Human pluripotent stem cells have been much anticipated as a powerful system to study developmental events, model genetic disorders, and serve as a source of autologous cells for cell therapy in genetic disorders. Precise genetic manipulation is crucial to all these applications, and many recent advances have been made in site specific nuclease systems like zinc finger nucleases, TALENs, and CRISPR/Cas. In this review, we address the importance of site-specific genome modification and how this technology can be applied to manipulate human pluripotent stem cells.

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression. For over a decade the deluge of research describing the biogenesis and activity of miRNAs has lead researchers to postulate rules to help make sense of the enormous amount of data produced. These rules are repeated in miRNA research papers and reviews. While these rules have been helpful one must be conscious of their limitations or risk missing future breakthroughs. Here we describe some of the most commonly stated rules, the reasoning behind their formation, their uses, and limitations.

The B cell antigen receptor (BCR) is the sensor on the B cell surface that surveys foreign molecules (antigen) in our bodies and activates B cells to generate antibody responses upon encountering cognate antigen. The binding of antigen to the BCR induces signaling cascades in the cytoplasm, which provides the first signal for B cell activation. Subsequently, BCRs internalize and target bound antigen to endosomes, where antigen is processed into T cell recognizable forms. T helper cells generate the second activation signal upon binding to antigen presented by B cells. The optimal activation of B cells requires both signals, thereby depending on the coordination of BCR signaling and antigen transport functions. Antigen binding to the BCR also induces rapid remodeling of the cortical actin network of B cells. While being initiated and controlled by BCR signaling, recent studies reveal that this actin remodeling is critical for both the signaling and antigen processing functions of the BCR, indicating a role for actin in coordinating these two pathways. Here we will review previous and recent studies on actin reorganization during BCR activation and BCR-mediated antigen processing, and discuss how actin remodeling translates BCR signaling into rapid antigen uptake and processing while providing positive and negative feedback to BCR signaling.

Neurotrophins are a family of growth factors that have been found to be central for the development and functional maintenance of the nervous system, participating in neurogenesis, neuronal survival, axonal growth, synaptogenesis and activity-dependent forms of synaptic plasticity. Trauma in the adult nervous system can disrupt the functional circuitry of neurons and result in severe functional deficits. The limitation of intrinsic growth capacity of adult nervous system and the presence of an inhospitable environment are the major hurdles for axonal regeneration of lesioned adult neurons. Neurotrophic factors have been shown to be excellent candidates in mediating neuronal repair and establishing functional circuitry via activating several growth signaling mechanisms including neuron-intrinsic regenerative programs. Here, we will review the effects of various neurotrophins in mediating recovery after injury to the adult spinal cord.

Neurotransmitter gamma-aminobutiric acid (GABA) through ionotropic GABA_A and metabotropic GABA_B receptors plays key roles in modulating the development, plasticity and function of neuronal networks. GABA is inhibitory in mature neurons but excitatory in immature neurons, neuroblasts and neural stem/progenitor cells (NSCs/NPCs). The switch from excitatory to inhibitory occurs following the development of glutamatergic synaptic input and results from the dynamic changes in the expression of Na⁺/K⁺/2Cl^- co-transporter NKCC1 driving Cl^- influx and neuron-specific K⁺/ Cl^- co-transporter KCC2 driving Cl^- efflux. The developmental transition of KCC2 expression is regulated by Disrupted-in-Schizophrenia 1 (DISC1) and brain-derived neurotrophic factor (BDNF) signaling. The excitatory GABA signaling during early neurogenesis is important to the activity/experience-induced regulation of NSC quiescence, NPC proliferation, neuroblast migration and new-born neuronal maturation/functional integration. The inhibitory GABA signaling allows for the sparse and static functional networking essential for learning/memory development and maintenance.

RasGRP proteins are activators of Ras and other related small GTPases by the virtue of functioning as guanine nucleotide exchange factors (GEFs). In vertebrates, four RasGRP family members have been described. RasGRP-1 through-4 share many structural domains but there are also subtle differences between each of the different family members. Whereas SOS RasGEFs are ubiquitously expressed, RasGRP proteins are expressed in distinct patterns, such as in different cells of the hematopoietic system and in the brain. Most studies have concentrated on the role of RasGRP proteins in the development and function of immune cell types because of the predominant RasGRP expression profiles in these cells and the immune phenotypes of mice deficient for Rasgrp genes. However, more recent studies demonstrate that RasGRPs also play an important role in tumorigenesis. Examples are skin- and hematological-cancers but also solid malignancies such as melanoma or prostate cancer. These novel studies bring up many new and unanswered questions related to the molecular mechanism of RasGRP-driven oncogenesis, such as new receptor systems that RasGRP appears to respond to as well as regulatory mechanisms for RasGRP expression that appear to be perturbed in these cancers. Here we will review some of the known aspects of RasGRP biology in lymphocytes and will discuss the exciting new notion that RasGRP Ras exchange factors play a role in oncogenesis downstream of various growth factor receptors.

Apolipoprotein C-I has evolved more rapidly than any of the other soluble apolipoproteins. During the course of primate evolution, the gene for this apolipoprotein was duplicated. Prompted by our observation that the two resulting genes encode two distinct forms of apoC-I in great apes, we have reviewed both the genomic and proteomic data to examine what changes have occurred during the course of primate evolution. We have found data showing that one of the duplicated genes, known to be a pseudogene in humans, was also a pseudogene in Denisovans and Neandertals. Using genomic and proteomic data for primates, we will provide in this review evidence that the duplication took place after the divergence of New World monkeys from the human lineage and that the formation of the pseudogene took place after the divergence of the bonobos and chimpanzees from the human lineage.

To assess the biological safety of Fe₃O₄ nanoparticles (NPs), the oxidative-damage effect of these NPs was studied. Twenty-five Kunming mice were exposed to Fe₃O₄ NPs by intraperitoneal injection daily for 1 week at doses of 0, 10, 20, and 40 mg·kg^-1. Five Kunming mice were also injected with 40 mg·kg^-1 ordinary Fe₃O₄ particles under the same physiological conditions. Biomarkers of reactive oxygen species (ROS), glutathione (GSH), and malondialdehyde (MDA) in the hepatic and brain tissues were detected. Results showed that no significant difference in oxidative damage existed at concentrations lower than 10 mg·kg^-1 for NPs compared with the control group. Fe₃O₄ NP concentration had obvious dose–effect relationships (P<0.05 or P<0.01) with ROS level, GSH content, and MDA content in mouse hepatic and brain tissues at>20 mg·kg^-1 concentrations. To some extent, ordinary Fe₃O₄ particles with 40 mg·kg^-1 concentration also affected hepatic and brain tissues in mice. The biological effect was similar to Fe₃O₄ NPs at 10?mg·kg^-1 concentration. Thus, Fe₃O₄ NPs had significant damage effects on the antioxidant defense system in the hepatic and brain tissues of mice, whereas ordinary Fe₃O₄ had less influence than Fe₃O₄ NPs at the same concentration.