抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

The HER-2/neu oncogene is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor. This gene has been shown to be amplified in human breast cancer cell lines. In the current study, alterations of the gene in 189 primary human breast cancers were investigated. HER-2/neu was found to be amplified from 2- to greater than 20-fold in 30% of the tumors. Correlation of gene amplification with several disease parameters was evaluated. Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer. It retained its significance even when adjustments were made for other known prognostic factors. Moreover, HER-2/neu amplification had greater prognostic value than most currently used prognostic factors, including hormonal-receptor status, in lymph node-positive disease. These data indicate that this gene may play a role in the biologic behavior and/or pathogenesis of human breast cancer.

https://science.sciencemag.org/content/sci/235/4785/177.full.pdf

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.

https://science.sciencemag.org/content/sci/264/5164/1415.full.pdf

Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins

Apoptosis plays an important role during neuronal development, and defects in apoptosis may underlie various neurodegenerative disorders. To characterize molecular mechanisms that regulate neuronal apoptosis, the contributions to cell death of mitogen-activated protein (MAP) kinase family members, including ERK (extracellular signal-regulated kinase), JNK (c-JUN NH2-terminal protein kinase), and p38, were examined after withdrawal of nerve growth factor (NGF) from rat PC-12 pheochromocytoma cells. NGF withdrawal led to sustained activation of the JNK and p38 enzymes and inhibition of ERKs. The effects of dominant-interfering or constitutively activated forms of various components of the JNK-p38 and ERK signaling pathways demonstrated that activation of JNK and p38 and concurrent inhibition of ERK are critical for induction of apoptosis in these cells. Therefore, the dynamic balance between growth factor-activated ERK and stress-activated JNK-p38 pathways may be important in determining whether a cell survives or undergoes apoptosis.

https://science.sciencemag.org/content/sci/270/5240/1326.full.pdf

Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis

Protein kinase C, an enzyme that is activated by the receptor-mediated hydrolysis of inositol phospholipids, relays information in the form of a variety of extracellular signals across the membrane to regulate many Ca2+-dependent processes. At an early phase of cellular responses, the enzyme appears to have a dual effect, providing positive forward as well as negative feedback controls over various steps of its own and other signaling pathways, such as the receptors that are coupled to inositol phospholipid hydrolysis and those of some growth factors. In biological systems, a positive signal is frequently followed by immediate negative feedback regulation. Such a novel role of this protein kinase system seems to give a logical basis for clarifying the biochemical mechanism of signal transduction, and to add a new dimension essential to our understanding of cell-to-cell communication.

https://science.sciencemag.org/content/sci/233/4761/305.full.pdf

Studies and perspectives of protein kinase C

Synaptic strength is altered during synaptic plasticity by controlling the number of AMPA receptors (AMPARs) at excitatory synapses. In particular, during long-term potentiation and synaptic up-scaling, AMPARs are accumulated at synapses to increase synaptic strength. Neuronal activity leads to activity-dependent phosphorylation of AMPAR subunit GluA1, and subsequent increases in GluA1 surface expression, which can be achieved by either an increase in exocytosis or a decrease in endocytosis of the receptors. However, the molecular pathways underlying GluA1 phosphorylation-induced elevation of surface AMPAR expression are not completely understood. Here, we first employ fluorescence recovery after photobleaching (FRAP) to reveal that phosphorylation of GluA1 Serine 845 (S845) plays a more important role in receptor endocytosis than exocytosis during synaptic plasticity. Notably, endocytosis of AMPARs depends upon the clathrin adaptor, AP2, which recruits cargo proteins into endocytic clathrin coated pits. Importantly, the KRMK (Lysine-Arginine-Methionine-Lysine) motif in the carboxyl-terminus of GluA1 is suggested to be an AP2 binding site, but the exact function has not been defined. Moreover, the GluA1 KRMK motif is closely located to one of GluA1 phosphorylation sites, serine 845 (S845), and GluA1 S845 dephosphorylation is suggested to enhance endocytosis during long-term depression. In fact, we show that an increase in GluA1 S845 phosphorylation by two distinct forms of synaptic plasticity, long-term potentiation and synaptic up-scaling, diminishes the binding of the AP2 adaptor. This reduces endocytosis, resulting in elevation of GluA1 surface expression. We thus demonstrate a mechanism of GluA1 phosphorylation-regulated clathrin-mediated endocytosis of AMPARs.

/pdf/phosphorylation-of-ampa-receptor-subunit-glua1-regulates-42vmagsday.pdf

Phosphorylation of AMPA receptor subunit GluA1 regulates clathrin-mediated receptor endocytosis

Background: Gamma-secretase, which generates amyloid peptide from APP, also cleaves other type I transmembrane proteins, including synaptic proteins such as N-cadherin. The cleavage pathway involves initial ectodomain shedding by a metalloprotease, followed by intramembrane cleavage by gamma-secretase. The C-terminal fragments generated from the cleavage of several of gamma-secretase substrates can have signaling functions and can regulate transcription (Hass et al., 2009). We have previously shown the existence of activity-dependent cleavage of APP and N-cadherin bymetalloproteases and gamma-secretase at synapses. Moreover, these cleavages modify synaptic transmission and can thus provide a novel formof functional synaptic auto regulation. Methods: We thus assayed if gamma-secretase cleavage couldmodify gene regulation in neurons.We performed a microarray expression profiling analysis using RNA isolated from 14 DIV primary hippocampal neurons in culture treated with the gamma-secretase inhibitors, L685458 for 2h or 4h and compared them to untreated controls. The experiment was carried out in duplicate and the normalized array data were analyzed with the DAVID bioinformatic database and the Gene Set Enrichment Analysis (GSEA) tool. Results: Using the DAVID bioinformatic database, we observed a down regulation of genes involved in Notch receptor signaling, including HES1, as expected. Moreover, we found that apoptosis and Wnt signaling programs were remodeled based on both up regulated and down regulated genes. Interestingly a number of genes coding for potassium channels, adhesionmolecules and synaptic proteinswere down regulated. Analogously, using GSEA, we identified down regulation of genes involved in theNotch receptor signaling, aswell as others involved in cell-cell adhesion, such asE-cadherin, and in synaptic transmission such as theNMDA NR2 receptor. Interestingly we also observed a down regulation of MT5MMP gene, a metalloprotease involved in N-cadherin cleavage in neurons, and of Presenilin1, one of the components of gamma-secretase.Conclusions: In conclusion, we generated a catalogue of candidate pathways involved in synaptic function that may be regulated by gamma-secretase. Reference: [1] Hass MR, Sato C, Kopan R, Zhao G (2009) Presenilin:RIP and beyond. Seminars in Cell & Developmental Biology 20:201-210.

Gene regulation by gamma-secretase analyzed by microarray

Potential anti-arthritic and analgesic properties of essential oil and viridiflorol obtained from Allophylus edulis leaves in mice.

Brain-injured patients may, with the assistance of life support, continue to perform basic bodily functions, but yet be deficient in wakefulness, awareness, decision making or other overt manifestations of consciousness. Here, we review two neurological states observed in brain injured patients with different degrees of brain impairment, the vegetative state (VS) and the minimally conscious state (MCS), and we discuss how these states are diagnosed through assessing patient behavioral responses during clinical examination. We consider how functional neuroimaging has revealed preserved cognitive capacities in patients that were supposed to be in the VS and has introduced a new diagnosis, cognitive motor dissociation. We review the GW Theory proposal that consciousness arises from functional connectivity (FC) of widely separated brain regions. We discuss how such high FC underlies the Default Mode Network (DMN), a group of neural circuits that are active when an individual is not involved with external tasks and engages in introspective thinking. Finally, we discuss the finding that the level of FC of the DMN is diminished in brain injured patients and the proposal that the level of residual DMN FC in brain injured patients is an index of their consciousness.

The state of consciousness in patients in the vegetative and minimally conscious states

/pdf/natural-products-as-sources-of-new-analgesic-drugs-i1bux17b.pdf

Edward B. Ziff

Papers

Phosphorylation of AMPA receptor subunit GluA1 regulates clathrin-mediated receptor endocytosis

Gene regulation by gamma-secretase analyzed by microarray

Potential anti-arthritic and analgesic properties of essential oil and viridiflorol obtained from Allophylus edulis leaves in mice.

The state of consciousness in patients in the vegetative and minimally conscious states

Natural Products as Sources of New Analgesic Drugs