no offloading) are optimal. We also explore how such system parameters as the latency constraint, task complexity, and local computing power affect the offloading strategy. Finally, the simulation results demonstrate the behavior of the proposed strategy and verify its energy efficiency.